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""## -$$$ . /"/"#012" ".")*3- +) *!4!& 5!6%55787&%% 0! 9! *& * !"#$% &'$("" -:&'()*+),-*&');8<7=".")*3- +) "1 '"" &8<7= Ɉɝɥɚɜɥɟɧɢɟ ȼɜɟɞɟɧɢɟ .....................................................................................................................................2 Ɏɚɤɬɨɪɵ ɪɨɫɬɚ ɷɧɞɨɬɟɥɢɹ ɫɨɫɭɞɨɜ VEGF – ɨɞɧɢ ɢɡ ɨɫɧɨɜɧɵɯ ɪɟɝɭɥɹɬɨɪɨɜ ɚɧɝɢɨɝɟɧɟɡɚ ɨɩɭɯɨɥɢ .......................................................................................................................................6 ɗɤɫɩɪɟɫɫɢɹ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ ɜ ɨɩɭɯɨɥɹɯ ɱɟɥɨɜɟɤɚ ........................12 Ʌɟɤɚɪɫɬɜɟɧɧɵɟ ɩɪɟɩɚɪɚɬɵ, ɨɫɧɨɜɚɧɧɵɟ ɧɚ ɢɧɝɢɛɢɪɨɜɚɧɢɢ VEGF-ɡɚɜɢɫɢɦɵɯ ɫɢɝɧɚɥɶɧɵɯ ɫɢɫɬɟɦ ........................................................................................................................................19 ɇɟɨɞɧɨɡɧɚɱɧɨɫɬɶ ɩɨɫɥɟɞɫɬɜɢɣ ɥɟɱɟɧɢɹ ɛɨɥɶɧɵɯ ɩɪɢ ɢɫɩɨɥɶɡɨɜɚɧɢɢ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ ................................................................................................................................23 ȼɨɡɦɨɠɧɵɟ ɩɪɢɱɢɧɵ ɧɟɨɞɧɨɡɧɚɱɧɵɯ ɩɨɫɥɟɞɫɬɜɢɣ ɩɪɢɦɟɧɟɧɢɹ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɨɣ ɬɟɪɚɩɢɢ......................................................................................................................................27 ɗɤɫɩɪɟɫɫɢɹ ɮɚɤɬɨɪɚ ɪɨɫɬɚ VEGF-C ɢ ɟɝɨ ɪɟɰɟɩɬɨɪɚ VEGFR3 ɩɪɢ ɪɚɡɥɢɱɧɵɯ ɩɚɬɨɥɨɝɢɹɯ ɳɢɬɨɜɢɞɧɨɣ ɠɟɥɟɡɵ.................................................................................................................30 ɗɤɫɩɪɟɫɫɢɹ ɦɊɇɄ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF-A, VEGF-C, VEGF-D ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ VEGFR2 ɢ VEGFR3 ɜ ɨɩɭɯɨɥɹɯ ɦɨɱɟɜɨɝɨ ɩɭɡɵɪɹ ɱɟɥɨɜɟɤɚ ɢ ɜ ɫɚɪɤɨɦɟ Ʉɚɩɨɲɢ. ...........................33 ɗɤɫɩɪɟɫɫɢɹ ɦɊɇɄ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ VEGFR ɭ ɛɨɥɶɧɵɯ ɦɧɨɠɟɫɬɜɟɧɧɨɣ ɦɢɟɥɨɦɨɣ.......................................................................................................39 ɉɪɨɞɭɤɰɢɹ ɩɚɪɚɩɪɨɬɟɢɧɚ ɭ ɛɨɥɶɧɵɯ ɦɧɨɠɟɫɬɜɟɧɧɨɣ ɦɢɟɥɨɦɨɣ, ɪɚɡɥɢɱɚɸɳɢɯɫɹ ɩɨ ɷɤɫɩɪɟɫɫɢɢ ɦɊɇɄ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ. .................................................46 ɉɪɢ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɨɣ ɬɟɪɚɩɢɢ ɦɨɠɟɬ ɩɪɨɢɫɯɨɞɢɬɶ ɨɬɛɨɪ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ, ɧɟ ɷɤɫɩɪɟɫɫɢɪɭɸɳɢɯ ɪɟɰɟɩɬɨɪɵ VEGFR ...................................................................................50 Ɂɚɤɥɸɱɟɧɢɟ ...............................................................................................................................54 ɋɩɢɫɨɤ ɥɢɬɟɪɚɬɭɪɵ ..................................................................................................................57 ȼɜɟɞɟɧɢɟ ɍɠɟ ɧɚ ɫɚɦɵɯ ɪɚɧɧɢɯ ɷɬɚɩɚɯ ɢɫɫɥɟɞɨɜɚɧɢɹ ɨɩɭɯɨɥɟɜɨɝɨ ɪɨɫɬɚ ɛɵɥɨ ɡɚɦɟɱɟɧɨ, ɱɬɨ ɜɨɡɧɢɤɧɨɜɟɧɢɟ ɡɥɨɤɚɱɟɫɬɜɟɧɧɵɯ ɨɩɭɯɨɥɟɣ ɫɨɩɪɨɜɨɠɞɚɟɬɫɹ ɫɬɢɦɭɥɹɰɢɟɣ ɪɨɫɬɚ ɫɨɫɭɞɨɜ ɢɥɢ ɧɟɨɚɧɝɢɨɝɟɧɟɡɨɦ [1, 2]. ȼ 1971 ɝ. Ⱦɠ. Ɏɨɥɤɦɚɧɨɦ ɛɵɥɚ ɜɵɫɤɚɡɚɧɚ ɢɞɟɹ ɨ ɬɨɦ, ɱɬɨ ɜ ɩɪɨɰɟɫɫɟ ɫɜɨɟɝɨ ɪɨɫɬɚ ɨɩɭɯɨɥɢ ɧɟɨɛɯɨɞɢɦɨ ɫɬɢɦɭɥɢɪɨɜɚɬɶ ɪɚɡɜɢɬɢɟ ɫɨɛɫɬɜɟɧɧɨɣ ɫɟɬɢ ɤɪɨɜɟɧɨɫɧɵɯ ɫɨɫɭɞɨɜ, ɩɨɫɤɨɥɶɤɭ ɧɚɪɚɫɬɚɸɳɚɹ ɦɚɫɫɚ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ ɧɭɠɞɚɟɬɫɹ ɜ ɤɢɫɥɨɪɨɞɟ ɢ ɩɢɬɚɬɟɥɶɧɵɯ ɜɟɳɟɫɬɜɚɯ [3]. ȼ ɨɬɫɭɬɫɬɜɢɟ ɪɚɡɜɢɬɨɣ ɫɨɫɭɞɢɫɬɨɣ ɫɟɬɢ ɪɚɡɦɟɪɵ ɨɩɭɯɨɥɟɜɨɝɨ ɭɡɟɥɤɚ ɧɟ ɩɪɟɜɵɲɚɸɬ 1-2 ɦɦ3, ɩɨɷɬɨɦɭ ɫɩɨɫɨɛɧɨɫɬɶ ɡɚɛɥɨɤɢɪɨɜɚɬɶ ɪɨɫɬ ɫɨɫɭɞɨɜ, ɤɚɤ ɩɪɟɞɫɬɚɜɥɹɥɨɫɶ, ɞɨɥɠɧɚ ɫɞɟɪɠɢɜɚɬɶ ɪɨɫɬ ɢ ɪɚɡɜɢɬɢɟ ɫɚɦɨɣ ɨɩɭɯɨɥɢ. ȼ ɬɚɤɨɦ ɫɥɭɱɚɟ, ɩɨɢɫɤ ɢ ɪɚɡɪɚɛɨɬɤɚ ɥɟɤɚɪɫɬɜɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ, ɧɚɩɪɚɜɥɟɧɧɵɯ ɧɚ ɢɧɝɢɛɢɪɨɜɚɧɢɟ ɧɟɨɚɧɝɢɨɝɟɧɟɡɚ ɨɩɭɯɨɥɢ ɦɨɝɥɨ ɛɵ ɩɪɟɞɨɫɬɚɜɢɬɶ ɟɳɟ ɨɞɢɧ ɩɨɞɯɨɞ ɤ ɩɪɨɬɢɜɨɨɩɭɯɨɥɟɜɨɣ ɬɟɪɚɩɢɢ. ȼ ɞɚɥɶɧɟɣɲɟɦ ɛɵɥɨ ɩɨɤɚɡɚɧɨ, ɱɬɨ ɜ ɫɚɦɨɣ ɨɩɭɯɨɥɟɜɨɣ ɬɤɚɧɢ ɫɭɳɟɫɬɜɭɸɬ ɦɨɥɟɤɭɥɹɪɧɵɟ ɦɟɯɚɧɢɡɦɵ, ɫɬɢɦɭɥɢɪɭɸɳɢɟ ɪɚɡɜɢɬɢɟ ɜ ɧɟɣ ɫɨɫɭɞɢɫɬɨɣ ɫɢɫɬɟɦɵ. Ȼɨɥɟɟ ɬɨɝɨ, ɜ ɪɹɞɟ ɪɚɛɨɬ ɛɵɥɨ ɩɪɨɞɟɦɨɧɫɬɪɢɪɨɜɚɧɨ, ɱɬɨ ɧɟɨɚɧɝɢɨɝɟɧɟɡ ɦɨɠɟɬ ɧɟ ɬɨɥɶɤɨ ɫɨɩɪɨɜɨɠɞɚɬɶ, ɧɨ ɢ ɩɪɟɞɲɟɫɬɜɨɜɚɬɶ ɨɩɭɯɨɥɟɜɨɣ ɬɪɚɧɫɮɨɪɦɚɰɢɢ [4, 5]. Ɍɚɤ, ɧɚɩɪɢɦɟɪ, ɜ ɪɚɛɨɬɟ Brem S.S. ɢ ɫɨɚɜɬ. ɫɪɚɜɧɢɜɚɥɚɫɶ ɚɧɝɢɨɝɟɧɧɚɹ ɚɤɬɢɜɧɨɫɬɶ ɨɛɪɚɡɰɨɜ ɡɥɨɤɚɱɟɫɬɜɟɧɧɵɯ ɢ ɞɨɛɪɨɤɚɱɟɫɬɜɟɧɧɵɯ ɨɩɭɯɨɥɟɣ ɦɨɥɨɱɧɨɣ ɠɟɥɟɡɵ ɱɟɥɨɜɟɤɚ, ɚ ɬɚɤɠɟ ɬɤɚɧɢ ɝɢɩɟɪɩɥɚɫɬɢɱɟɫɤɢɯ ɞɨɥɟɤ, ɫ ɚɧɝɢɨɝɟɧɧɨɣ ɚɤɬɢɜɧɨɫɬɶɸ ɧɨɪɦɚɥɶɧɨɣ ɬɤɚɧɢ [5]. ɋɚɦɵɣ ɜɵɫɨɤɢɣ ɩɪɨɰɟɧɬ ɨɛɪɚɡɰɨɜ ɫ ɚɧɝɢɨɝɟɧɧɨɣ ɚɤɬɢɜɧɨɫɬɶɸ ɛɵɥ ɨɛɧɚɪɭɠɟɧ ɜ ɫɥɭɱɚɟ ɜɧɭɬɪɢɞɨɥɶɤɨɜɵɯ (intraductal) ɩɚɩɢɥɥɨɦ (100%); ɨɛɪɚɡɰɵ ɤɚɪɰɢɧɨɦ, ɤɚɤ ɢɧɜɚɡɢɜɧɵɯ, ɬɚɤ ɢ in situ, ɛɵɥɢ ɚɧɝɢɨɝɟɧɧɵ ɜ 65% ɫɥɭɱɚɹɯ. Ɉɞɧɚɤɨ ɩɨɜɵɲɟɧɧɚɹ ɚɧɝɢɨɝɟɧɧɚɹ ɚɤɬɢɜɧɨɫɬɶ ɦɨɠɟɬ ɛɵɬɶ ɯɚɪɚɤɬɟɪɧɚ ɧɟ ɬɨɥɶɤɨ ɞɥɹ ɨɩɭɯɨɥɟɜɨɣ ɬɤɚɧɢ. ȼ ɷɬɨɣ ɠɟ ɪɚɛɨɬɟ ɩɨɜɵɲɟɧɧɵɣ ɭɪɨɜɟɧɶ ɚɧɝɢɨɝɟɧɟɡɚ ɛɵɥ ɨɛɧɚɪɭɠɟɧ ɜ 30% ɫɥɭɱɚɟɜ ɩɪɢ ɢɫɫɥɟɞɨɜɚɧɢɢ ɨɛɪɚɡɰɨɜ ɬɤɚɧɢ ɝɢɩɟɪɩɥɚɫɬɢɱɟɫɤɢɯ ɞɨɥɟɤ, ɩɪɢɱɟɦ ɧɢ ɜ ɨɞɧɨɦ ɢɡ ɷɬɢɯ ɨɛɪɚɡɰɨɜ ɧɟ ɛɵɥɨ ɨɛɧɚɪɭɠɟɧɨ ɤɚɤɨɝɨ-ɥɢɛɨ ɦɨɪɮɨɥɨɝɢɱɟɫɤɨɝɨ ɩɨɞɬɜɟɪɠɞɟɧɢɹ ɧɚɥɢɱɢɹ ɤɚɪɰɢɧɨɦ, 2 ɨɬɫɭɬɫɬɜɨɜɚɥɢ ɢ ɞɪɭɝɢɟ ɩɪɢɡɧɚɤɢ ɨɡɥɨɤɚɱɟɫɬɜɥɟɧɢɹ ɬɤɚɧɢ. Ⱥɧɝɢɨɝɟɧɧɚɹ ɚɤɬɢɜɧɨɫɬɶ ɬɚɤɠɟ ɛɵɥɚ ɜɵɹɜɥɟɧɚ ɜ 3-7% ɨɛɪɚɡɰɨɜ ɧɨɪɦɚɥɶɧɨɣ ɬɤɚɧɢ, ɨɤɪɭɠɚɸɳɟɣ ɤɚɪɰɢɧɨɦɭ, ɜ ɬɨ ɜɪɟɦɹ ɤɚɤ ɨɛɪɚɡɰɵ ɧɨɪɦɚɥɶɧɨɣ ɬɤɚɧɢ ɜ ɫɥɭɱɚɟ ɞɨɛɪɨɤɚɱɟɫɬɜɟɧɧɵɯ ɢɡɦɟɧɟɧɢɣ ɦɨɥɨɱɧɨɣ ɠɟɥɟɡɵ ɛɵɥɢ ɩɨɥɧɨɫɬɶɸ ɧɟɝɚɬɢɜɧɵ. Ⱥɧɚɥɨɝɢɱɧɵɟ ɞɚɧɧɵɟ ɛɵɥɢ ɩɨɥɭɱɟɧɵ ɩɪɢ ɢɫɫɥɟɞɨɜɚɧɢɢ ɚɧɝɢɨɝɟɧɧɵɯ ɫɜɨɣɫɬɜ ɩɚɩɢɥɥɨɦ ɢ ɤɚɪɰɢɧɨɦ ɦɨɥɨɱɧɨɣ ɠɟɥɟɡɵ ɦɵɲɟɣ [6]. Ⱥɧɝɢɨɝɟɧɧɭɸ ɚɤɬɢɜɧɨɫɬɶ ɩɪɨɹɜɥɹɥɢ ɧɟ ɬɨɥɶɤɨ ɤɚɪɰɢɧɨɦɵ, ɧɨ ɢ ɬɤɚɧɶ ɦɨɥɨɱɧɨɣ ɠɟɥɟɡɵ ɫ ɩɚɩɢɥɥɹɪɧɵɦɢ ɝɢɩɟɪɩɥɚɫɬɢɱɟɫɤɢɦɢ ɢɡɦɟɧɟɧɢɹɦɢ. ɉɪɢɱɟɦ, ɬɚɤ ɠɟ ɤɚɤ ɢ ɜ ɩɪɟɞɵɞɭɳɟɣ ɪɚɛɨɬɟ, ɚɧɝɢɨɝɟɧɧɵɟ ɫɜɨɣɫɬɜɚ ɩɪɨɹɜɥɹɥɢɫɶ ɡɧɚɱɢɬɟɥɶɧɨ ɪɚɧɶɲɟ, ɱɟɦ ɤɚɤɢɟ-ɥɢɛɨ ɦɨɪɮɨɥɨɝɢɱɟɫɤɢɟ ɢɥɢ ɤɥɢɧɢɱɟɫɤɢɟ ɩɪɢɡɧɚɤɢ ɤɚɪɰɢɧɨɦɵ. ɉɨɜɵɲɟɧɧɵɣ ɭɪɨɜɟɧɶ ɚɧɝɢɨɝɟɧɧɨɫɬɢ ɬɤɚɧɢ, ɩɨ-ɜɢɞɢɦɨɦɭ, ɫɩɨɫɨɛɫɬɜɭɟɬ ɟɟ ɨɡɥɨɤɚɱɟɫɬɜɥɟɧɢɸ. ȼ ɷɤɫɩɟɪɢɦɟɧɬɚɥɶɧɨɣ ɦɨɞɟɥɢ ɧɚ ɦɵɲɚɯ ɛɵɥɨ ɩɨɤɚɡɚɧɨ, ɱɬɨ ɱɚɫɬɨɬɚ ɡɥɨɤɚɱɟɫɬɜɟɧɧɨɣ ɬɪɚɧɫɮɨɪɦɚɰɢɢ ɜɵɲɟ ɜ ɬɟɯ ɫɥɭɱɚɹɯ, ɤɨɝɞɚ ɭɱɚɫɬɤɢ ɫ ɝɢɩɟɪɩɥɚɫɬɢɱɟɫɤɢɦɢ ɢɡɦɟɧɟɧɢɹɦɢ ɩɪɨɹɜɥɹɸɬ ɩɨɥɨɠɢɬɟɥɶɧɭɸ ɚɧɝɢɨɝɟɧɧɭɸ ɚɤɬɢɜɧɨɫɬɶ [7]. Ɍɚɤɢɦ ɨɛɪɚɡɨɦ, ɩɨɜɵɲɟɧɧɚɹ ɚɤɬɢɜɧɨɫɬɶ ɚɧɝɢɨɝɟɧɟɡɚ ɧɟ ɬɨɥɶɤɨ ɯɚɪɚɤɬɟɪɧɚ ɞɥɹ ɨɩɭɯɨɥɟɜɵɯ ɢɡɦɟɧɟɧɢɣ ɬɤɚɧɢ, ɧɨ ɬɚɤɠɟ ɦɨɠɟɬ ɩɪɟɞɲɟɫɬɜɨɜɚɬɶ ɜɨɡɧɢɤɧɨɜɟɧɢɸ ɨɩɭɯɨɥɟɣ ɢ ɹɜɥɹɟɬɫɹ ɮɚɤɬɨɪɨɦ, ɫɩɨɫɨɛɫɬɜɭɸɳɢɦ ɪɚɡɜɢɬɢɸ ɨɩɭɯɨɥɢ. ȼɦɟɫɬɟ ɫ ɬɟɦ, ɨɫɬɚɜɚɥɨɫɶ ɧɟ ɹɫɧɵɦ, ɪɟɝɭɥɢɪɭɟɬɫɹ ɥɢ ɩɪɨɰɟɫɫ ɨɛɪɚɡɨɜɚɧɢɹ ɫɨɫɭɞɨɜ ɜ ɨɩɭɯɨɥɢ ɬɚɤ ɠɟ, ɤɚɤ ɢ ɜ ɩɪɨɰɟɫɫɟ ɷɦɛɪɢɨɧɚɥɶɧɨɝɨ ɚɧɝɢɨɝɟɧɟɡɚ, ɢɥɢ ɜ ɫɥɭɱɚɟ ɧɟɨɚɧɝɢɨɝɟɧɟɡɚ ɨɩɭɯɨɥɢ ɜɤɥɸɱɚɸɬɫɹ ɫɩɟɰɢɮɢɱɟɫɤɢɟ ɞɥɹ ɨɩɭɯɨɥɟɜɨɝɨ ɪɨɫɬɚ ɦɟɯɚɧɢɡɦɵ. Ɏɨɪɦɢɪɨɜɚɧɢɟ ɫɨɫɭɞɢɫɬɨɣ ɫɟɬɢ ɜ ɩɪɨɰɟɫɫɟ ɷɦɛɪɢɨɧɚɥɶɧɨɝɨ ɪɚɡɜɢɬɢɹ ɜɤɥɸɱɚɟɬ ɜ ɫɟɛɹ 2 ɷɬɚɩɚ: ɜɚɫɤɭɥɨɝɟɧɟɡ, ɢɥɢ ɨɛɪɚɡɨɜɚɧɢɟ de novo ɩɟɪɜɢɱɧɨɣ ɩɪɢɦɢɬɢɜɧɨɣ ɫɟɬɢ ɫɨɫɭɞɨɜ, ɜɤɥɸɱɚɸɳɟɟ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɭ ɦɟɡɨɞɟɪɦɚɥɶɧɵɯ ɤɥɟɬɨɤ ɜ ɤɥɟɬɤɢ ɷɧɞɨɬɟɥɢɹ, ɢ ɫɨɛɫɬɜɟɧɧɨ ɚɧɝɢɨɝɟɧɟɡ – ɮɨɪɦɢɪɨɜɚɧɢɟ ɡɪɟɥɨɣ ɫɨɫɭɞɢɫɬɨɣ ɫɢɫɬɟɦɵ ɢɡ ɭɠɟ ɢɦɟɸɳɟɣɫɹ ɩɟɪɜɢɱɧɨɣ ɫɟɬɢ. ɉɪɢ ɚɧɝɢɨɝɟɧɟɡɟ ɧɨɜɵɟ ɫɨɫɭɞɵ ɨɛɪɚɡɭɸɬɫɹ ɢɡ ɩɪɟɞɫɭɳɟɫɬɜɭɸɳɟɣ ɫɨɫɭɞɢɫɬɨɣ ɫɢɫɬɟɦɵ; ɩɪɨɥɢɮɟɪɚɰɢɹ ɢ ɦɢɝɪɚɰɢɹ ɩɨɥɧɨɫɬɶɸ ɞɢɮɮɟɪɟɧɰɢɪɨɜɚɧɧɵɯ ɤɥɟɬɨɤ ɷɧɞɨɬɟɥɢɹ ɩɪɢɜɨɞɢɬ ɤ ɨɛɪɚɡɨɜɚɧɢɸ ɫɨɫɭɞɨɜ ɪɚɡɧɨɣ ɜɟɥɢɱɢɧɵ ɢ ɢɯ ɨɪɝɚɧɢɡɚɰɢɢ ɜ 3 ɪɚɡɜɟɬɜɥɟɧɧɭɸ ɫɟɬɶ. ȼɨ ɜɡɪɨɫɥɨɦ ɨɪɝɚɧɢɡɦɟ ɫɨɫɭɞɢɫɬɚɹ ɫɢɫɬɟɦɚ ɨɛɵɱɧɨ ɧɚɯɨɞɢɬɫɹ ɜ ɩɨɤɨɹɳɟɦɫɹ ɫɨɫɬɨɹɧɢɢ; ɚɧɝɢɨɝɟɧɟɡ ɦɨɠɟɬ ɚɤɬɢɜɢɪɨɜɚɬɶɫɹ ɥɢɲɶ ɜ ɬɚɤɢɯ ɫɬɪɨɝɨ ɤɨɧɬɪɨɥɢɪɭɟɦɵɯ ɫɥɭɱɚɹɯ, ɤɚɤ ɡɚɠɢɜɥɟɧɢɟ ɪɚɧ ɢɥɢ ɩɪɨɰɟɫɫɵ, ɫɜɹɡɚɧɧɵɟ ɫ ɠɟɧɫɤɢɦɢ ɪɟɩɪɨɞɭɤɬɢɜɧɵɦɢ ɰɢɤɥɚɦɢ, ɚ ɬɚɤɠɟ ɩɪɢ ɧɟɤɨɬɨɪɵɯ ɩɚɬɨɥɨɝɢɱɟɫɤɢɯ ɩɪɨɰɟɫɫɚɯ, ɜ ɬɨɦ ɱɢɫɥɟ ɢ ɩɪɢ ɪɨɫɬɟ ɨɩɭɯɨɥɢ. ȼɧɨɜɶ ɨɛɪɚɡɨɜɚɧɧɚɹ ɫɨɫɭɞɢɫɬɚɹ ɫɢɫɬɟɦɚ ɨɩɭɯɨɥɢ ɩɪɨɢɫɯɨɞɢɬ ɢɡ ɫɨɫɭɞɨɜ ɬɤɚɧɢ, ɨɤɪɭɠɚɸɳɟɣ ɨɩɭɯɨɥɶ, ɢ ɬɚɤɢɦ ɨɛɪɚɡɨɦ, ɤɥɟɬɤɢ, ɩɪɢɧɢɦɚɸɳɢɟ ɭɱɚɫɬɢɟ ɜ ɟɟ ɮɨɪɦɢɪɨɜɚɧɢɢ, ɢɡɧɚɱɚɥɶɧɨ ɧɟ ɹɜɥɹɸɬɫɹ ɬɪɚɧɫɮɨɪɦɢɪɨɜɚɧɧɵɦɢ. ȼɦɟɫɬɟ ɫ ɬɟɦ, ɜ ɨɬɥɢɱɢɟ ɨɬ ɷɦɛɪɢɨɝɟɧɟɡɚ, ɦɟɯɚɧɢɡɦɵ ɮɨɪɦɢɪɨɜɚɧɢɹ ɭɩɨɪɹɞɨɱɟɧɧɨɣ ɫɨɫɭɞɢɫɬɨɣ ɫɟɬɢ ɜ ɨɩɭɯɨɥɢ ɨɬɫɭɬɫɬɜɭɸɬ. Ⱦɚɧɧɵɟ ɦɨɪɮɨɥɨɝɢɱɟɫɤɢɯ ɧɚɛɥɸɞɟɧɢɣ ɫɜɢɞɟɬɟɥɶɫɬɜɭɸɬ, ɱɬɨ ɜɧɨɜɶ ɨɛɪɚɡɨɜɚɧɧɵɟ ɫɨɫɭɞɵ ɨɩɭɯɨɥɢ, ɤɚɤ ɩɪɚɜɢɥɨ, ɨɬɥɢɱɚɸɬɫɹ ɨɬ ɧɨɪɦɚɥɶɧɵɯ ɫɨɫɭɞɨɜ ɨɪɝɚɧɢɡɦɚ: ɨɧɢ ɞɟɮɟɤɬɧɵ, ɧɟɡɪɟɥɵ, ɢɯ ɫɬɟɧɤɢ ɨɛɥɚɞɚɸɬ ɩɨɜɵɲɟɧɧɨɣ ɩɪɨɧɢɰɚɟɦɨɫɬɶɸ, ɨɧɢ ɧɟ ɨɛɪɚɡɭɸɬ ɯɨɪɨɲɨ ɫɮɨɪɦɢɪɨɜɚɧɧɭɸ ɫɨɫɭɞɢɫɬɭɸ ɫɟɬɶ, ɞɥɹ ɧɢɯ ɯɚɪɚɤɬɟɪɧɚ ɩɪɟɪɵɜɢɫɬɨɫɬɶ ɛɚɡɚɥɶɧɨɣ ɦɟɦɛɪɚɧɵ ɢɥɢ ɟɟ ɩɨɥɧɨɟ ɨɬɫɭɬɫɬɜɢɟ [8, 9]. Ʉɥɟɬɤɢ ɷɧɞɨɬɟɥɢɹ ɜɧɨɜɶ ɨɛɪɚɡɨɜɚɧɧɨɣ ɨɩɭɯɨɥɟɜɨɣ ɫɨɫɭɞɢɫɬɨɣ ɫɟɬɢ ɬɚɤɠɟ ɩɪɨɹɜɥɹɸɬ ɚɧɨɦɚɥɶɧɵɟ ɱɟɪɬɵ: ɨɧɢ ɨɛɥɚɞɚɸɬ ɩɨɜɵɲɟɧɧɨɣ ɩɪɨɥɢɮɟɪɚɬɢɜɧɨɣ ɚɤɬɢɜɧɨɫɬɶɸ, ɦɨɝɭɬ ɪɚɫɬɢ ɯɚɨɬɢɱɧɨ, ɧɟ ɮɨɪɦɢɪɭɹ ɦɨɧɨɫɥɨɣ ɢ ɫɨɡɞɚɜɚɹ ɜɵɪɨɫɬɵ ɜɧɭɬɪɢ ɩɪɨɫɜɟɬɚ ɫɨɫɭɞɚ, ɦɟɠɤɥɟɬɨɱɧɵɟ ɤɨɧɬɚɤɬɵ ɜ ɬɚɤɢɯ ɫɨɫɭɞɚɯ ɭɜɟɥɢɱɟɧɵ, ɨɛɪɚɡɭɹ ɳɟɥɢ [10]. ɗɧɞɨɬɟɥɢɚɥɶɧɵɟ ɤɥɟɬɤɢ ɫɨɫɭɞɨɜ ɨɩɭɯɨɥɢ ɦɨɝɭɬ ɩɪɨɹɜɥɹɬɶ ɝɟɧɟɬɢɱɟɫɤɭɸ ɧɟɫɬɚɛɢɥɶɧɨɫɬɶ [11]. ɏɨɬɹ ɜɧɨɜɶ ɨɛɪɚɡɨɜɚɧɧɚɹ ɫɨɫɭɞɢɫɬɚɹ ɫɢɫɬɟɦɚ ɨɩɭɯɨɥɢ ɯɚɪɚɤɬɟɪɢɡɭɟɬɫɹ ɚɧɨɦɚɥɶɧɵɦɢ ɫɜɨɣɫɬɜɚɦɢ ɢ, ɜɨɡɦɨɠɧɨ, ɧɟ ɫɩɨɫɨɛɧɚ ɩɨɥɧɨɫɬɶɸ ɨɛɟɫɩɟɱɢɬɶ ɩɨɬɪɟɛɧɨɫɬɢ ɪɚɫɬɭɳɟɣ ɨɩɭɯɨɥɢ ɜ ɤɢɫɥɨɪɨɞɟ ɢ ɩɢɬɚɧɢɢ, ɚɤɬɢɜɧɨɫɬɶ ɚɧɝɢɨɝɟɧɟɡɚ ɨɩɭɯɨɥɟɜɨɣ ɬɤɚɧɢ ɦɨɠɟɬ ɫɥɭɠɢɬɶ ɨɞɧɨɣ ɢɡ ɜɚɠɧɵɯ ɯɚɪɚɤɬɟɪɢɫɬɢɤ ɩɪɨɰɟɫɫɚ ɪɚɡɜɢɬɢɹ ɡɥɨɤɚɱɟɫɬɜɟɧɧɨɝɨ ɧɨɜɨɨɛɪɚɡɨɜɚɧɢɹ. Ɇɧɨɝɨɱɢɫɥɟɧɧɵɟ ɢɫɫɥɟɞɨɜɚɧɢɹ ɜɚɫɤɭɥɹɪɢɡɚɰɢɢ ɨɩɭɯɨɥɟɜɨɣ ɬɤɚɧɢ, 2 ɨɩɪɟɞɟɥɹɟɦɨɣ ɤɚɤ ɤɨɥɢɱɟɫɬɜɨ ɤɚɩɢɥɥɹɪɨɜ ɧɚ 1 ɦɦ ɝɢɫɬɨɥɨɝɢɱɟɫɤɨɝɨ ɫɪɟɡɚ, ɜ ɨɩɭɯɨɥɹɯ ɫɚɦɨɣ ɪɚɡɥɢɱɧɨɣ ɥɨɤɚɥɢɡɚɰɢɢ ɢ ɫɨɩɨɫɬɚɜɥɟɧɢɟ ɷɬɨɣ ɯɚɪɚɤɬɟɪɢɫɬɢɤɢ ɫ ɤɥɢɧɢɱɟɫɤɢɦɢ ɩɨɤɚɡɚɬɟɥɹɦɢ ɜ ɛɨɥɶɲɢɧɫɬɜɟ ɫɥɭɱɚɟɜ ɜɵɹɜɢɥɢ ɤɨɪɪɟɥɹɰɢɢ 4 ɦɟɠɞɭ ɜɚɫɤɭɥɹɪɢɡɚɰɢɟɣ ɨɩɭɯɨɥɢ ɢ ɦɟɬɚɫɬɚɡɢɪɨɜɚɧɢɟɦ, ɚ ɬɚɤɠɟ ɫ ɩɪɨɝɧɨɡɨɦ ɪɚɡɜɢɬɢɹ ɡɚɛɨɥɟɜɚɧɢɹ (ɫɦ., ɧɚɩɪɢɦɟɪ, ɨɛɡɨɪ Gasparini G., Harris A.L. [12]). ɍɱɢɬɵɜɚɹ ɜɚɠɧɭɸ ɩɪɨɝɧɨɫɬɢɱɟɫɤɭɸ ɡɧɚɱɢɦɨɫɬɶ ɚɤɬɢɜɧɨɫɬɢ ɚɧɝɢɨɝɟɧɟɡɚ ɨɩɭɯɨɥɢ, ɧɟɨɛɯɨɞɢɦɨ ɛɵɥɨ ɜɵɹɜɢɬɶ ɦɨɥɟɤɭɥɹɪɧɵɟ ɦɚɪɤɟɪɵ, ɫɩɨɫɨɛɧɵɟ ɚɞɟɤɜɚɬɧɨ ɨɰɟɧɢɜɚɬɶ ɷɬɨɬ ɩɚɪɚɦɟɬɪ. ɂ ɤɪɨɦɟ ɬɨɝɨ, ɨɛɧɚɪɭɠɟɧɢɟ ɬɚɤɢɯ ɦɚɪɤɟɪɨɜ, ɚ ɬɚɤɠɟ ɢɞɟɧɬɢɮɢɤɚɰɢɹ ɫɢɝɧɚɥɶɧɵɯ ɫɢɫɬɟɦ, ɪɟɝɭɥɢɪɭɸɳɢɯ ɧɟɨɚɧɝɢɨɝɟɧɟɡ ɨɩɭɯɨɥɢ, ɦɨɝɥɢ ɫɩɨɫɨɛɫɬɜɨɜɚɬɶ ɜɵɹɜɥɟɧɢɸ ɧɨɜɵɯ ɦɨɥɟɤɭɥɹɪɧɵɯ ɦɢɲɟɧɟɣ ɞɥɹ ɪɚɡɪɚɛɨɬɤɢ ɩɪɨɬɢɜɨɨɩɭɯɨɥɟɜɵɯ ɥɟɤɚɪɫɬɜɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ, ɧɚɰɟɥɟɧɧɵɯ ɧɚ ɩɨɞɚɜɥɟɧɢɟ ɚɧɝɢɨɝɟɧɧɨɣ ɚɤɬɢɜɧɨɫɬɢ ɨɩɭɯɨɥɢ. 5 Ɏɚɤɬɨɪɵ ɪɨɫɬɚ ɷɧɞɨɬɟɥɢɹ ɫɨɫɭɞɨɜ VEGF – ɨɞɧɢ ɢɡ ɨɫɧɨɜɧɵɯ ɪɟɝɭɥɹɬɨɪɨɜ ɚɧɝɢɨɝɟɧɟɡɚ ɨɩɭɯɨɥɢ ȼ ɤɚɱɟɫɬɜɟ ɩɨɬɟɧɰɢɚɥɶɧɵɯ ɤɚɧɞɢɞɚɬɨɜ ɧɚ ɪɨɥɶ ɦɚɪɤɟɪɨɜ ɚɧɝɢɨɝɟɧɟɡɚ, ɜ ɬɨɦ ɱɢɫɥɟ ɢ ɧɟɨɚɧɝɢɨɝɟɧɟɡɚ ɨɩɭɯɨɥɢ, ɜ ɩɟɪɜɭɸ ɨɱɟɪɟɞɶ ɪɚɫɫɦɚɬɪɢɜɚɥɢɫɶ ɮɚɤɬɨɪɵ, ɫɩɨɫɨɛɧɵɟ ɪɟɝɭɥɢɪɨɜɚɬɶ ɚɧɝɢɨɝɟɧɟɡ, ɢ ɫɜɹɡɚɧɧɵɟ ɫ ɧɢɦɢ ɫɢɝɧɚɥɶɧɵɟ ɫɢɫɬɟɦɵ. ȼ ɧɚɫɬɨɹɳɟɟ ɜɪɟɦɹ ɢɡɜɟɫɬɧɨ ɞɨɜɨɥɶɧɨ ɛɨɥɶɲɨɟ ɱɢɫɥɨ ɚɧɝɢɨɝɟɧɧɵɯ ɮɚɤɬɨɪɨɜ. Ʉ ɢɯ ɱɢɫɥɭ ɨɬɧɨɫɹɬɫɹ ɮɚɤɬɨɪɵ ɪɨɫɬɚ ɷɧɞɨɬɟɥɢɹ ɫɨɫɭɞɨɜ VEGF, ɮɚɤɬɨɪɵ ɪɨɫɬɚ ɮɢɛɪɨɛɥɚɫɬɨɜ aFGF ɢ bFGF, ɬɪɚɧɫɮɨɪɦɢɪɭɸɳɢɟ ɮɚɤɬɨɪɵ ɪɨɫɬɚ TGF, ɬɪɨɦɛɨɰɢɬɚɪɧɵɟ ɮɚɤɬɨɪɵ ɪɨɫɬɚ PDGF, ɬɪɨɦɛɨɰɢɬɚɪɧɵɣ ɮɚɤɬɨɪ ɪɨɫɬɚ ɤɥɟɬɨɤ ɷɧɞɨɬɟɥɢɹ PD-ȿɋGF, ɚɧɝɢɨɝɟɧɢɧ, ɚɧɝɢɨɩɨɷɬɢɧɵ ɢ ɧɟɤɨɬɨɪɵɟ ɞɪɭɝɢɟ. Ɉɛɧɚɪɭɠɟɧɢɟ ɚɧɝɢɨɝɟɧɧɵɯ ɮɚɤɬɨɪɨɜ ɜɞɨɯɧɭɥɨ ɧɨɜɭɸ ɠɢɡɧɶ ɜ ɜɵɫɤɚɡɚɧɧɭɸ Ⱦɠ. Ɏɨɥɤɦɚɧɨɦ ɟɳɟ ɞɨ ɢɯ ɨɛɧɚɪɭɠɟɧɢɹ ɢɞɟɸ ɨ ɬɨɦ, ɱɬɨ ɜ ɨɩɭɯɨɥɟɜɨɣ ɬɤɚɧɢ, ɞɥɹ ɨɛɟɫɩɟɱɟɧɢɹ ɜɵɠɢɜɚɧɢɹ, ɞɨɥɠɧɵ ɫɭɳɟɫɬɜɨɜɚɬɶ ɦɟɯɚɧɢɡɦɵ, ɫɬɢɦɭɥɢɪɭɸɳɢɟ ɪɚɡɜɢɬɢɟ ɫɨɫɭɞɢɫɬɨɣ ɫɟɬɢ [3]. ɉɨɫɤɨɥɶɤɭ ɫɨɫɭɞɵ ɫɨɫɬɨɹɬ, ɜ ɨɫɧɨɜɧɨɦ, ɢɡ ɤɥɟɬɨɤ ɷɧɞɨɬɟɥɢɹ, ɚ ɬɚɤɠɟ ɩɟɪɢɰɢɬɨɜ ɢ ɝɥɚɞɤɨɦɵɲɟɱɧɵɯ ɤɥɟɬɨɤ, ɮɨɪɦɢɪɭɸɳɢɯ ɫɬɟɧɤɢ ɫɨɫɭɞɨɜ, ɜɚɠɧɨ ɛɵɥɨ ɢɞɟɧɬɢɮɢɰɢɪɨɜɚɬɶ ɫɢɝɧɚɥɶɧɵɟ ɫɢɫɬɟɦɵ, ɪɟɝɭɥɢɪɭɸɳɢɟ ɪɚɡɦɧɨɠɟɧɢɟ ɢ ɦɢɝɪɚɰɢɸ ɷɬɢɯ ɬɢɩɨɜ ɤɥɟɬɨɤ. ɇɚɢɛɨɥɟɟ ɜɚɠɧɵɦ ɩɪɟɞɫɬɚɜɥɹɥɨɫɶ ɢɫɫɥɟɞɨɜɚɧɢɟ ɦɟɯɚɧɢɡɦɨɜ ɪɟɝɭɥɹɰɢɢ ɤɥɟɬɨɤ ɷɧɞɨɬɟɥɢɹ, ɩɨɫɤɨɥɶɤɭ ɮɨɪɦɢɪɨɜɚɧɢɟ ɫɨɫɭɞɚ ɧɚɱɢɧɚɟɬɫɹ ɫ ɪɚɡɦɧɨɠɟɧɢɹ ɢ ɦɢɝɪɚɰɢɢ ɢɦɟɧɧɨ ɷɬɢɯ ɤɥɟɬɨɤ, ɨɛɪɚɡɭɸɳɢɯ ɜ ɞɚɥɶɧɟɣɲɟɦ ɬɪɭɛɱɚɬɵɟ ɫɬɪɭɤɬɭɪɵ. ɂɡ ɜɫɟɯ ɢɡɜɟɫɬɧɵɯ ɚɧɝɢɨɝɟɧɧɵɯ ɮɚɤɬɨɪɨɜ ɧɚɢɛɨɥɟɟ ɩɨɞɯɨɞɹɳɢɦ ɧɚ ɪɨɥɶ ɪɟɝɭɥɹɬɨɪɚ ɚɧɝɢɨɝɟɧɟɡɚ ɨɩɭɯɨɥɢ ɩɪɟɞɫɬɚɜɥɹɥɫɹ ɮɚɤɬɨɪ ɪɨɫɬɚ ɷɧɞɨɬɟɥɢɹ ɫɨɫɭɞɨɜ VEGF, ɜɩɟɪɜɵɟ ɨɩɢɫɚɧɧɵɣ ɜ ɪɚɛɨɬɚɯ Senger D.R. ɢ ɫɨɬɪ. [13, 14]. ȼ ɨɬɥɢɱɢɟ ɨɬ ɞɪɭɝɢɯ ɚɧɝɢɨɝɟɧɧɵɯ ɮɚɤɬɨɪɨɜ, VEGF ɜɵɫɨɤɨ ɫɩɟɰɢɮɢɱɟɧ ɞɥɹ ɤɥɟɬɨɤ ɷɧɞɨɬɟɥɢɹ ɫɨɫɭɞɨɜ. ȼɚɠɧɨɣ ɨɫɨɛɟɧɧɨɫɬɶɸ ɷɬɨɝɨ ɮɚɤɬɨɪɚ ɛɵɥɚ ɟɝɨ ɫɩɨɫɨɛɧɨɫɬɶ ɩɨɜɵɲɚɬɶ ɫɬɨɥɶ ɯɚɪɚɤɬɟɪɧɭɸ ɞɥɹ ɨɩɭɯɨɥɢ ɩɪɨɧɢɰɚɟɦɨɫɬɶ ɫɨɫɭɞɨɜ, ɜ ɫɜɹɡɢ ɫ ɱɟɦ ɨɧ ɩɟɪɜɨɧɚɱɚɥɶɧɨ ɛɵɥ ɧɚɡɜɚɧ ɚɜɬɨɪɚɦɢ ɮɚɤɬɨɪɨɦ ɩɪɨɧɢɰɚɟɦɨɫɬɢ ɫɨɫɭɞɨɜ, ɢɥɢ VPF (Vascular Permeability Factor). 6 ȼɵɫɨɤɨ ɤɨɧɫɟɪɜɚɬɢɜɧɵɣ ɮɚɤɬɨɪ VEGF, ɤɚɤ ɛɵɥɨ ɩɨɤɚɡɚɧɨ, ɫɟɤɪɟɬɢɪɨɜɚɥɫɹ ɤɥɟɬɤɚɦɢ ɨɩɭɯɨɥɟɣ ɝɪɵɡɭɧɨɜ ɢ ɱɟɥɨɜɟɤɚ ɢ ɨɛɥɚɞɚɥ ɟɳɟ ɨɞɧɨɣ ɜɚɠɧɨɣ ɯɚɪɚɤɬɟɪɢɫɬɢɤɨɣ: ɨɧ, ɜ ɨɬɥɢɱɢɟ ɨɬ ɞɪɭɝɢɯ ɢɡɜɟɫɬɧɵɯ ɚɧɝɢɨɝɟɧɧɵɯ ɮɚɤɬɨɪɨɜ, ɛɵɥ ɜɵɫɨɤɨ ɫɩɟɰɢɮɢɱɟɧ ɜ ɨɬɧɨɲɟɧɢɢ ɤɥɟɬɨɤ ɷɧɞɨɬɟɥɢɹ ɫɨɫɭɞɨɜ, ɫɬɢɦɭɥɢɪɭɹ ɢɯ ɩɪɨɥɢɮɟɪɚɰɢɸ ɢ ɦɢɝɪɚɰɢɸ [15]. ȼ 1989 ɝ. ɩɪɚɤɬɢɱɟɫɤɢ ɨɞɧɨɜɪɟɦɟɧɧɨ ɜ ɧɟɫɤɨɥɶɤɢɯ ɥɚɛɨɪɚɬɨɪɢɹɯ ɛɵɥ ɤɥɨɧɢɪɨɜɚɧ ɝɟɧ, ɤɨɞɢɪɭɸɳɢɣ ɷɬɨɬ ɮɚɤɬɨɪ [16, 17, 18]. ɉɨɡɞɧɟɟ ɛɵɥɢ ɨɛɧɚɪɭɠɟɧɵ ɟɳɟ ɧɟɫɤɨɥɶɤɨ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ, ɩɪɢɧɚɞɥɟɠɚɳɢɯ ɷɬɨɦɭ ɠɟ ɫɟɦɟɣɫɬɜɭ, ɜɫɥɟɞɫɬɜɢɟ ɱɟɝɨ ɮɚɤɬɨɪ ɪɨɫɬɚ VEGF ɛɵɥ ɩɟɪɟɢɦɟɧɨɜɚɧ ɜ VEGF-A, (ɜ ɥɢɬɟɪɚɬɭɪɟ ɱɚɫɬɨ ɢɫɩɨɥɶɡɭɟɬɫɹ ɩɟɪɜɨɧɚɱɚɥɶɧɨɟ ɧɚɡɜɚɧɢɟ – VEGF), ɚ ɧɨɜɵɟ ɮɚɤɬɨɪɵ ɫɟɦɟɣɫɬɜɚ ɩɨɥɭɱɢɥɢ ɧɚɡɜɚɧɢɹ VEGF-B [19, 20], VEGF-C [21, 22], VEGF-D [23, 24] ɢ VEGF-E [25]. Ɉɛɧɚɪɭɠɟɧɧɵɣ ɪɚɧɟɟ ɩɥɚɰɟɧɬɚɪɧɵɣ ɮɚɤɬɨɪ ɪɨɫɬɚ PlGF ɬɚɤɠɟ ɨɬɧɨɫɢɬɫɹ ɤ ɷɬɨɦɭ ɫɟɦɟɣɫɬɜɭ [26]. ɉɟɪɟɞɚɱɚ ɫɢɝɧɚɥɨɜ, ɩɟɪɟɞɚɜɚɟɦɵɯ ɜ ɤɥɟɬɤɭ ɫɟɤɪɟɬɢɪɭɟɦɵɦɢ ɮɚɤɬɨɪɚɦɢ ɪɨɫɬɚ, ɩɪɨɢɫɯɨɞɢɬ ɛɥɚɝɨɞɚɪɹ ɢɯ ɜɡɚɢɦɨɞɟɣɫɬɜɢɸ ɫɨ ɫɜɨɢɦɢ ɪɟɰɟɩɬɨɪɚɦɢ, ɪɚɫɩɨɥɨɠɟɧɧɵɦɢ ɧɚ ɤɥɟɬɨɱɧɨɣ ɦɟɦɛɪɚɧɟ. ɂɡɜɟɫɬɧɵ 3 ɨɫɧɨɜɧɵɯ ɪɟɰɟɩɬɨɪɚ, ɜɡɚɢɦɨɞɟɣɫɬɜɭɸɳɢɯ ɫ ɫɟɦɟɣɫɬɜɨɦ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF. ɗɬɨ – VEGFR1 (FLT1) [27], VEGFR2 (Flk1/KDR) [28, 29] ɢ VEGFR3 (FLT4) [30, 31] (ɜ ɫɤɨɛɤɚɯ ɩɪɢɜɟɞɟɧɵ ɩɟɪɜɨɧɚɱɚɥɶɧɵɟ ɧɚɡɜɚɧɢɹ ɪɟɰɟɩɬɨɪɨɜ, ɧɚɡɜɚɧɢɟ Flk1 ɫɨɨɬɜɟɬɫɬɜɭɟɬ ɪɟɰɟɩɬɨɪɭ VEGFR2 ɦɵɲɢ, ɚ KDR – ɱɟɥɨɜɟɤɚ). Ɋɟɰɟɩɬɨɪɵ VEGFR1 ɢ VEGFR2 ɩɪɟɢɦɭɳɟɫɬɜɟɧɧɨ ɥɨɤɚɥɢɡɨɜɚɧɵ ɧɚ ɤɥɟɬɤɚɯ ɷɧɞɨɬɟɥɢɹ ɤɪɨɜɟɧɨɫɧɵɯ ɫɨɫɭɞɨɜ, ɬɨɝɞɚ ɤɚɤ ɷɤɫɩɪɟɫɫɢɹ ɪɟɰɟɩɬɨɪɚ VEGFR3 ɫɩɟɰɢɮɢɱɧɚ ɞɥɹ ɷɧɞɨɬɟɥɢɹ ɥɢɦɮɚɬɢɱɟɫɤɢɯ ɫɨɫɭɞɨɜ. Ɋɟɰɟɩɬɨɪɵ VEGFR ɨɬɧɨɫɹɬɫɹ ɤ ɫɭɩɟɪɫɟɦɟɣɫɬɜɭ ɪɟɰɟɩɬɨɪɧɵɯ ɬɢɪɨɡɢɧɤɢɧɚɡ (ɊɌɄ), ɨɧɢ ɢɦɟɸɬ ɫɯɨɞɧɭɸ ɫɬɪɭɤɬɭɪɭ ɢ ɨɛɪɚɡɭɸɬ ɨɬɞɟɥɶɧɭɸ ɩɨɞɝɪɭɩɩɭ ɜɧɭɬɪɢ ɷɬɨɝɨ ɫɭɩɟɪɫɟɦɟɣɫɬɜɚ. ȼɫɟ ɊɌɄ ɩɪɟɞɫɬɚɜɥɹɸɬ ɫɨɛɨɣ ɬɪɚɧɫɦɟɦɛɪɚɧɧɵɟ ɛɟɥɤɢ, ɜɧɟɤɥɟɬɨɱɧɚɹ ɪɟɰɟɩɬɨɪɧɚɹ ɨɛɥɚɫɬɶ ɤɨɬɨɪɵɯ ɫɜɹɡɵɜɚɟɬɫɹ ɫɨ ɫɜɨɢɦɢ ɫɩɟɰɢɮɢɱɟɫɤɢɦɢ ɮɚɤɬɨɪɚɦɢ, ɚ ɜɧɭɬɪɢɤɥɟɬɨɱɧɚɹ ɨɛɥɚɫɬɶ ɫɨɞɟɪɠɢɬ ɞɨɦɟɧ ɨɛɥɚɞɚɸɳɢɣ ɬɢɪɨɡɢɧɤɢɧɚɡɧɨɣ ɚɤɬɢɜɧɨɫɬɶɸ. 7 ȼ ɫɭɩɟɪɫɟɦɟɣɫɬɜɟ ɊɌɄ ɜɵɞɟɥɹɟɬɫɹ ɞɨɜɨɥɶɧɨ ɛɨɥɶɲɨɣ ɤɥɚɫɫ ɪɟɰɟɩɬɨɪɨɜ (ɬɚɤ ɧɚɡɵɜɚɟɦɵɣ ɤɥɚɫɫ III), ɫɯɨɞɧɵɯ ɤɚɤ ɩɨ ɨɪɝɚɧɢɡɚɰɢɢ ɫɜɨɟɝɨ ɬɢɪɨɡɢɧɤɢɧɚɡɧɨɝɨ ɞɨɦɟɧɚ, ɬɚɤ ɢ ɩɨ ɫɬɪɭɤɬɭɪɟ ɜɧɟɤɥɟɬɨɱɧɨɣ ɨɛɥɚɫɬɢ (Ɋɢɫ.1). ɂȽ I ɂȽ II ɂȽ I ɂȽ III ɂȽ II ɂȽ IV ɂȽ I ɂȽ III ɂȽ V ɂȽ II ɂȽ IV ɂȽ VI ɂȽ III ɂȽ V ɂȽ VII Ʉɥɟɬɨɱɧɚɹ ɦɟɦɛɪɚɧɚ ɌɄ-1 ɌɄ-2 FGFR1 FGFR2 FGFR3 FGFR4 PDGFR-Į PDGFR-ȕ FMS/CSFR1 KIT FLT3 VEGFR1 (FLT1) VEGFR2 (Flk1/KDR) VEGFR3 (FLT4) Ɋɢɫ.1. Ɋɟɰɟɩɬɨɪɵ, ɨɬɧɨɫɹɳɢɟɫɹ ɤ ɤɥɚɫɫɭ III ɫɭɩɟɪɫɟɦɟɣɫɬɜɚ ɪɟɰɟɩɬɨɪɧɵɯ ɬɢɪɨɡɢɧɤɢɧɚɡ. ȼɧɟɤɥɟɬɨɱɧɚɹ ɪɟɰɟɩɬɨɪɧɚɹ ɨɛɥɚɫɬɶ ɪɟɰɟɩɬɨɪɨɜ ɷɬɨɝɨ ɤɥɚɫɫɚ ɫɮɨɪɦɢɪɨɜɚɧɚ ɬɚɤ ɧɚɡɵɜɚɟɦɵɦɢ ɢɦɦɭɧɨɝɥɨɛɭɥɢɧ-ɩɨɞɨɛɧɵɦɢ (ɂȽ) ɞɨɦɟɧɚɦɢ, ɚ ɜɧɭɬɪɢɤɥɟɬɨɱɧɵɣ ɬɢɪɨɡɢɧɤɢɧɚɡɧɵɣ ɞɨɦɟɧ ɪɚɡɞɟɥɟɧ ɧɚ 2 ɱɚɫɬɢ (ɌɄ-1 ɢ ɌɄ-2) ɢɧɬɟɪɤɢɧɚɡɧɨɣ ɜɫɬɚɜɤɨɣ. Ʉ ɷɬɨɦɭ ɤɥɚɫɫɭ ɨɬɧɨɫɹɬɫɹ ɢ ɪɟɰɟɩɬɨɪɵ VEGFR, ɨɛɪɚɡɭɹ ɜ ɧɟɦ ɨɬɞɟɥɶɧɭɸ ɩɨɞɝɪɭɩɩɭ. Ƚɨɦɨɥɨɝɢɹ ɦɟɠɞɭ ɪɟɰɟɩɬɨɪɚɦɢ ɷɬɨɝɨ ɤɥɚɫɫɚ, ɨɫɨɛɟɧɧɨ ɜ ɨɛɥɚɫɬɢ ɢɯ ɬɢɪɨɡɢɧɤɢɧɚɡɧɵɯ ɞɨɦɟɧɨɜ, ɨɫɨɛɟɧɧɨ ɜɵɫɨɤɚ. 8 ȼ ɪɟɡɭɥɶɬɚɬɟ ɜɡɚɢɦɨɞɟɣɫɬɜɢɹ ɪɟɰɟɩɬɨɪɨɜ VEGFR ɫɨ ɫɜɨɢɦɢ ɥɢɝɚɧɞɚɦɢ ɩɪɨɢɫɯɨɞɢɬ ɢɯ ɞɢɦɟɪɢɡɚɰɢɹ ɫ ɩɨɫɥɟɞɭɸɳɢɦ ɚɭɬɨɮɨɫɮɨɪɢɥɢɪɨɜɚɧɢɟɦ ɨɫɬɚɬɤɨɜ ɬɢɪɨɡɢɧɨɜ, ɪɚɫɩɨɥɨɠɟɧɧɵɯ Ⱥɦɢɧɨɤɢɫɥɨɬɧɵɟ ɜɨ ɜɧɭɬɪɢɤɥɟɬɨɱɧɨɣ ɩɨɫɥɟɞɨɜɚɬɟɥɶɧɨɫɬɢ, ɫɨɞɟɪɠɚɳɢɟ ɨɛɥɚɫɬɢ ɪɟɰɟɩɬɨɪɚ. ɮɨɫɮɨɪɢɥɢɪɨɜɚɧɧɵɟ ɨɫɬɚɬɤɢ ɬɢɪɨɡɢɧɨɜ, ɩɪɟɞɫɬɚɜɥɹɸɬ ɫɨɛɨɣ ɫɚɣɬɵ ɫɜɹɡɵɜɚɧɢɹ ɞɥɹ ɪɚɡɥɢɱɧɵɯ ɫɢɝɧɚɥɶɧɵɯ ɦɨɥɟɤɭɥ, ɬɚɤɠɟ ɚɤɬɢɜɢɪɭɟɦɵɯ ɮɨɫɮɨɪɢɥɢɪɨɜɚɧɢɟɦ ɢ ɭɱɚɫɬɜɭɸɳɢɯ ɜ ɞɚɥɶɧɟɣɲɟɣ ɩɟɪɟɞɚɱɟ ɫɢɝɧɚɥɚ. VEGF-B VEGF-E VEGF-C PlGF VEGFR1 (FLT1) VEGF-A VEGFR2 (Flk1/KDR) VEGF-D VEGFR3 (FLT4) Ɋɢɫ. 2. ȼɡɚɢɦɨɞɟɣɫɬɜɢɟ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF ɫɨ ɫɜɨɢɦɢ ɪɟɰɟɩɬɨɪɚɦɢ. 9 ɇɚ ɪɢɫɭɧɤɟ 2 ɩɪɟɞɫɬɚɜɥɟɧɚ ɫɯɟɦɚ ɜɡɚɢɦɨɞɟɣɫɬɜɢɹ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF ɫɨ ɫɜɨɢɦɢ ɪɟɰɟɩɬɨɪɚɦɢ, ɢɡ ɤɨɬɨɪɨɣ ɜɢɞɧɨ, ɱɬɨ ɤɚɠɞɵɣ ɢɡ ɪɟɰɟɩɬɨɪɨɜ VEGFR ɦɨɠɟɬ ɜɡɚɢɦɨɞɟɣɫɬɜɨɜɚɬɶ ɫ ɧɟɫɤɨɥɶɤɢɦɢ ɮɚɤɬɨɪɚɦɢ VEGF, ɫɜɹɡɵɜɚɸɳɢɦɢɫɹ ɫ ɧɢɦ ɫ ɪɚɡɧɨɣ ɚɮɮɢɧɧɨɫɬɶɸ. ɂɧɬɟɪɟɫɧɨ, ɱɬɨ ɩɨɫɥɟɞɫɬɜɢɹ ɜɡɚɢɦɨɞɟɣɫɬɜɢɹ ɨɞɧɨɝɨ ɢ ɬɨɝɨ ɠɟ ɪɟɰɟɩɬɨɪɚ ɫ ɪɚɡɧɵɦɢ ɮɚɤɬɨɪɚɦɢ ɪɨɫɬɚ VEGF ɬɚɤɠɟ ɦɨɝɭɬ ɛɵɬɶ ɪɚɡɥɢɱɧɵ. Ɍɚɤ, ɧɚɩɪɢɦɟɪ, ɧɚɪɭɲɟɧɢɹ ɚɧɝɢɨɝɟɧɟɡɚ, ɧɚɛɥɸɞɚɟɦɵɟ ɭ ɦɵɲɟɣ ɫ ɧɟɪɚɛɨɬɚɸɳɢɦ ɝɟɧɨɦ plgf ɧɟ ɤɨɦɩɟɧɫɢɪɭɸɬɫɹ ɮɚɤɬɨɪɨɦ ɪɨɫɬɚ VEGF-B [32]. ɋɯɟɦɚ, ɩɪɟɞɫɬɚɜɥɟɧɧɚɹ ɧɚ ɪɢɫ.2, ɢɥɥɸɫɬɪɢɪɭɟɬ ɦɧɨɠɟɫɬɜɟɧɧɨɫɬɶ ɢ ɜɡɚɢɦɨɫɜɹɡɶ ɩɭɬɟɣ ɩɟɪɟɞɚɱɢ ɫɢɝɧɚɥɨɜ ɮɚɤɬɨɪɚɦɢ ɪɨɫɬɚ VEGF. ȼ ɤɥɟɬɤɚɯ ɷɧɞɨɬɟɥɢɹ ɧɚɢɛɨɥɟɟ ɮɭɧɤɰɢɨɧɚɥɶɧɨ ɜɚɠɧɵɦ ɹɜɥɹɟɬɫɹ ɫɢɝɧɚɥɶɧɵɣ ɩɭɬɶ VEGFA/VEGFR2. Ɋɟɰɟɩɬɨɪ VEGFR2 ɜɵɫɨɤɨ ɫɩɟɰɢɮɢɱɟɧ ɞɥɹ ɤɥɟɬɨɤ ɷɧɞɨɬɟɥɢɹ ɫɨɫɭɞɨɜ, ɱɟɪɟɡ ɜɡɚɢɦɨɞɟɣɫɬɜɢɟ ɫ VEGFR2 ɩɟɪɟɞɚɸɬɫɹ ɫɢɝɧɚɥɵ, ɪɟɝɭɥɢɪɭɸɳɢɟ ɬɚɤɢɟ ɧɚɢɛɨɥɟɟ ɜɚɠɧɵɟ ɞɥɹ ɮɨɪɦɢɪɨɜɚɧɢɹ ɫɨɫɭɞɨɜ ɩɪɨɰɟɫɫɵ ɤɚɤ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɚ, ɩɪɨɥɢɮɟɪɚɰɢɹ ɢ ɦɢɝɪɚɰɢɹ ɤɥɟɬɨɤ ɷɧɞɨɬɟɥɢɹ, ɚ ɬɚɤɠɟ ɨɛɪɚɡɨɜɚɧɢɟ ɢɦɢ ɬɪɭɛɱɚɬɵɯ ɫɬɪɭɤɬɭɪ. Ɋɟɰɟɩɬɨɪ VEGFR1 ɜ ɤɥɟɬɤɚɯ ɷɧɞɨɬɟɥɢɹ, ɩɨ-ɜɢɞɢɦɨɦɭ, ɜɨ ɦɧɨɝɨɦ ɢɝɪɚɟɬ ɪɨɥɶ ɪɟɝɭɥɹɬɨɪɚ ɫɢɝɧɚɥɶɧɨɝɨ ɩɭɬɢ VEGF-A/VEGFR2. ɋɩɨɫɨɛɧɨɫɬɶ ɪɟɰɟɩɬɨɪɚ VEGFR1 ɫɜɹɡɵɜɚɬɶɫɹ ɫ VEGF ɧɚ ɩɨɪɹɞɨɤ ɩɪɟɜɵɲɚɟɬ ɬɚɤɨɜɭɸ ɪɟɰɟɩɬɨɪɚ VEGFR2, ɚ ɬɢɪɨɡɢɧɤɢɧɚɡɧɚɹ ɚɤɬɢɜɧɨɫɬɶ VEGFR1, ɧɚɨɛɨɪɨɬ, ɧɚ ɩɨɪɹɞɨɤ ɧɢɠɟ, ɱɟɦ ɭ VEGFR2, ɬ.ɟ. ɚɤɬɢɜɧɨɫɬɶ ɩɟɪɟɞɚɱɢ ɫɢɝɧɚɥɚ ɱɟɪɟɡ ɷɬɨɬ ɪɟɰɟɩɬɨɪ ɨɱɟɧɶ ɧɟɜɵɫɨɤɚ. Ʉ ɬɨɦɭ ɠɟ, ɛɟɥɤɨɜɚɹ ɦɨɥɟɤɭɥɚ VEGFR1 ɫɭɳɟɫɬɜɭɟɬ ɜ 2-ɯ ɮɨɪɦɚɯ: ɩɨɦɢɦɨ ɩɨɥɧɨɪɚɡɦɟɪɧɨɝɨ ɬɪɚɧɫɦɟɦɛɪɚɧɧɨɝɨ ɪɟɰɟɩɬɨɪɚ ɨɛɧɚɪɭɠɟɧɚ ɟɝɨ ɪɚɫɬɜɨɪɢɦɚɹ ɮɨɪɦɚ, ɩɪɟɞɫɬɚɜɥɹɸɳɚɹ ɫɨɛɨɣ ɫɜɹɡɵɜɚɸɳɭɸɫɹ ɫ ɥɢɝɚɧɞɨɦ ɜɧɟɤɥɟɬɨɱɧɭɸ ɨɛɥɚɫɬɶ ɷɬɨɝɨ ɪɟɰɟɩɬɨɪɚ. Ʉɨɧɤɭɪɢɪɭɹ ɫ ɪɟɰɟɩɬɨɪɨɦ VEGFR2 ɡɚ ɫɜɹɡɵɜɚɧɢɟ ɫ VEGF-A, VEGFR1 ɪɟɝɭɥɢɪɭɟɬ ɢɧɬɟɧɫɢɜɧɨɫɬɶ ɩɟɪɟɞɚɱɢ ɫɢɝɧɚɥɚ ɷɬɨɝɨ ɮɚɤɬɨɪɚ ɪɨɫɬɚ ɱɟɪɟɡ VEGFR2, ɨɫɧɨɜɧɨɣ ɮɭɧɤɰɢɨɧɚɥɶɧɵɣ ɪɟɰɟɩɬɨɪ VEGF-A-ɡɚɜɢɫɢɦɨɣ ɫɢɝɧɚɥɶɧɨɣ ɫɢɫɬɟɦɵ. ȿɫɬɶ ɞɚɧɧɵɟ, ɫɜɢɞɟɬɟɥɶɫɬɜɭɸɳɢɟ ɨ ɬɨɦ, ɱɬɨ ɜ ɧɟ ɷɧɞɨɬɟɥɢɚɥɶɧɵɯ ɤɥɟɬɤɚɯ ɪɨɥɶ VEGFR1-ɫɢɝɧɚɥɢɧɝɚ ɦɨɠɟɬ ɨɬɥɢɱɚɬɶɫɹ ɨɬ ɬɚɤɨɜɨɣ ɜ ɤɥɟɬɤɚɯ ɷɧɞɨɬɟɥɢɹ. 10 Ɍɚɤ, ɧɚɩɪɢɦɟɪ, ɛɵɥɨ ɩɨɤɚɡɚɧɨ, ɱɬɨ ɚɤɬɢɜɚɰɢɹ ɪɟɰɟɩɬɨɪɚ VEGFR1 ɮɚɤɬɨɪɚɦɢ ɪɨɫɬɚ VEGF-Ⱥ ɢɥɢ PLGF ɫɬɢɦɭɥɢɪɭɟɬ ɩɪɨɥɢɮɟɪɚɰɢɸ ɢ ɦɢɝɪɚɰɢɸ ɦɨɧɨɰɢɬɨɜ [33, 34]. ȼ ɨɬɥɢɱɢɟ ɨɬ ɪɟɰɟɩɬɨɪɨɜ VEGFR1 ɢ VEGFR2, ɷɤɫɩɪɟɫɫɢɪɭɸɳɢɯɫɹ ɩɪɟɢɦɭɳɟɫɬɜɟɧɧɨ ɧɚ ɤɥɟɬɤɚɯ ɷɧɞɨɬɟɥɢɹ ɤɪɨɜɟɧɨɫɧɵɯ ɫɨɫɭɞɨɜ, ɪɟɰɟɩɬɨɪ VEGFR3 ɜɨ ɜɡɪɨɫɥɨɦ ɨɪɝɚɧɢɡɦɟ ɥɨɤɚɥɢɡɨɜɚɧ ɢɫɤɥɸɱɢɬɟɥɶɧɨ ɧɚ ɤɥɟɬɤɚɯ ɷɧɞɨɬɟɥɢɹ ɥɢɦɮɚɬɢɱɟɫɤɢɯ ɫɨɫɭɞɨɜ. ȼɚɠɧɚɹ ɪɨɥɶ VEGFR3-ɡɚɜɢɫɢɦɨɣ ɫɢɝɧɚɥɶɧɨɣ ɫɢɫɬɟɦɵ ɜ ɪɟɝɭɥɹɰɢɢ ɥɢɦɮɚɧɝɢɨɝɟɧɟɡɚ ɜ ɧɚɫɬɨɹɳɟɟ ɜɪɟɦɹ ɩɨɞɬɜɟɪɠɞɟɧɚ ɜɡɚɢɦɨɞɟɣɫɬɜɢɹ ɜ ɰɟɥɨɦ VEGFR3 ɪɹɞɟ ɫɨ ɪɚɛɨɬ. ɫɜɨɢɦ Ɍɚɤ, ɧɚɩɪɢɦɟɪ, ɥɢɝɚɧɞɨɦ VEGF-C ɛɥɨɤɢɪɨɜɚɧɢɟ ɩɪɢɜɨɞɢɥɨ ɤ ɢɧɝɢɛɢɪɨɜɚɧɢɸ ɷɦɛɪɢɨɧɚɥɶɧɨɝɨ ɥɢɦɮɚɧɝɢɨɝɟɧɟɡɚ ɭ ɦɵɲɟɣ, ɩɪɢ ɷɬɨɦ ɤɪɨɜɟɧɨɫɧɚɹ ɫɢɫɬɟɦɚ ɬɚɤɢɯ ɦɵɲɟɣ ɪɚɡɜɢɜɚɥɚɫɶ ɧɨɪɦɚɥɶɧɨ. Ɍɚɤɢɦ ɨɛɪɚɡɨɦ, ɛɵɥɢ ɢɞɟɧɬɢɮɢɰɢɪɨɜɚɧɵ ɜɚɠɧɵɟ ɦɨɥɟɤɭɥɹɪɧɵɟ ɦɢɲɟɧɢ, ɢɫɫɥɟɞɨɜɚɧɢɟ ɤɨɬɨɪɵɯ ɩɪɟɞɨɫɬɚɜɢɥɨ ɧɨɜɵɟ ɜɨɡɦɨɠɧɨɫɬɢ ɞɥɹ ɨɰɟɧɤɢ ɚɤɬɢɜɧɨɫɬɢ ɧɟɨɚɧɝɢɨɝɟɧɟɡɚ ɨɩɭɯɨɥɢ, ɩɪɢ ɷɬɨɦ ɜ ɩɟɪɜɭɸ ɨɱɟɪɟɞɶ ɢɫɫɥɟɞɨɜɚɥɚɫɶ ɷɤɫɩɪɟɫɫɢɹ ɮɚɤɬɨɪɚ ɪɨɫɬɚ VEGF-A ɢ ɟɝɨ ɨɫɧɨɜɧɨɝɨ ɪɟɰɟɩɬɨɪɚ VEGFR2. 11 ɗɤɫɩɪɟɫɫɢɹ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ ɜ ɨɩɭɯɨɥɹɯ ɱɟɥɨɜɟɤɚ ɋɪɚɜɧɟɧɢɟ ɷɤɫɩɪɟɫɫɢɢ VEGF-A ɢ ɪɹɞɚ ɞɪɭɝɢɯ ɚɧɝɢɨɝɟɧɧɵɯ ɮɚɤɬɨɪɨɜ ɜ ɨɩɭɯɨɥɹɯ ɭɤɚɡɵɜɚɥɨ ɧɚ ɬɨ, ɱɬɨ ɢɦɟɧɧɨ ɚɤɬɢɜɚɰɢɹ VEGF-A ɧɚɢɛɨɥɟɟ ɯɚɪɚɤɬɟɪɧɚ ɞɥɹ ɪɚɡɜɢɬɢɹ ɨɩɭɯɨɥɟɜɨɝɨ ɩɪɨɰɟɫɫɚ. Ɍɚɤ, ɧɚɩɪɢɦɟɪ, Yoshiji H. ɢ ɫɨɚɜɬ. [35] ɜ ɫɜɨɟɣ ɪɚɛɨɬɟ ɢɫɫɥɟɞɨɜɚɥɢ ɷɤɫɩɪɟɫɫɢɸ ɝɟɧɨɜ VEGF-A, ɟɝɨ ɪɟɰɟɩɬɨɪɚ VEGFR1 ɢ ɧɟɤɨɬɨɪɵɯ ɞɪɭɝɢɯ ɝɟɧɨɜ (bFGF, TGF-Į, TGF-ȕ), ɬɚɤɠɟ ɤɨɞɢɪɭɸɳɢɯ ɚɧɝɢɨɝɟɧɧɵɟ ɮɚɤɬɨɪɵ, ɜ ɤɚɪɰɢɧɨɦɚɯ ɦɨɥɨɱɧɨɣ ɠɟɥɟɡɵ ɢ ɜ ɨɤɪɭɠɚɸɳɟɣ ɨɩɭɯɨɥɶ ɨɤɨɥɨɧɨɪɦɚɥɶɧɨɣ ɬɤɚɧɢ. Ɉɤɚɡɚɥɨɫɶ, ɱɬɨ ɜ ɬɤɚɧɢ ɤɚɪɰɢɧɨɦ ɩɨɜɵɲɟɧɚ ɬɨɥɶɤɨ ɷɤɫɩɪɟɫɫɢɹ ɝɟɧɚ VEGF-A, ɧɨ ɧɟ ɝɟɧɨɜ, ɤɨɞɢɪɭɸɳɢɯ ɞɪɭɝɢɟ ɚɧɝɢɨɝɟɧɧɵɟ ɮɚɤɬɨɪɵ, ɢɫɫɥɟɞɨɜɚɧɧɵɟ ɜ ɞɚɧɧɨɣ ɪɚɛɨɬɟ. ɇɟ ɛɵɥɚ ɩɨɜɵɲɟɧɚ ɢ ɷɤɫɩɪɟɫɫɢɹ ɝɟɧɚ, ɤɨɞɢɪɭɸɳɟɝɨ ɪɟɰɟɩɬɨɪ VEGFR1. ɂɦɦɭɧɨɝɢɫɬɨɯɢɦɢɱɟɫɤɨɟ ɨɤɪɚɲɢɜɚɧɢɟ ɩɨɤɚɡɚɥɨ, ɱɬɨ ɨɫɧɨɜɧɵɦ ɢɫɬɨɱɧɢɤɨɦ VEGF-A ɹɜɥɹɸɬɫɹ ɫɚɦɢ ɨɩɭɯɨɥɟɜɵɟ ɤɥɟɬɤɢ. ɉɨɜɵɲɟɧɧɚɹ ɷɤɫɩɪɟɫɫɢɹ VEGF-Ⱥ ɨɛɧɚɪɭɠɟɧɚ ɩɪɚɤɬɢɱɟɫɤɢ ɜɨ ɜɫɟɯ ɫɨɥɢɞɧɵɯ ɨɩɭɯɨɥɹɯ. Ɍɚɤ, ɚɤɬɢɜɚɰɢɹ ɷɤɫɩɪɟɫɫɢɢ ɷɬɨɝɨ ɮɚɤɬɨɪɚ ɪɨɫɬɚ ɧɚɣɞɟɧɚ ɜ ɤɚɪɰɢɧɨɦɚɯ ɥɟɝɤɨɝɨ, ɳɢɬɨɜɢɞɧɨɣ ɠɟɥɟɡɵ, ɦɨɥɨɱɧɨɣ ɠɟɥɟɡɵ, ɠɟɥɭɞɤɚ, ɬɨɥɫɬɨɣ ɤɢɲɤɢ, ɩɨɱɤɢ, ɦɨɱɟɜɨɝɨ ɩɭɡɵɪɹ, ɹɢɱɧɢɤɚ ɢ ɲɟɣɤɢ ɦɚɬɤɢ, ɜ ɚɧɝɢɨɫɚɪɤɨɦɚɯ ɢ ɧɟɨɩɥɚɡɢɹɯ ɰɟɧɬɪɚɥɶɧɨɣ ɧɟɪɜɧɨɣ ɫɢɫɬɟɦɵ. ȼɵɫɨɤɢɣ ɭɪɨɜɟɧɶ ɷɤɫɩɪɟɫɫɢɢ VEGFȺ, ɧɚɛɥɸɞɚɜɲɢɣɫɹ ɜ ɦɟɬɚɫɬɚɬɢɱɟɫɤɢɯ ɨɩɭɯɨɥɹɯ ɝɨɥɨɜɧɨɝɨ ɦɨɡɝɚ, ɜɨɡɧɢɤɲɢɯ ɢɡ ɚɧɝɢɨɫɚɪɤɨɦɵ, ɤɚɪɰɢɧɨɦ ɩɨɱɤɢ, ɦɟɥɚɧɨɦ ɢ ɚɞɟɧɨɤɚɪɰɢɧɨɦ, ɫɜɢɞɟɬɟɥɶɫɬɜɭɟɬ ɨ ɟɝɨ ɜɵɫɨɤɨɣ ɚɤɬɢɜɧɨɫɬɢ ɜ ɦɟɬɚɫɬɚɡɚɯ ɨɩɭɯɨɥɟɣ ɱɟɥɨɜɟɤɚ. ɉɪɢ ɥɨɤɚɥɢɡɚɰɢɢ ɢɫɫɥɟɞɨɜɚɧɢɢ ɛɨɥɶɲɨɟ ɚɤɬɢɜɧɨɫɬɢ ɜɧɢɦɚɧɢɟ VEGF-A ɭɞɟɥɹɥɨɫɶ ɜ ɩɨɢɫɤɭ ɨɩɭɯɨɥɹɯ ɪɚɡɥɢɱɧɨɣ ɤɨɪɪɟɥɹɰɢɣ ɦɟɠɞɭ ɷɤɫɩɪɟɫɫɢɟɣ ɷɬɨɝɨ ɮɚɤɬɨɪɚ ɪɨɫɬɚ ɢ ɬɚɤɢɦɢ ɤɥɢɧɢɱɟɫɤɢɦɢ ɯɚɪɚɤɬɟɪɢɫɬɢɤɚɦɢ ɤɚɤ ɪɚɡɦɟɪ ɢ ɫɬɚɞɢɹ ɪɚɡɜɢɬɢɹ ɨɩɭɯɨɥɢ, ɧɚɥɢɱɢɟ ɦɟɬɚɫɬɚɡɨɜ. ȼ ɪɚɛɨɬɟ Maeda K. ɢ ɫɨɚɜɬ. ɩɪɢ ɫɨɩɨɫɬɚɜɥɟɧɢɢ ɷɤɫɩɪɟɫɫɢɢ VEGF-A ɫ ɪɹɞɨɦ ɤɥɢɧɢɱɟɫɤɢɯ ɩɨɤɚɡɚɬɟɥɟɣ ɭ ɛɨɥɶɧɵɯ ɪɚɤɨɦ ɠɟɥɭɞɤɚ ɛɵɥɢ ɭɫɬɚɧɨɜɥɟɧɵ ɤɨɪɪɟɥɹɰɢɢ ɦɟɠɞɭ ɤɨɥɢɱɟɫɬɜɨɦ ɛɟɥɤɚ ɷɬɨɝɨ ɮɚɤɬɨɪɚ ɪɨɫɬɚ ɢ ɦɟɬɚɫɬɚɡɢɪɨɜɚɧɢɟɦ ɜ ɥɢɦɮɨɭɡɥɵ [36]. ɉɨɜɵɲɟɧɧɨɟ ɤɨɥɢɱɟɫɬɜɨ ɮɚɤɬɨɪɚ ɪɨɫɬɚ VEGF-A ɬɚɤɠɟ ɛɵɥɨ ɫɜɹɡɚɧɨ ɫ ɯɭɞɲɢɦ 12 ɩɪɨɝɧɨɡɨɦ. Ⱥɧɚɥɨɝɢɱɧɵɟ ɤɨɪɪɟɥɹɰɢɢ ɦɟɠɞɭ ɷɤɫɩɪɟɫɫɢɟɣ ɛɟɥɤɚ VEGF-A, ɦɟɬɚɫɬɚɡɢɪɨɜɚɧɢɟɦ ɢ ɩɪɨɝɧɨɡɨɦ ɛɵɥɢ ɩɨɥɭɱɟɧɵ ɩɪɢ ɢɫɫɥɟɞɨɜɚɧɢɢ ɩɥɨɫɤɨɤɥɟɬɨɱɧɨɝɨ ɪɚɤɚ ɩɢɳɟɜɨɞɚ [37], ɦɟɥɚɧɨɦɵ [38] ɢ ɪɹɞɚ ɞɪɭɝɢɯ ɡɥɨɤɚɱɟɫɬɜɟɧɧɵɯ ɧɨɜɨɨɛɪɚɡɨɜɚɧɢɣ ɱɟɥɨɜɟɤɚ. Ȼɨɥɶɲɨɟ ɤɨɥɢɱɟɫɬɜɨ ɢɫɫɥɟɞɨɜɚɧɢɣ ɛɵɥɨ ɩɨɫɜɹɳɟɧɨ ɜɵɹɜɥɟɧɢɸ ɤɨɪɪɟɥɹɰɢɣ ɦɟɠɞɭ ɷɤɫɩɪɟɫɫɢɟɣ VEGF-Ⱥ ɢ ɤɥɢɧɢɱɟɫɤɢɦɢ ɩɨɤɚɡɚɬɟɥɹɦɢ ɩɪɢ ɪɚɤɟ ɦɨɥɨɱɧɨɣ ɠɟɥɟɡɵ (ɫɦ., ɧɚɩɪɢɦɟɪ, ɨɛɡɨɪ Gasparini G. [39]). ȼ ɷɬɢɯ ɪɚɛɨɬɚɯ ɬɚɤɠɟ ɜɵɹɜɥɹɥɢɫɶ ɤɨɪɪɟɥɹɰɢɢ ɦɟɠɞɭ ɷɤɫɩɪɟɫɫɢɟɣ VEGF-Ⱥ ɢ ɦɟɬɚɫɬɚɡɢɪɨɜɚɧɢɟɦ. ȼɨ ɦɧɨɝɢɯ ɪɚɛɨɬɚɯ ɨɬɦɟɱɚɥɚɫɶ ɜɡɚɢɦɨɫɜɹɡɶ ɦɟɠɞɭ ɩɨɜɵɲɟɧɧɵɦ ɭɪɨɜɧɟɦ ɷɤɫɩɪɟɫɫɢɢ VEGF-Ⱥ ɜ ɨɩɭɯɨɥɢ ɢ ɬɚɤɢɦɢ ɤɥɢɧɢɱɟɫɤɢɦɢ ɩɨɤɚɡɚɬɟɥɹɦɢ ɤɚɤ ɩɪɨɞɨɥɠɢɬɟɥɶɧɨɫɬɶ ɛɟɡɪɟɰɢɞɢɜɧɨɝɨ ɜɪɟɦɟɧɢ ɠɢɡɧɢ ɢ ɨɛɳɚɹ ɜɵɠɢɜɚɟɦɨɫɬɶ ɛɨɥɶɧɵɯ. ɉɪɢɱɟɦ, VEGF-Ⱥ ɯɚɪɚɤɬɟɪɢɡɨɜɚɥɫɹ ɤɚɤ ɡɧɚɱɚɳɢɣ ɢ ɧɟɡɚɜɢɫɢɦɵɣ ɩɨɤɚɡɚɬɟɥɶ, ɧɚɪɹɞɭ ɫ ɬɚɤɢɦɢ ɩɨɤɚɡɚɬɟɥɹɦɢ ɤɚɤ ɪɚɡɦɟɪ ɨɩɭɯɨɥɢ, ɫɬɚɬɭɫ ɥɢɦɮɨɭɡɥɨɜ, ɷɤɫɩɪɟɫɫɢɹ ɪɟɰɟɩɬɨɪɨɜ ɷɫɬɪɨɝɟɧɚ. ɉɨɥɭɱɟɧɧɵɟ ɞɚɧɧɵɟ ɭɤɚɡɵɜɚɥɢ ɧɚ ɬɨ, ɱɬɨ VEGF-Ⱥ ɦɨɠɟɬ ɧɟ ɬɨɥɶɤɨ ɫɥɭɠɢɬɶ ɧɟɡɚɜɢɫɢɦɵɦ ɩɪɨɝɧɨɫɬɢɱɟɫɤɢɦ ɩɨɤɚɡɚɬɟɥɟɦ, ɧɨ ɢ ɩɪɟɞɫɬɚɜɥɹɬɶ ɫɨɛɨɣ ɜɚɠɧɭɸ ɦɢɲɟɧɶ ɞɥɹ ɪɚɡɪɚɛɨɬɤɢ ɚɧɬɢɚɧɝɢɨɝɟɧɧɵɯ ɥɟɤɚɪɫɬɜɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ. ɗɤɫɩɪɟɫɫɢɹ ɜ ɨɩɭɯɨɥɟɜɨɣ ɬɤɚɧɢ VEGFR2, ɨɫɧɨɜɧɨɝɨ ɮɭɧɤɰɢɨɧɚɥɶɧɨɝɨ ɪɟɰɟɩɬɨɪɚ VEGF-Ⱥ, ɬɚɤɠɟ ɦɨɠɟɬ ɪɚɫɫɦɚɬɪɢɜɚɬɶɫɹ ɤɚɤ ɨɞɢɧ ɢɡ ɜɚɠɧɵɯ ɩɪɨɝɧɨɫɬɢɱɟɫɤɢɯ ɮɚɤɬɨɪɨɜ. Ɍɚɤ, ɧɚɩɪɢɦɟɪ, Takahashi Y. ɢ ɫɨɬɪ. ɢɫɫɥɟɞɨɜɚɥɢ ɷɤɫɩɪɟɫɫɢɸ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF-Ⱥ, bFGF ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ KDR (VEGFR2), FLT1 (VEGFR1), BEC ɢ FLG ɜ ɤɚɪɰɢɧɨɦɚɯ ɢ ɚɞɟɧɨɦɚɯ ɬɨɥɫɬɨɣ ɤɢɲɤɢ ɱɟɥɨɜɟɤɚ [40]. ɂɡ ɜɫɟɯ ɢɫɫɥɟɞɨɜɚɧɧɵɯ ɜ ɷɬɨɣ ɪɚɛɨɬɟ ɩɨɤɚɡɚɬɟɥɟɣ ɬɨɥɶɤɨ ɷɤɫɩɪɟɫɫɢɹ ɮɚɤɬɨɪɚ ɪɨɫɬɚ VEGF-Ⱥ ɢ ɪɟɰɟɩɬɨɪɚ VEGFR2 ɤɨɪɪɟɥɢɪɨɜɚɥɚ ɫɨ ɫɬɚɞɢɟɣ ɡɚɛɨɥɟɜɚɧɢɹ. ɉɪɢɱɟɦ, ɟɫɥɢ ɜ ɫɥɭɱɚɟ VEGF-Ⱥ ɢɧɬɟɧɫɢɜɧɨɫɬɶ ɷɤɫɩɪɟɫɫɢɢ ɛɵɥɚ ɜɵɲɟ ɜ ɦɟɬɚɫɬɚɡɢɪɭɸɳɢɯ ɨɩɭɯɨɥɹɯ, ɧɨ ɧɟ ɪɚɡɥɢɱɚɥɚɫɶ ɜ ɧɟɦɟɬɚɫɬɚɡɢɪɭɸɳɢɯ ɨɩɭɯɨɥɹɯ ɢ ɚɞɟɧɨɦɚɯ, ɬɨ ɜ ɫɥɭɱɚɟ VEGFR2 ɜ ɚɞɟɧɨɦɚɯ ɛɵɥ ɜɵɹɜɥɟɧ 1% VEGFR2-ɩɨɥɨɠɢɬɟɥɶɧɵɯ ɨɩɭɯɨɥɟɣ, ɜ ɧɟɦɟɬɚɫɬɚɡɢɪɭɸɳɢɯ ɤɚɪɰɢɧɨɦɚɯ – 28,6%, ɚ ɜ ɦɟɬɚɫɬɚɡɢɪɭɸɳɢɯ ɤɚɪɰɢɧɨɦɚɯ – 62,5%. 13 ɂɫɬɨɱɧɢɤɨɦ ɩɨɜɵɲɟɧɧɨɝɨ ɤɨɥɢɱɟɫɬɜɚ VEGF-Ⱥ ɜ ɨɩɭɯɨɥɹɯ ɹɜɥɹɸɬɫɹ ɫɚɦɢ ɨɩɭɯɨɥɟɜɵɟ ɤɥɟɬɤɢ. ȼ ɰɟɥɨɦ ɪɹɞɟ ɪɚɛɨɬ ɩɪɨɞɟɦɨɧɫɬɪɢɪɨɜɚɧɚ ɢɧɞɭɤɰɢɹ ɷɤɫɩɪɟɫɫɢɢ VEGF-Ⱥ ɜ ɤɥɟɬɤɚɯ ɜ ɭɫɥɨɜɢɹɯ ɝɢɩɨɤɫɢɢ, ɯɚɪɚɤɬɟɪɧɨɣ ɞɥɹ ɨɩɭɯɨɥɟɜɨɣ ɬɤɚɧɢ. ɗɤɫɩɪɟɫɫɢɹ ɠɟ ɪɟɰɟɩɬɨɪɨɜ VEGF-Ⱥ, ɤɚɤ ɩɪɟɞɩɨɥɚɝɚɥɨɫɶ, ɩɪɢɫɭɳɚ ɢɫɤɥɸɱɢɬɟɥɶɧɨ ɤɥɟɬɤɚɦ ɷɧɞɨɬɟɥɢɹ ɫɨɫɭɞɨɜ. Ɉɞɧɚɤɨ ɜ ɞɚɥɶɧɟɣɲɟɦ ɛɵɥɨ ɨɛɧɚɪɭɠɟɧɨ, ɱɬɨ ɜ ɤɥɟɬɤɚɯ ɨɩɭɯɨɥɟɣ ɷɤɫɩɪɟɫɫɢɪɨɜɚɧ ɧɟ ɬɨɥɶɤɨ ɮɚɤɬɨɪ ɪɨɫɬɚ VEGF-Ⱥ, ɧɨ ɢ ɟɝɨ ɪɟɰɟɩɬɨɪɵ. ȼ ɧɚɲɟɣ ɪɚɛɨɬɟ ɩɪɢ ɢɫɫɥɟɞɨɜɚɧɢɢ ɷɤɫɩɪɟɫɫɢɢ ɪɟɰɟɩɬɨɪɚ VEGFR3 ɜ ɨɛɪɚɡɰɚɯ ɫ ɪɚɡɥɢɱɧɨɣ ɩɚɬɨɥɨɝɢɟɣ ɳɢɬɨɜɢɞɧɨɣ ɠɟɥɟɡɵ ɱɟɥɨɜɟɤɚ ɩɨɥɨɠɢɬɟɥɶɧɨ ɨɤɪɚɲɟɧɧɵɦɢ ɧɚ VEGFR3 ɛɵɥɢ ɧɟ ɬɨɥɶɤɨ ɤɥɟɬɤɢ ɷɧɞɨɬɟɥɢɹ ɫɨɫɭɞɨɜ, ɧɨ ɢ ɤɥɟɬɤɢ ɚɞɟɧɨɦɵ ɢ ɚɞɟɧɨɤɚɪɰɢɧɨɦɵ ɳɢɬɨɜɢɞɧɨɣ ɠɟɥɟɡɵ (Ɋɢɫ. 3) [44]. Ⱥ Ȼ Ɋɢɫ. 3. ɗɤɫɩɪɟɫɫɢɹ VEGFR3 (FLT4) ɜ ɨɩɭɯɨɥɹɯ ɳɢɬɨɜɢɞɧɨɣ ɠɟɥɟɡɵ ɱɟɥɨɜɟɤɚ; ɪɚɡɦɟɪ ɩɪɢɜɟɞɟɧɧɨɣ ɧɚ ɪɢɫɭɧɤɟ ɲɤɚɥɵ ɫɨɫɬɚɜɥɹɟɬ 40 ȝɦ. Ⱥ. Ⱥɞɟɧɨɦɚ ɳɢɬɨɜɢɞɧɨɣ ɠɟɥɟɡɵ. Ȼ. Ⱥɞɟɧɨɤɚɪɰɢɧɨɦɚ ɳɢɬɨɜɢɞɧɨɣ ɠɟɥɟɡɵ. Ʉɨ-ɷɤɫɩɪɟɫɫɢɹ VEGF-Ⱥ ɢ ɟɝɨ ɪɟɰɟɩɬɨɪɚ VEGFR2 (KDR) ɛɵɥɚ ɨɛɧɚɪɭɠɟɧɚ ɜ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɤɚɯ ɤɚɪɰɢɧɨɦɵ ɹɢɱɧɢɤɚ [41] ɢ ɜ ɤɥɟɬɤɚɯ ɫɚɪɤɨɦɵ Ʉɚɩɨɲɢ [42], ɷɤɫɩɪɟɫɫɢɹ ɪɟɰɟɩɬɨɪɨɜ VEGFR1 ɢ VEGFR2 ɩɪɨɞɟɦɨɧɫɬɪɢɪɨɜɚɧɚ ɜ ɤɥɟɬɤɚɯ ɝɥɢɨɦɵ, ɩɥɨɫɤɨɤɥɟɬɨɱɧɨɣ ɤɚɪɰɢɧɨɦɵ ɝɨɥɨɜɵ ɢ ɲɟɢ, ɦɟɥɚɧɨɦɵ [43]. 14 ɗɤɫɩɪɟɫɫɢɹ ɪɟɰɟɩɬɨɪɚ VEGFR3 ɜ ɤɥɟɬɤɚɯ ɫɚɪɤɨɦɵ Ʉɚɩɨɲɢ ɛɵɥɚ ɜɵɹɜɥɟɧɚ ɫ ɩɨɦɨɳɶɸ ɢɦɦɭɧɨɝɢɫɬɨɯɢɦɢɱɟɫɤɨɝɨ ɚɧɚɥɢɡɚ ɢ ɜ ɨɞɧɨɣ ɢɡ ɧɚɲɢɯ ɪɚɛɨɬ (Ɋɢɫ. 4) [45]. Ɋɢɫ. 4. ɗɤɫɩɪɟɫɫɢɹ ɪɟɰɟɩɬɨɪɚ VEGFR3 ɜ ɨɛɪɚɡɰɚɯ ɫɚɪɤɨɦɵ Ʉɚɩɨɲɢ ɱɟɥɨɜɟɤɚ. Ⱥ. VEGFR3 ɥɨɤɚɥɢɡɨɜɚɧ ɜ ɤɥɟɬɤɚɯ ɷɧɞɨɬɟɥɢɹ ɫɨɫɭɞɨɜ; ɯ 200. ȼ, ɋ. ɗɤɫɩɪɟɫɫɢɹ VEGFR3 ɜ ɜɟɪɟɬɟɧɨɜɢɞɧɵɯ ɤɥɟɬɤɚɯ ɫɚɪɤɨɦɵ Ʉɚɩɨɲɢ; ɯ 100 (ȼ), ɯ 400 (ɋ). Ɉɞɧɨɜɪɟɦɟɧɧɚɹ ɷɤɫɩɪɟɫɫɢɹ ɜ ɤɥɟɬɤɚɯ ɨɩɭɯɨɥɢ ɤɚɤ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ, ɬɚɤ ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ ɜɵɫɜɟɱɢɜɚɟɬ ɧɨɜɭɸ ɪɨɥɶ VEGF-ɫɢɝɧɚɥɢɧɝɚ ɜ ɪɚɡɜɢɬɢɢ ɡɥɨɤɚɱɟɫɬɜɟɧɧɵɯ ɧɨɜɨɨɛɪɚɡɨɜɚɧɢɣ. Ʉɨ-ɷɤɫɩɪɟɫɫɢɹ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ ɜ ɤɥɟɬɤɚɯ ɨɩɭɯɨɥɢ ɦɨɠɟɬ ɩɪɢɜɨɞɢɬɶ ɤ ɫɬɢɦɭɥɹɰɢɢ ɪɚɡɦɧɨɠɟɧɢɹ ɫɚɦɢɯ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ ɩɨ ɚɭɬɨɤɪɢɧɧɨɦɭ ɦɟɯɚɧɢɡɦɭ. ȼ ɬɚɤɨɦ ɫɥɭɱɚɟ, VEGFɡɚɜɢɫɢɦɚɹ ɫɢɝɧɚɥɶɧɚɹ ɫɢɫɬɟɦɚ ɛɭɞɟɬ ɜɧɨɫɢɬɶ ɫɜɨɣ ɜɤɥɚɞ ɜ ɩɨɞɞɟɪɠɚɧɢɟ ɜɵɠɢɜɚɟɦɨɫɬɢ ɢ ɪɚɡɦɧɨɠɟɧɢɹ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ ɧɟ ɬɨɥɶɤɨ ɡɚ ɫɱɟɬ ɮɨɪɦɢɪɨɜɚɧɢɹ ɜ ɬɤɚɧɢ ɨɩɭɯɨɥɢ ɧɨɜɨɣ ɫɨɫɭɞɢɫɬɨɣ ɫɢɫɬɟɦɵ, ɧɨ ɢ ɫɬɢɦɭɥɢɪɭɹ ɪɚɡɦɧɨɠɟɧɢɟ ɫɚɦɢɯ ɤɥɟɬɨɤ ɨɩɭɯɨɥɢ. ɂ ɛɥɨɤɢɪɨɜɚɧɢɟ ɚɤɬɢɜɧɨɫɬɢ ɷɬɨɣ ɫɢɝɧɚɥɶɧɨɣ ɫɢɫɬɟɦɵ ɦɨɠɟɬ ɫɞɟɪɠɢɜɚɬɶ ɪɨɫɬ ɨɩɭɯɨɥɢ ɧɟ ɬɨɥɶɤɨ ɡɚ ɫɱɟɬ ɢɧɝɢɛɢɪɨɜɚɧɢɹ ɧɟɨ-ɚɧɝɢɨɝɟɧɟɡɚ, ɧɨ ɢ ɛɥɚɝɨɞɚɪɹ ɩɨɞɚɜɥɟɧɢɸ ɪɚɡɦɧɨɠɟɧɢɹ ɫɚɦɢɯ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ. ɗɮɮɟɤɬ ɬɨɪɦɨɠɟɧɢɹ ɩɪɨɥɢɮɟɪɚɰɢɢ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ ɜ ɪɟɡɭɥɶɬɚɬɟ ɢɧɝɢɛɢɪɨɜɚɧɢɹ ɜɡɚɢɦɨɞɟɣɫɬɜɢɹ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF-C ɢ VEGF-D ɫɨ ɫɜɨɢɦ 15 ɫɩɟɰɢɮɢɱɟɫɤɢɦ ɪɟɰɟɩɬɨɪɨɦ VEGFR3 ɛɵɥ ɩɪɨɞɟɦɨɧɫɬɪɢɪɨɜɚɧ ɜ ɧɚɲɟɣ ɪɚɛɨɬɟ [46]. ȼ ɤɭɥɶɬɭɪɟ ɤɥɟɬɨɤ ɤɚɪɰɢɧɨɦɵ ɥɟɝɤɨɝɨ ɱɟɥɨɜɟɤɚ Ⱥ549 ɧɚɛɥɸɞɚɥɚɫɶ ɤɨɷɤɫɩɪɟɫɫɢɹ ɦɊɇɄ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF-C ɢ VEGF-D ɢ ɢɯ ɪɟɰɟɩɬɨɪɚ VEGFR3(FLT4). ȼ ɤɭɥɶɬɭɪɚɥɶɧɭɸ ɫɪɟɞɭ ɤɥɟɬɨɤ Ⱥ549 ɞɨɛɚɜɥɹɥɫɹ ɪɚɫɬɜɨɪɢɦɵɣ ɪɟɤɨɦɛɢɧɚɧɬɧɵɣ ɛɟɥɨɤ sFLT4, ɩɪɟɞɫɬɚɜɥɹɸɳɢɣ ɫɨɛɨɣ ɪɟɰɟɩɬɨɪɧɵɣ ɞɨɦɟɧ VEGFR3 (ɩɪɟɠɧɟɟ ɧɚɡɜɚɧɢɟ sFLT4), ɩɪɢɫɨɟɞɢɧɟɧɧɵɣ ɤ Fc-ɨɛɥɚɫɬɢ ɌɄ-1 Ɋɟɰɟɩɬɨɪɧɚɹ ɨɛɥɚɫɬɶ FLT4 Ɋɟɰɟɩɬɨɪɧɚɹ ɨɛɥɚɫɬɶ ɢɦɦɭɧɨɝɥɨɛɭɥɢɧɚ IgG1 ɱɟɥɨɜɟɤɚ (Ɋɢɫ.5). + Fc-ɨɛɥɚɫɬɶ Fc-ɨɛɥɚɫɬɶ IgG1 ɌɄ-2 VEGFR3 (FLT4) IgG1 sFLT4 Ɋɢɫ.5 ɋɯɟɦɚɬɢɱɟɫɤɨɟ ɢɡɨɛɪɚɠɟɧɢɟ ɫɬɪɭɤɬɭɪɵ ɪɟɤɨɦɛɢɧɚɧɬɧɨɝɨ ɛɟɥɤɚ sFLT4. Ɋɟɤɨɦɛɢɧɚɧɬɧɵɣ ɛɟɥɨɤ sFLT4 ɩɪɢ ɞɨɛɚɜɥɟɧɢɢ ɤ ɤɭɥɶɬɭɪɟ ɤɥɟɬɨɤ Ⱥ549 ɫɜɹɡɵɜɚɥ ɮɚɤɬɨɪɵ ɪɨɫɬɚ VEGF-C ɢ VEGF-D, ɹɜɥɹɸɳɢɟɫɹ ɥɢɝɚɧɞɚɦɢ ɪɟɰɟɩɬɨɪɚ VEGFR3, ɱɬɨ ɩɪɢɜɨɞɢɥɨ ɤ ɤɨɧɤɭɪɟɧɬɧɨɦɭ ɢɧɝɢɛɢɪɨɜɚɧɢɸ ɜɡɚɢɦɨɞɟɣɫɬɜɢɹ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF-ɋ ɢ VEGF-D ɫ ɪɟɰɟɩɬɨɪɨɦ (Ɋɢɫ.6). 16 VEGF-C VEGF-D sFLT4 Ʉɥɟɬɨɱɧɚɹ ɦɟɦɛɪɚɧɚ VEGFR3 (FLT4) Ɋɢɫ. 6. Ʉɨɧɤɭɪɟɧɬɧɨɟ ɢɧɝɢɛɢɪɨɜɚɧɢɟ ɜɡɚɢɦɨɞɟɣɫɬɜɢɹ ɪɟɰɟɩɬɨɪɚ VEGFR3 ɫɨ ɫɜɨɢɦɢ ɥɢɝɚɧɞɚɦɢ ɩɪɢ ɞɨɛɚɜɥɟɧɢɢ ɜ ɤɭɥɶɬɭɪɚɥɶɧɭɸ ɫɪɟɞɭ ɤɥɟɬɨɤ Ⱥ549 ɪɟɤɨɦɛɢɧɚɧɬɧɨɝɨ ɛɟɥɤɚ sFLT4. ȼ ɪɟɡɭɥɶɬɚɬɟ ɚɤɬɢɜɧɨɫɬɶ ɪɚɡɦɧɨɠɟɧɢɹ ɤɥɟɬɨɤ Ⱥ549 ɫɧɢɠɚɥɚɫɶ ɧɚ 40-60% (Ɋɢɫ. 7). Ⱦɨɛɚɜɥɟɧɢɟ ɞɟɧɚɬɭɪɢɪɨɜɚɧɧɨɝɨ ɛɟɥɤɚ sFLT4, ɜɡɹɬɨɝɨ ɜ ɤɚɱɟɫɬɜɟ ɤɨɧɬɪɨɥɹ, ɧɚ ɪɚɡɦɧɨɠɟɧɢɢ ɤɥɟɬɨɤ ɩɪɚɤɬɢɱɟɫɤɢ ɧɟ ɫɤɚɡɵɜɚɥɨɫɶ. 17 Ʉɨɥɢɱɟɫɬɜɨ ɤɥɟɬɨɤ, % ɨɬ ɤɨɧɬɪɨɥɹ 140 120 100 80 60 40 20 ɧɝ/ɦɥ 0 0 10 sFLT4 100 200 sFLT4 ɞɟɧɚɬɭɪɢɪɨɜɚɧɧɵɣ Ɋɢɫ. 7. ȼɥɢɹɧɢɟ ɞɨɛɚɜɥɟɧɢɹ ɛɟɥɤɚ sFLT4 ɧɚ ɪɚɡɦɧɨɠɟɧɢɟ ɤɥɟɬɨɤ Ⱥ 549 ɢ Ⱥ 431. Ɍɨɬ ɮɚɤɬ, ɱɬɨ ɢɧɝɢɛɢɪɨɜɚɧɢɟ VEGFR3-ɡɚɜɢɫɢɦɨɝɨ ɫɢɝɧɚɥɶɧɨɝɨ ɩɭɬɢ ɩɪɚɤɬɢɱɟɫɤɢ ɜ 2 ɪɚɡɚ ɫɧɢɡɢɥ ɩɪɨɥɢɮɟɪɚɬɢɜɧɭɸ ɚɤɬɢɜɧɨɫɬɶ ɤɥɟɬɨɤ Ⱥ549, ɨɤɚɡɚɥɫɹ ɜ ɤɚɤɨɣ-ɬɨ ɫɬɟɩɟɧɢ ɧɟɨɠɢɞɚɧɧɵɦ, ɩɨɫɤɨɥɶɤɭ ɜ ɤɥɟɬɤɚɯ ɜɫɟɝɞɚ ɫɭɳɟɫɬɜɭɟɬ ɰɟɥɵɣ ɪɹɞ ɫɢɝɧɚɥɶɧɵɯ ɩɭɬɟɣ, ɪɟɝɭɥɢɪɭɸɳɢɯ ɢɯ ɪɚɡɦɧɨɠɟɧɢɟ. Ɉɞɧɚɤɨ ɩɨɥɭɱɟɧɧɵɟ ɧɚɦɢ ɞɚɧɧɵɟ ɫɜɢɞɟɬɟɥɶɫɬɜɭɸɬ ɜ ɩɨɥɶɡɭ ɬɨɝɨ, ɱɬɨ ɜ ɤɥɟɬɤɚɯ, ɤɨ-ɷɤɫɩɪɟɫɫɢɪɭɸɳɢɯ VEGFR3 ɢ ɜɡɚɢɦɨɞɟɣɫɬɜɭɸɳɢɟ ɫ ɷɬɢɦ ɪɟɰɟɩɬɨɪɨɦ ɮɚɤɬɨɪɵ, ɜɤɥɚɞ ɷɬɨɣ ɫɢɝɧɚɥɶɧɨɣ ɫɢɫɬɟɦɵ ɜ ɪɟɝɭɥɹɰɢɸ ɪɚɡɦɧɨɠɟɧɢɹ ɤɥɟɬɨɤ ɦɨɠɟɬ ɛɵɬɶ ɜɟɫɶɦɚ ɡɧɚɱɢɬɟɥɶɧɵɦ. Ɉɛɧɚɪɭɠɟɧɢɟ ɤɨ-ɷɤɫɩɪɟɫɫɢɢ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ ɜ ɫɚɦɢɯ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɤɚɯ ɦɨɝɥɨ ɫɬɚɬɶ ɞɨɩɨɥɧɢɬɟɥɶɧɵɦ ɫɬɢɦɭɥɨɦ ɞɥɹ ɪɚɡɪɚɛɨɬɤɢ ɧɨɜɵɯ ɥɟɤɚɪɫɬɜɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ, ɧɚɩɪɚɜɥɟɧɧɵɯ ɧɚ ɩɨɞɚɜɥɟɧɢɟ VEGF-ɫɢɝɧɚɥɢɧɝɚ. 18 Ʌɟɤɚɪɫɬɜɟɧɧɵɟ ɩɪɟɩɚɪɚɬɵ, ɨɫɧɨɜɚɧɧɵɟ ɧɚ ɢɧɝɢɛɢɪɨɜɚɧɢɢ VEGFɡɚɜɢɫɢɦɵɯ ɫɢɝɧɚɥɶɧɵɯ ɫɢɫɬɟɦ ɉɟɪɜɵɟ ɫɢɧɬɟɡɢɪɨɜɚɧɧɵɟ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɟ ɥɟɤɚɪɫɬɜɟɧɧɵɟ ɩɪɟɩɚɪɚɬɵ ɛɵɥɢ ɧɚɩɪɚɜɥɟɧɵ ɧɚ ɩɨɞɚɜɥɟɧɢɟ, ɩɪɟɠɞɟ ɜɫɟɝɨ, ɫɢɝɧɚɥɶɧɨɝɨ ɩɭɬɢ VEGFA/VEGFR2, ɜɨɡɞɟɣɫɬɜɭɹ ɧɚ ɤɨɬɨɪɵɣ ɦɨɠɧɨ ɛɵɥɨ ɛɵ ɡɚɛɥɨɤɢɪɨɜɚɬɶ ɪɨɫɬ ɫɨɫɭɞɨɜ ɨɩɭɯɨɥɢ. ɂ ɞɟɣɫɬɜɢɬɟɥɶɧɨ, ɧɚ ɦɨɞɟɥɹɯ ɷɤɫɩɟɪɢɦɟɧɬɚɥɶɧɨɝɨ ɪɚɤɚ ɛɵɥɨ ɩɨɤɚɡɚɧɨ, ɱɬɨ ɢɧɝɢɛɢɪɨɜɚɧɢɟ VEGF-Ⱥ/VEGFR2 ɫɢɝɧɚɥɢɧɝɚ ɫ ɩɨɦɨɳɶɸ ɚɧɬɢɬɟɥ ɤ VEGF-Ⱥ ɢɥɢ ɤ ɪɟɰɟɩɬɨɪɭ VEGFR2 ɩɪɢɜɨɞɢɬ ɤ ɭɦɟɧɶɲɟɧɢɸ ɜɚɫɤɭɥɹɪɢɡɚɰɢɢ ɨɩɭɯɨɥɟɣ ɢ ɬɨɪɦɨɠɟɧɢɸ ɢɯ ɪɨɫɬɚ [47, 48]. ɗɬɢ ɞɚɧɧɵɟ ɩɨɫɥɭɠɢɥɢ ɨɫɧɨɜɚɧɢɟɦ ɞɥɹ ɪɚɡɪɚɛɨɬɤɢ ɫɨɨɬɜɟɬɫɬɜɭɸɳɢɯ ɩɪɨɬɢɜɨɨɩɭɯɨɥɟɜɵɯ ɥɟɤɚɪɫɬɜɟɧɧɵɯ ɫɪɟɞɫɬɜ. ɉɟɪɜɵɦ ɤɨɦɦɟɪɱɟɫɤɢɦ ɥɟɤɚɪɫɬɜɟɧɧɵɦ ɫɪɟɞɫɬɜɨɦ, ɧɚɩɪɚɜɥɟɧɧɵɦ ɧɚ ɢɧɝɢɛɢɪɨɜɚɧɢɟ ɡɚɜɢɫɢɦɨɝɨ ɨɬ VEGF-A ɫɢɝɧɚɥɶɧɨɝɨ ɩɭɬɢ ɛɵɥ ɫɨɡɞɚɧɧɵɣ ɤɨɦɩɚɧɢɟɣ Genentech/Roche ɩɪɟɩɚɪɚɬ Avastin (Bevacizumab), ɩɪɟɞɫɬɚɜɥɹɸɳɢɣ ɫɨɛɨɣ ɦɨɧɨɤɥɨɧɚɥɶɧɵɟ ɚɧɬɢɬɟɥɚ, ɫɜɹɡɵɜɚɸɳɢɟ VEGF-A ɱɟɥɨɜɟɤɚ [49]. ɉɪɟɩɚɪɚɬ ɛɵɥ ɜɩɟɪɜɵɟ ɨɩɪɨɛɨɜɚɧ ɜ 2004 ɝ. ɜ ɤɨɦɛɢɧɚɰɢɢ ɫɨ ɫɬɚɧɞɚɪɬɧɨɣ ɯɢɦɢɨɬɟɪɚɩɢɟɣ ɩɪɢ ɥɟɱɟɧɢɢ ɦɟɬɚɫɬɚɡɢɪɭɸɳɟɝɨ ɪɚɤɚ ɬɨɥɫɬɨɣ ɤɢɲɤɢ ɢ ɧɟɦɟɥɤɨɤɥɟɬɨɱɧɨɝɨ ɪɚɤɚ ɥɟɝɤɨɝɨ. ȼ ɞɚɥɶɧɟɣɲɟɦ Avastin, ɤɚɤ ɩɪɚɜɢɥɨ, ɜ ɤɨɦɛɢɧɚɰɢɢ ɫ ɯɢɦɢɨɬɟɪɚɩɢɟɣ, ɩɪɢɦɟɧɹɥɢ ɩɪɢ ɥɟɱɟɧɢɢ ɧɟɦɟɬɚɫɬɚɡɢɪɭɸɳɟɝɨ ɪɚɤɚ ɦɨɥɨɱɧɨɣ ɠɟɥɟɡɵ, ɤɚɪɰɢɧɨɦɵ ɩɨɱɤɢ, ɦɭɥɶɬɢɮɨɪɦɧɨɣ ɝɥɢɨɛɥɚɫɬɨɦɵ, ɪɚɤɚ ɹɢɱɧɢɤɚ ɢ ɧɟɤɨɬɨɪɵɯ ɞɪɭɝɢɯ ɮɨɪɦ ɪɚɤɚ. ȿɳɟ ɨɞɢɧ ɤɥɚɫɫ ɩɪɟɩɚɪɚɬɨɜ, ɧɚɩɪɚɜɥɟɧɧɵɯ ɧɚ ɩɨɞɚɜɥɟɧɢɟ ɚɧɝɢɨɝɟɧɟɡɚ, ɛɵɥ ɪɚɡɪɚɛɨɬɚɧ ɧɚ ɨɫɧɨɜɟ ɧɟɛɨɥɶɲɢɯ ɩɨ ɪɚɡɦɟɪɭ ɦɨɥɟɤɭɥ, ɢɧɝɢɛɢɪɭɸɳɢɯ ɬɢɪɨɡɢɧɤɢɧɚɡɧɭɸ ɚɤɬɢɜɧɨɫɬɶ ɪɟɰɟɩɬɨɪɨɜ VEGF-Ⱥ. ȼɚɠɧɵɦ ɩɪɟɢɦɭɳɟɫɬɜɨɦ ɩɪɟɩɚɪɚɬɨɜ, ɧɚɩɪɚɜɥɟɧɧɵɯ ɧɚ ɩɨɞɚɜɥɟɧɢɟ ɚɤɬɢɜɧɨɫɬɢ ɪɟɰɟɩɬɨɪɨɜ, ɹɜɥɹɟɬɫɹ ɬɨɬ ɮɚɤɬ, ɱɬɨ ɚɧɬɚɝɨɧɢɫɬɵ VEGF-Ⱥ ɧɟ ɢɧɝɢɛɢɪɭɸɬ ɜɡɚɢɦɨɞɟɣɫɬɜɢɟ ɪɟɰɟɩɬɨɪɨɜ ɫ ɞɪɭɝɢɦɢ ɮɚɤɬɨɪɚɦɢ ɪɨɫɬɚ ɫɟɦɟɣɫɬɜɚ VEGF. ȼ ɷɬɨɦ ɫɥɭɱɚɟ ɫɢɝɧɚɥɶɧɵɟ ɩɭɬɢ VEGF-C,VEGF-D,VEGF-E/VEGFR2 ɢ VEGF-B,PlGF/VEGFR1 ɨɫɬɚɸɬɫɹ ɚɤɬɢɜɧɵɦɢ. ȿɫɥɢ ɠɟ ɩɪɟɩɚɪɚɬ ɩɨɞɚɜɥɹɟɬ ɚɤɬɢɜɧɨɫɬɶ ɪɟɰɟɩɬɨɪɚ, ɬɨ ɨɧ ɛɥɨɤɢɪɭɟɬ ɜɫɸ ɫɜɹɡɚɧɧɭɸ ɫ ɷɬɢɦ ɪɟɰɟɩɬɨɪɨɦ ɫɢɝɧɚɥɶɧɭɸ ɰɟɩɶ. Ʉɪɨɦɟ ɬɨɝɨ, ɤɚɤ ɭɠɟ 19 ɨɬɦɟɱɚɥɨɫɶ ɪɚɧɟɟ, ɫɚɦɢ ɨɩɭɯɨɥɟɜɵɟ ɤɥɟɬɤɢ ɦɨɝɭɬ ɷɤɫɩɪɟɫɫɢɪɨɜɚɬɶ ɪɟɰɟɩɬɨɪɵ VEGF, ɢ ɜ ɷɬɨɦ ɫɥɭɱɚɟ ɫɢɝɧɚɥɶɧɚɹ ɫɢɫɬɟɦɚ VEGF/VEGFR ɦɨɠɟɬ ɜɧɨɫɢɬɶ ɫɭɳɟɫɬɜɟɧɧɵɣ ɜɤɥɚɞ ɜ ɪɟɝɭɥɹɰɢɸ ɪɚɡɦɧɨɠɟɧɢɹ ɫɚɦɢɯ ɤɥɟɬɨɤ ɨɩɭɯɨɥɢ. ɂ, ɫɨɨɬɜɟɬɫɬɜɟɧɧɨ, ɢɧɝɢɛɢɪɨɜɚɧɢɟ ɪɟɰɟɩɬɨɪɨɜ VEGFR ɦɨɠɟɬ ɧɟ ɬɨɥɶɤɨ ɛɥɨɤɢɪɨɜɚɬɶ ɚɧɝɢɨɝɟɧɟɡ ɨɩɭɯɨɥɢ, ɧɨ ɢ ɡɚɦɟɞɥɹɬɶ ɪɚɡɦɧɨɠɟɧɢɟ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ. ɇɚɢɛɨɥɟɟ ɢɡɜɟɫɬɧɵɦɢ ɢɡ ɩɪɟɩɚɪɚɬɨɜ ɷɬɨɝɨ ɤɥɚɫɫɚ ɹɜɥɹɸɬɫɹ ɬɚɤɢɟ ɢɧɝɢɛɢɬɨɪɵ ɬɢɪɨɡɢɧɤɢɧɚɡɧɨɣ ɚɤɬɢɜɧɨɫɬɢ ɪɟɰɟɩɬɨɪɨɜ VEGFR ɢ, ɫɨɨɬɜɟɬɫɬɜɟɧɧɨ, ɫɜɹɡɚɧɧɵɯ ɫ ɷɬɢɦ ɩɨɫɥɟɞɭɸɳɢɯ ɫɨɛɵɬɢɣ ɤɚɤ Vatalanib (PTK787) (ɪɚɡɪɚɛɨɬɚɧ ɤɨɦɩɚɧɢɟɣ Novartis), Sunitinib (SU11248) (ɤɨɦɩɚɧɢɹ Pfizer), Sorafenib (BAY 43-9006) (ɤɨɦɩɚɧɢɢ Bayer AG ɢ Onyx Pharmaceuticals) ɢ Vandetanib (ZD6474) (ɤɨɦɩɚɧɢɹ AstraZeneca) [49, 50, 51]. Ɉɞɧɚɤɨ, ɤɚɤ ɭɠɟ ɨɬɦɟɱɚɥɨɫɶ, ɩɨɫɤɨɥɶɤɭ ɪɟɰɟɩɬɨɪɵ VEGFR ɩɪɢɧɚɞɥɟɠɚɬ ɤ ɫɭɩɟɪɫɟɦɟɣɫɬɜɭ ɪɟɰɟɩɬɨɪɧɵɯ ɬɢɪɨɡɢɧɤɢɧɚɡ, ɜ ɢɯ ɫɬɪɭɤɬɭɪɟ ɢɦɟɸɬɫɹ ɞɨɜɨɥɶɧɨ ɩɪɨɬɹɠɟɧɧɵɟ ɭɱɚɫɬɤɢ ɫ ɜɵɫɨɤɨɣ ɫɬɟɩɟɧɶɸ ɝɨɦɨɥɨɝɢɢ ɫ ɞɪɭɝɢɦɢ ɪɟɰɟɩɬɨɪɚɦɢ ɷɬɨɝɨ ɫɭɩɟɪɫɟɦɟɣɫɬɜɚ, ɨɫɨɛɟɧɧɨ ɜ ɨɛɥɚɫɬɢ ɬɢɪɨɡɢɧɤɢɧɚɡɧɵɯ ɞɨɦɟɧɨɜ (ɫɦ. ɪɢɫ.1). ȼ ɫɜɹɡɢ ɫ ɷɬɢɦ ɩɪɟɩɚɪɚɬɵ, ɧɚɩɪɚɜɥɟɧɧɵɟ ɧɚ ɛɥɨɤɢɪɨɜɚɧɢɟ ɬɢɪɨɡɢɧɤɢɧɚɡɧɨɣ ɚɤɬɢɜɧɨɫɬɢ ɪɟɰɟɩɬɨɪɨɜ VEGF, ɧɟ ɹɜɥɹɸɬɫɹ ɜɵɫɨɤɨɫɩɟɰɢɮɢɱɧɵɦɢ ɢ ɢɧɝɢɛɢɪɭɸɬ ɫɪɚɡɭ ɧɟɫɤɨɥɶɤɨ ɪɟɰɟɩɬɨɪɨɜ ɷɬɨɝɨ ɫɟɦɟɣɫɬɜɚ. Ɍɚɤ, Vatalanib (RTK787/ZK222584) ɹɜɥɹɟɬɫɹ ɫɩɟɰɢɮɢɱɟɫɤɢɦ ɢɧɝɢɛɢɬɨɪɨɦ ɚɤɬɢɜɧɨɫɬɢ ɪɟɰɟɩɬɨɪɚ VEGFR2 ɢ VEGFR1, ɚ ɩɪɢ ɛɨɥɶɲɢɯ ɤɨɧɰɟɧɬɪɚɰɢɹɯ ɩɨɞɚɜɥɹɟɬ ɚɤɬɢɜɧɨɫɬɶ ɪɟɰɟɩɬɨɪɨɜ PDGFR-ȕ ɢ c-Kit; Sunitinib (SU11248) ɢɧɝɢɛɢɪɭɟɬ VEGFR2 ɢ ɪɟɰɟɩɬɨɪ ɬɪɨɦɛɨɰɢɬɚɪɧɨɝɨ ɮɚɤɬɨɪɚ ɪɨɫɬɚ PDGFR-ȕ; Sorafenib (BAY 43-9006), ɹɜɥɹɹɫɶ ɦɨɳɧɵɦ ɢɧɝɢɛɢɬɨɪɨɦ ɪɟɰɟɩɬɨɪɚ Raf-1, ɛɥɨɤɢɪɭɟɬ ɬɚɤɠɟ ɚɤɬɢɜɧɨɫɬɶ ɪɟɰɟɩɬɨɪɚ VEGFR3 ɢ, ɜ ɦɟɧɶɲɟɣ ɫɬɟɩɟɧɢ, ɪɟɰɟɩɬɨɪɨɜ VEGFR2, PDGFR-ȕ ɢ c-Kit; ɚ Vandetanib (ZD6474) ɩɨɞɚɜɥɹɟɬ ɚɤɬɢɜɧɨɫɬɶ VEGFR2, VEGFR3 ɢ, ɜ ɤɚɤɨɣ-ɬɨ ɫɬɟɩɟɧɢ, ɪɟɰɟɩɬɨɪɚ ɷɩɢɞɟɪɦɚɥɶɧɨɝɨ ɮɚɤɬɨɪɚ ɪɨɫɬɚ EGFR [51, 52, 53, 54]. ȼ ɧɚɫɬɨɹɳɟɟ ɜɪɟɦɹ ɧɚɤɨɩɥɟɧɨ ɞɨɫɬɚɬɨɱɧɨɟ ɤɨɥɢɱɟɫɬɜɨ ɞɚɧɧɵɯ, ɤɚɫɚɸɳɢɯɫɹ ɢɫɩɨɥɶɡɨɜɚɧɢɹ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ ɜ ɤɥɢɧɢɤɟ. ɍɠɟ 20 ɫɚɦɵɟ ɩɟɪɜɵɟ ɪɟɡɭɥɶɬɚɬɵ ɩɪɢɦɟɧɟɧɢɹ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ ɞɥɹ ɥɟɱɟɧɢɹ ɨɧɤɨɥɨɝɢɱɟɫɤɢɯ ɡɚɛɨɥɟɜɚɧɢɣ, ɜ ɬɨɦ ɱɢɫɥɟ ɬɚɤɢɯ ɜɢɞɨɜ ɪɚɤɚ, ɤɨɬɨɪɵɟ ɯɚɪɚɤɬɟɪɢɡɭɸɬɫɹ ɜɵɫɨɤɢɦ ɭɪɨɜɧɟɦ ɜɚɫɤɭɥɹɪɢɡɚɰɢɢ, ɨɤɚɡɚɥɢɫɶ ɩɪɨɬɢɜɨɪɟɱɢɜɵɦɢ. ɇɚɪɹɞɭ ɫɨ ɫɜɢɞɟɬɟɥɶɫɬɜɚɦɢ ɭɫɩɟɲɧɨɝɨ ɩɪɢɦɟɧɟɧɢɹ ɚɧɬɢɚɧɝɢɨɝɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ, ɯɢɦɢɨɬɟɪɚɩɢɟɣ, ɛɵɥɢ ɨɞɧɢɯ ɢɥɢ ɜ ɩɨɥɭɱɟɧɵ ɢ ɞɚɧɧɵɟ ɫɨɱɟɬɚɧɢɢ ɫɨ ɫɬɚɧɞɚɪɬɧɨɣ ɨɛ ɨɬɫɭɬɫɬɜɢɢ ɭɥɭɱɲɟɧɢɹ ɤɥɢɧɢɱɟɫɤɢɯ ɩɨɤɚɡɚɬɟɥɟɣ ɩɪɢ ɢɯ ɢɫɩɨɥɶɡɨɜɚɧɢɢ. ȼ ɨɛɡɨɪɧɨɣ ɪɚɛɨɬɟ Jain R.K. ɢ ɫɨɚɜɬ. ɩɪɢɜɟɞɟɧɵ ɞɚɧɧɵɟ ɨ ɪɟɡɭɥɶɬɚɬɚɯ ɩɪɢɦɟɧɟɧɢɹ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ, ɛɥɨɤɢɪɭɸɳɢɯ ɞɟɣɫɬɜɢɟ VEGF ɢɥɢ ɪɟɰɟɩɬɨɪɨɜ ɷɬɨɝɨ ɮɚɤɬɨɪɚ ɪɨɫɬɚ ɭ ɛɨɥɶɧɵɯ ɪɚɤɨɦ ɦɨɥɨɱɧɨɣ ɠɟɥɟɡɵ, ɥɟɝɤɨɝɨ, ɩɨɱɤɢ, ɬɨɥɫɬɨɣ ɤɢɲɤɢ ɢ ɠɟɥɭɞɨɱɧɨ-ɤɢɲɟɱɧɨɝɨ ɬɪɚɤɬɚ [55]. Ⱦɨɛɚɜɥɟɧɢɟ ɩɪɟɩɚɪɚɬɚ Avastin (Bevacizumab) ɤ ɫɬɚɧɞɚɪɬɧɨɣ ɰɢɬɨɬɨɤɫɢɱɟɫɤɨɣ ɬɟɪɚɩɢɢ ɩɪɢɜɨɞɢɥɨ ɤ ɫɬɚɬɢɫɬɢɱɟɫɤɢ ɞɨɫɬɨɜɟɪɧɨɦɭ ɭɜɟɥɢɱɟɧɢɸ ɤɚɤ ɩɪɨɞɨɥɠɢɬɟɥɶɧɨɫɬɢ ɛɟɡɪɟɰɢɞɢɜɧɨɝɨ ɩɟɪɢɨɞɚ ɠɢɡɧɢ, ɬɚɤ ɢ ɨɛɳɟɣ ɩɪɨɞɨɥɠɢɬɟɥɶɧɨɫɬɢ ɠɢɡɧɢ, ɭ ɧɟ ɥɟɱɟɧɵɯ ɛɨɥɶɧɵɯ ɦɟɬɚɫɬɚɡɢɪɭɸɳɢɦ ɪɚɤɨɦ ɥɟɝɤɨɝɨ, ɦɨɥɨɱɧɨɣ ɠɟɥɟɡɵ ɢ ɬɨɥɫɬɨɣ ɤɢɲɤɢ. ɍ ɛɨɥɶɧɵɯ, ɪɚɧɟɟ ɩɨɥɭɱɚɜɲɢɯ ɤɭɪɫ ɯɢɦɢɨɬɟɪɚɩɢɢ, ɭɜɟɥɢɱɟɧɢɟ ɨɛɳɟɣ ɩɪɨɞɨɥɠɢɬɟɥɶɧɨɫɬɢ ɠɢɡɧɢ ɧɚɛɥɸɞɚɥɨɫɶ ɜ ɫɥɭɱɚɟ ɦɟɬɚɫɬɚɡɢɪɭɸɳɟɝɨ ɪɚɤɚ ɬɨɥɫɬɨɣ ɤɢɲɤɢ, ɧɨ ɧɟ ɦɨɥɨɱɧɨɣ ɠɟɥɟɡɵ. ɂɫɩɨɥɶɡɨɜɚɧɢɟ ɩɪɟɩɚɪɚɬɨɜ, ɧɚɰɟɥɟɧɧɵɯ ɧɚ ɛɥɨɤɢɪɨɜɚɧɢɟ ɬɢɪɨɡɢɧɤɢɧɚɡɧɨɣ ɚɤɬɢɜɧɨɫɬɢ ɪɟɰɟɩɬɨɪɨɜ VEGF, ɩɪɢɜɨɞɢɥɨ ɤ ɫɬɚɬɢɫɬɢɱɟɫɤɢ ɞɨɫɬɨɜɟɪɧɨɦɭ ɭɜɟɥɢɱɟɧɢɸ ɩɟɪɢɨɞɚ ɛɟɡɪɟɰɢɞɢɜɧɨɝɨ ɜɪɟɦɟɧɢ ɠɢɡɧɢ ɩɪɢ ɩɨɡɞɧɢɯ ɫɬɚɞɢɹɯ ɪɚɤɚ ɩɨɱɤɢ (ɩɪɢɦɟɧɹɥɫɹ ɩɪɟɩɚɪɚɬ Sorafenib) ɢ ɜ ɫɥɭɱɚɟ ɪɚɧɟɟ ɥɟɱɟɧɨɝɨ ɪɚɤɚ ɠɟɥɭɞɨɱɧɨ-ɤɢɲɟɱɧɨɝɨ ɬɪɚɤɬɚ (ɩɪɟɩɚɪɚɬ Sunitinib). Ɉɞɧɚɤɨ, ɜ ɫɥɭɱɚɟ ɤɚɤ ɥɟɱɟɧɨɝɨ, ɬɚɤ ɢ ɧɟ ɥɟɱɟɧɨɝɨ ɪɚɤɚ ɤɢɲɟɱɧɢɤɚ, ɜ ɨɬɥɢɱɢɟ ɨɬ ɩɪɢɦɟɧɹɜɲɟɣɫɹ (Bevacizumab), ɫɯɟɦɵ ɥɟɱɟɧɢɹ ɪɟɡɭɥɶɬɚɬɵ ɜ ɤɨɦɛɢɧɚɰɢɢ ɩɪɢɦɟɧɟɧɢɹ ɫ ɩɪɟɩɚɪɚɬɚ ɩɪɟɩɚɪɚɬɨɦ Vatalanib Avastin ɨɤɚɡɚɥɢɫɶ ɩɪɨɬɢɜɨɪɟɱɢɜɵɦɢ. ȼ ɪɹɞɟ ɪɚɛɨɬ ɨɬɦɟɱɚɥɨɫɶ, ɱɬɨ ɩɪɢ ɩɪɢɦɟɧɟɧɢɢ ɷɬɨɝɨ ɩɪɟɩɚɪɚɬɚ ɜ ɤɨɦɛɢɧɚɰɢɢ ɫɨ ɫɬɚɧɞɚɪɬɧɨɣ ɯɢɦɢɨɬɟɪɚɩɢɟɣ ɨɛɳɢɣ ɨɬɜɟɬ ɧɚ ɥɟɱɟɧɢɟ ɧɚɛɥɸɞɚɥɫɹ ɜ 44-54% ɫɥɭɱɚɟɜ [56, 57], ɬɨɝɞɚ ɤɚɤ ɜ ɞɪɭɝɢɯ ɪɚɛɨɬɚɯ 21 ɫɨɨɛɳɚɥɨɫɶ ɨ ɬɨɦ, ɱɬɨ ɩɪɨɞɨɥɠɢɬɟɥɶɧɨɫɬɶ ɛɟɡɪɟɰɢɞɢɜɧɨɝɨ ɜɪɟɦɟɧɢ ɠɢɡɧɢ ɧɟ ɢɡɦɟɧɹɥɚɫɶ [58]. Ɍɚɤɢɦ ɨɛɪɚɡɨɦ, ɪɟɡɭɥɶɬɚɬɵ ɩɪɢɦɟɧɟɧɢɹ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ ɜɟɫɶɦɚ ɧɟɨɞɧɨɡɧɚɱɧɵ. Ɍɟɦ ɧɟ ɦɟɧɟɟ, ɜ ɧɚɫɬɨɹɳɟɟ ɜɪɟɦɹ ɜɨ ɦɧɨɝɢɯ ɫɬɪɚɧɚɯ, ɜ ɬɨɦ ɱɢɫɥɟ ɜ ɋɒȺ (ɨɞɨɛɪɟɧɨ U.S. Food and Drug Administration, FDA) ɢ ɫɬɪɚɧɚɯ ȿɋ (ɨɞɨɛɪɟɧɨ European Medicines Agency, EMEA), ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɟ ɩɪɟɩɚɪɚɬɵ ɜɤɥɸɱɟɧɵ ɜ ɫɬɚɧɞɚɪɬɧɵɟ ɫɯɟɦɵ ɥɟɱɟɧɢɹ ɞɥɹ ɬɟɯ ɢɥɢ ɢɧɵɯ ɜɢɞɨɜ ɨɧɤɨɥɨɝɢɱɟɫɤɢɯ ɡɚɛɨɥɟɜɚɧɢɣ. Ɍɚɤ, Avastin (Bevacizumab) ɜ ɤɨɦɛɢɧɚɰɢɢ ɫ ɯɢɦɢɨɬɟɪɚɩɢɟɣ ɪɚɡɪɟɲɟɧ ɤ ɩɪɢɦɟɧɟɧɢɸ ɞɥɹ ɥɟɱɟɧɢɹ ɪɚɤɚ ɤɢɲɟɱɧɢɤɚ, ɦɨɥɨɱɧɨɣ ɠɟɥɟɡɵ, ɧɟɦɟɥɤɨɤɥɟɬɨɱɧɨɝɨ ɪɚɤɚ ɥɟɝɤɨɝɨ, ɩɨɱɤɢ ɢ ɝɥɢɨɛɥɚɫɬɨɦɵ; Sunitinib – ɩɪɢ ɥɟɱɟɧɢɢ ɪɚɤɚ ɩɨɱɤɢ ɢ ɠɟɥɭɞɨɱɧɨ-ɤɢɲɟɱɧɨɝɨ ɬɪɚɤɬɚ; Sorafenib – ɩɪɢ ɥɟɱɟɧɢɢ ɪɚɤɚ ɩɨɱɤɢ ɢ ɝɟɩɚɬɨɰɟɥɥɸɥɹɪɧɨɣ ɤɚɪɰɢɧɨɦɵ. Sunitinib ɢ Sorafenib ɪɟɤɨɦɟɧɞɨɜɚɧɵ ɤ ɩɪɢɦɟɧɟɧɢɸ ɜ ɤɚɱɟɫɬɜɟ ɦɨɧɨɬɟɪɚɩɢɢ. ɉɨɞɪɨɛɧɭɸ ɢɧɮɨɪɦɚɰɢɸ ɨ ɪɟɡɭɥɶɬɚɬɚɯ ɩɪɢɦɟɧɟɧɢɹ ɷɬɢɯ, ɚ ɬɚɤɠɟ ɧɟɤɨɬɨɪɵɯ ɩɨɤɚ ɟɳɟ ɧɟ ɭɬɜɟɪɠɞɟɧɧɵɯ ɤ ɩɪɢɦɟɧɟɧɢɸ ɩɪɟɩɚɪɚɬɨɜ ɦɨɠɧɨ ɧɚɣɬɢ ɜ ɪɚɛɨɬɟ Meadows K.L., Hurwitz H.I. [59]. 22 ɇɟɨɞɧɨɡɧɚɱɧɨɫɬɶ ɩɨɫɥɟɞɫɬɜɢɣ ɥɟɱɟɧɢɹ ɛɨɥɶɧɵɯ ɩɪɢ ɢɫɩɨɥɶɡɨɜɚɧɢɢ ɚɧɬɢɚɧɝɢɨɝɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ Ʉɚɤ ɭɠɟ ɛɵɥɨ ɨɬɦɟɱɟɧɨ, ɤɥɢɧɢɱɟɫɤɢɟ ɪɟɡɭɥɶɬɚɬɵ ɩɪɢɦɟɧɟɧɢɹ ɚɧɬɢɚɧɝɢɨɝɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ ɨɤɚɡɚɥɢɫɶ ɧɟ ɫɬɨɥɶ ɨɞɧɨɡɧɚɱɧɵɦɢ, ɤɚɤ ɦɨɠɧɨ ɛɵɥɨ ɛɵ ɩɪɟɞɩɨɥɚɝɚɬɶ ɧɚ ɨɫɧɨɜɚɧɢɢ ɦɧɨɝɨɱɢɫɥɟɧɧɵɯ ɞɚɧɧɵɯ, ɭɤɚɡɵɜɚɸɳɢɯ ɧɚ ɬɨ, ɱɬɨ ɩɨɜɵɲɟɧɧɨɟ ɤɨɥɢɱɟɫɬɜɨ ɤɚɩɢɥɥɹɪɨɜ ɜ ɨɩɭɯɨɥɢ ɹɜɥɹɟɬɫɹ ɧɟɝɚɬɢɜɧɵɦ ɩɪɨɝɧɨɫɬɢɱɟɫɤɢɦ ɩɨɤɚɡɚɬɟɥɟɦ. ɇɚɪɹɞɭ ɫ ɭɫɩɟɲɧɵɦɢ ɫɥɭɱɚɹɦɢ ɩɪɢɦɟɧɟɧɢɹ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɨɣ ɬɟɪɚɩɢɢ ɜ ɪɹɞɟ ɫɥɭɱɚɟɜ ɬɟɪɚɩɟɜɬɢɱɟɫɤɢɣ ɷɮɮɟɤɬ ɨɬɫɭɬɫɬɜɨɜɚɥ ɢɥɢ ɨɤɚɡɵɜɚɥɫɹ ɥɢɲɶ ɜɪɟɦɟɧɧɵɦ. ɉɪɢɱɢɧɵ ɬɚɤɨɣ ɧɟɨɞɧɨɡɧɚɱɧɨɫɬɢ ɜ ɧɚɫɬɨɹɳɟɟ ɜɪɟɦɹ ɧɟ ɹɫɧɵ. ɉɪɟɠɞɟ ɜɫɟɝɨ, ɨɫɬɚɟɬɫɹ ɞɨ ɤɨɧɰɚ ɧɟ ɜɵɹɫɧɟɧɧɵɦ ɦɟɯɚɧɢɡɦ ɞɟɣɫɬɜɢɹ ɚɧɬɢɚɧɝɢɨɝɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ. ɑɟɦ ɨɛɴɹɫɧɹɟɬɫɹ ɪɚɡɥɢɱɢɟ ɜ ɷɮɮɟɤɬɢɜɧɨɫɬɢ ɞɟɣɫɬɜɢɹ ɩɪɟɩɚɪɚɬɚ Avastin (Bevacizumab) ɜ ɫɥɭɱɚɟ ɥɟɱɟɧɨɝɨ ɢ ɧɟ ɥɟɱɟɧɨɝɨ ɦɟɬɚɫɬɚɡɢɪɭɸɳɟɝɨ ɪɚɤɚ ɦɨɥɨɱɧɨɣ ɠɟɥɟɡɵ? ɉɨɱɟɦɭ ɫɜɹɡɵɜɚɧɢɟ VEGF-A ɩɪɢ ɞɟɣɫɬɜɢɢ ɷɬɨɝɨ ɠɟ ɩɪɟɩɚɪɚɬɚ ɜ ɫɥɭɱɚɟ ɪɚɤɚ ɤɢɲɟɱɧɢɤɚ ɞɚɟɬ ɡɚɦɟɬɧɵɣ ɷɮɮɟɤɬ, ɚ ɛɥɨɤɢɪɨɜɚɧɢɟ VEGF-A-ɡɚɜɢɫɢɦɨɣ ɫɢɝɧɚɥɶɧɨɣ ɰɟɩɢ ɩɪɟɩɚɪɚɬɨɦ Vatalanib ɧɟ ɫɤɚɡɵɜɚɟɬɫɹ ɧɚ ɪɚɡɜɢɬɢɢ ɡɚɛɨɥɟɜɚɧɢɹ? ɂ ɜ ɰɟɥɨɦ, ɩɪɢɦɟɧɟɧɢɟ ɢɧɝɢɛɢɬɨɪɨɜ ɬɢɪɨɡɢɧɤɢɧɚɡɧɨɣ ɚɤɬɢɜɧɨɫɬɢ ɪɟɰɟɩɬɨɪɨɜ VEGF ɨɤɚɡɚɥɨɫɶ ɦɟɧɟɟ ɷɮɮɟɤɬɢɜɧɵɦ, ɱɟɦ ɫɜɹɡɵɜɚɧɢɟ VEGF-A ɦɨɧɨɤɥɨɧɚɥɶɧɵɦɢ ɚɧɬɢɬɟɥɚɦɢ (ɩɪɟɩɚɪɚɬ Avastin), ɯɨɬɹ, ɤɚɡɚɥɨɫɶ ɛɵ, ɢɦɟɧɧɨ ɢɧɝɢɛɢɬɨɪɵ ɪɟɰɟɩɬɨɪɨɜ VEGF ɛɨɥɟɟ ɫɩɟɰɢɮɢɱɧɨ ɧɚɰɟɥɟɧɵ ɧɚ ɛɥɨɤɢɪɨɜɚɧɢɟ VEGF-A-ɡɚɜɢɫɢɦɨɣ ɫɢɝɧɚɥɶɧɨɣ ɫɢɫɬɟɦɵ. ȼ ɱɢɫɥɟ ɨɞɧɨɣ ɢɡ ɜɨɡɦɨɠɧɵɯ ɩɪɢɱɢɧ ɪɚɡɥɢɱɢɣ ɜ ɷɮɮɟɤɬɢɜɧɨɫɬɢ ɩɪɟɩɚɪɚɬɨɜ, ɫɜɹɡɵɜɚɸɳɢɯ VEGF-A, ɢ ɢɧɝɢɛɢɬɨɪɨɜ ɚɤɬɢɜɧɨɫɬɢ ɪɟɰɟɩɬɨɪɨɜ VEGF ɪɚɫɫɦɚɬɪɢɜɚɸɬɫɹ ɪɚɡɥɢɱɢɹ ɜ ɮɚɪɦɚɤɨɤɢɧɟɬɢɱɟɫɤɢɯ ɯɚɪɚɤɬɟɪɢɫɬɢɤɚɯ ɦɟɠɞɭ ɷɬɢɦɢ ɞɜɭɦɹ ɤɥɚɫɫɚɦɢ ɩɪɟɩɚɪɚɬɨɜ. Ɍɚɤɠɟ ɩɪɢɜɨɞɹɬɫɹ ɞɚɧɧɵɟ ɨ ɬɨɦ, ɱɬɨ ɩɪɢ ɢɫɩɨɥɶɡɨɜɚɧɢɢ ɥɟɤɚɪɫɬɜɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ, ɢɧɝɢɛɢɪɭɸɳɢɯ ɚɤɬɢɜɧɨɫɬɶ ɪɟɰɟɩɬɨɪɨɜ VEGF, ɩɨɜɵɲɚɟɬɫɹ ɫɨɞɟɪɠɚɧɢɟ ɫɚɦɨɝɨ ɷɬɨɝɨ ɮɚɤɬɨɪɚ ɪɨɫɬɚ ɜ ɩɥɚɡɦɟ ɛɨɥɶɧɵɯ. Ɉɞɧɚɤɨ ɨɱɟɧɶ ɦɧɨɝɢɟ ɜɨɩɪɨɫɵ ɩɪɨɞɨɥɠɚɸɬ ɨɫɬɚɜɚɬɶɫɹ ɧɟ ɢɫɫɥɟɞɨɜɚɧɧɵɦɢ. 23 Ⱦɚɥɶɧɟɣɲɟɝɨ ɢɡɭɱɟɧɢɹ ɬɪɟɛɭɸɬ ɧɟ ɬɨɥɶɤɨ ɦɟɯɚɧɢɡɦɵ ɞɟɣɫɬɜɢɹ ɚɧɬɢɚɧɝɢɨɝɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ, ɧɨ ɢ ɩɨɜɟɞɟɧɢɟ ɫɚɦɢɯ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ ɩɨɞ ɞɟɣɫɬɜɢɟɦ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɨɣ ɬɟɪɚɩɢɢ. ȼ ɧɚɫɬɨɹɳɟɟ ɜɪɟɦɹ ɧɚɤɚɩɥɢɜɚɟɬɫɹ ɜɫɟ ɛɨɥɶɲɟ ɞɚɧɧɵɯ ɨ ɬɨɦ, ɱɬɨ ɨɩɭɯɨɥɟɜɵɟ ɤɥɟɬɤɢ ɫɩɨɫɨɛɧɵ ɤɚɤɢɦ-ɬɨ ɨɛɪɚɡɨɦ ɩɪɨɬɢɜɨɫɬɨɹɬɶ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɨɣ ɬɟɪɚɩɢɢ, ɚ ɜ ɫɥɭɱɚɟ ɦɨɧɨɬɟɪɚɩɢɢ ɚɧɬɢɚɧɝɢɨɝɟɧɧɵɦɢ ɩɪɟɩɚɪɚɬɚɦɢ ɜɵɪɚɛɚɬɵɜɚɬɶ ɤ ɧɢɦ ɨɩɪɟɞɟɥɟɧɧɭɸ ɪɟɡɢɫɬɟɧɬɧɨɫɬɶ. Ɉɬɦɟɱɚɟɬɫɹ ɬɚɤɠɟ, ɱɬɨ ɩɪɟɩɚɪɚɬɵ ɷɬɨɝɨ ɤɥɚɫɫɚ ɦɨɝɭɬ ɜɵɡɵɜɚɬɶ ɥɢɲɶ ɜɪɟɦɟɧɧɵɣ ɷɮɮɟɤɬ, ɢ ɩɨ ɩɪɨɲɟɫɬɜɢɢ ɧɟɤɨɬɨɪɨɝɨ ɩɟɪɢɨɞɚ ɪɨɫɬ ɨɩɭɯɨɥɢ ɜɨɡɨɛɧɨɜɥɹɟɬɫɹ. ɉɨɫɥɟ ɨɬɦɟɧɵ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɨɣ ɬɟɪɚɩɢɢ ɦɨɠɟɬ ɜɨɡɧɢɤɚɬɶ ɛɵɫɬɪɚɹ ɪɟɜɚɫɤɭɥɹɪɢɡɚɰɢɹ ɨɩɭɯɨɥɢ. ɇɟɨɞɧɨɡɧɚɱɧɵ ɪɟɡɭɥɶɬɚɬɵ, ɤɚɫɚɸɳɢɟɫɹ ɬɚɤɢɯ ɨɫɨɛɟɧɧɨ ɜɚɠɧɵɯ ɤɥɢɧɢɱɟɫɤɢɯ ɩɨɤɚɡɚɬɟɥɟɣ ɤɚɤ ɨɛɳɚɹ ɩɪɨɞɨɥɠɢɬɟɥɶɧɨɫɬɶ ɠɢɡɧɢ ɛɨɥɶɧɨɝɨ ɢ ɛɟɡɪɟɰɢɞɢɜɧɵɣ ɩɟɪɢɨɞ ɬɟɱɟɧɢɹ ɡɚɛɨɥɟɜɚɧɢɹ. ȼ ɪɹɞɟ ɫɥɭɱɚɟɜ ɨɬɦɟɱɚɟɬɫɹ ɭɜɟɥɢɱɟɧɢɟ ɩɪɨɞɨɥɠɢɬɟɥɶɧɨɫɬɢ ɛɟɡɪɟɰɢɞɢɜɧɨɝɨ ɜɪɟɦɟɧɢ ɠɢɡɧɢ, ɧɨ ɧɟ ɨɛɳɟɣ ɩɪɨɞɨɥɠɢɬɟɥɶɧɨɫɬɢ ɠɢɡɧɢ. Ⱥ ɜ ɢɫɫɥɟɞɨɜɚɧɢɢ, ɩɪɨɜɟɞɟɧɧɨɦ Allegra ɢ ɫɨɬɪ., ɩɪɢ ɢɫɩɨɥɶɡɨɜɚɧɢɢ ɩɪɟɩɚɪɚɬɚ Avastin (Bevacizumab) ɞɥɹ ɥɟɱɟɧɢɹ ɤɚɪɰɢɧɨɦɵ ɬɨɥɫɬɨɣ ɤɢɲɤɢ ɧɟ ɨɬɦɟɱɚɥɨɫɶ ɭɜɟɥɢɱɟɧɢɹ ɧɢ ɨɛɳɟɣ ɩɪɨɞɨɥɠɢɬɟɥɶɧɨɫɬɢ ɠɢɡɧɢ, ɧɢ ɩɪɨɞɨɥɠɢɬɟɥɶɧɨɫɬɢ ɛɟɡɪɟɰɢɞɢɜɧɨɝɨ ɜɪɟɦɟɧɢ ɠɢɡɧɢ [60]. ɇɟ ɧɚɛɥɸɞɚɥɨɫɶ ɭɥɭɱɲɟɧɢɹ ɤɥɢɧɢɱɟɫɤɢɯ ɩɨɤɚɡɚɬɟɥɟɣ ɩɪɢ ɢɫɩɨɥɶɡɨɜɚɧɢɢ ɷɬɨɝɨ ɩɪɟɩɚɪɚɬɚ ɜ ɤɚɱɟɫɬɜɟ ɦɨɧɨɬɟɪɚɩɢɢ ɢɥɢ ɜ ɤɨɦɛɢɧɚɰɢɢ ɫɨ ɫɬɚɧɞɚɪɬɧɨɣ ɯɢɦɢɨɬɟɪɚɩɢɟɣ ɢ ɜ ɪɹɞɟ ɞɪɭɝɢɯ ɢɫɫɥɟɞɨɜɚɧɢɣ [ɫɦ., ɧɚɩɪɢɦɟɪ, 61, 62, 63]. Ⱦɥɹ ɨɛɴɹɫɧɟɧɢɹ ɨɬɫɭɬɫɬɜɢɹ ɢɥɢ ɧɟɨɞɧɨɡɧɚɱɧɨɫɬɢ ɩɪɨɬɢɜɨɨɩɭɯɨɥɟɜɨɝɨ ɷɮɮɟɤɬɚ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ ɛɵɥɨ ɜɵɞɜɢɧɭɬɨ ɧɟɫɤɨɥɶɤɨ ɩɪɟɞɩɨɥɨɠɟɧɢɣ, ɨɞɧɨ ɢɡ ɤɨɬɨɪɵɯ ɡɚɤɥɸɱɚɟɬɫɹ ɜ ɬɨɦ, ɱɬɨ ɜ ɫɥɭɱɚɟ ɩɨɞɚɜɥɟɧɢɹ ɮɨɪɦɢɪɨɜɚɧɢɹ ɫɨɫɭɞɢɫɬɨɣ ɫɢɫɬɟɦɵ ɨɩɭɯɨɥɢ ɡɚɬɪɭɞɧɹɟɬɫɹ ɞɨɫɬɭɩ ɤ ɨɩɭɯɨɥɟɜɵɦ ɤɥɟɬɤɚɦ ɰɢɬɨɬɨɤɫɢɱɟɫɤɢɯ ɩɪɨɬɢɜɨɨɩɭɯɨɥɟɜɵɯ ɩɪɟɩɚɪɚɬɨɜ. Ʉɪɨɦɟ ɬɨɝɨ, ɤɚɤ ɢɡɜɟɫɬɧɨ, ɩɨɦɢɦɨ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF, ɫɭɳɟɫɬɜɭɟɬ ɟɳɟ ɪɹɞ ɞɪɭɝɢɯ ɮɚɤɬɨɪɨɜ, ɯɨɬɹ ɢ ɦɟɧɟɟ ɫɩɟɰɢɮɢɱɧɵɯ ɜ ɨɬɧɨɲɟɧɢɢ ɤɥɟɬɨɤ ɷɧɞɨɬɟɥɢɹ ɫɨɫɭɞɨɜ, ɧɨ ɬɚɤɠɟ ɨɛɥɚɞɚɸɳɢɯ ɚɧɝɢɨɝɟɧɧɨɣ ɚɤɬɢɜɧɨɫɬɶɸ, ɤ ɧɢɦ ɨɬɧɨɫɹɬɫɹ ɬɪɨɦɛɨɰɢɬɚɪɧɵɣ ɮɚɤɬɨɪ ɪɨɫɬɚ PDGF, ɬɪɨɦɛɨɰɢɬɚɪɧɵɣ ɮɚɤɬɨɪ ɪɨɫɬɚ 24 ɤɥɟɬɨɤ ɷɧɞɨɬɟɥɢɹ PD-ECGF, ɚɧɝɢɨɝɟɧɢɧ, ɚɧɝɢɨɩɨɷɬɢɧɵ, Tie-2, ɮɚɤɬɨɪɵ ɪɨɫɬɚ ɮɢɛɪɨɛɥɚɫɬɨɜ FGF. Ⱥɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɟ ɩɪɟɩɚɪɚɬɵ, ɛɥɨɤɢɪɭɸɳɢɟ ɞɟɣɫɬɜɢɟ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF, (ɬɚɤɢɟ ɤɚɤ ɩɪɟɩɚɪɚɬ Avastin, ɩɪɟɞɫɬɚɜɥɹɸɳɢɣ ɫɨɛɨɣ ɚɧɬɢɬɟɥɚ ɤ VEGF-A), ɧɟ ɨɤɚɡɵɜɚɸɬ ɞɟɣɫɬɜɢɟ ɧɚ ɚɤɬɢɜɧɨɫɬɶ ɞɪɭɝɢɯ ɚɧɝɢɨɝɟɧɧɵɯ ɮɚɤɬɨɪɨɜ. ɉɪɟɩɚɪɚɬɵ, ɩɨɞɚɜɥɹɸɳɢɟ ɬɢɪɨɡɢɧɤɢɧɚɡɧɭɸ ɚɤɬɢɜɧɨɫɬɶ ɪɟɰɟɩɬɨɪɨɜ VEGF, ɧɟ ɹɜɥɹɸɬɫɹ ɜɵɫɨɤɨɫɩɟɰɢɮɢɱɧɵɦɢ ɞɥɹ ɷɬɢɯ ɪɟɰɟɩɬɨɪɨɜ ɢ ɦɨɝɭɬ, ɯɨɬɹ ɢ ɜ ɦɟɧɶɲɟɣ ɫɬɟɩɟɧɢ, ɢɧɝɢɛɢɪɨɜɚɬɶ ɚɤɬɢɜɧɨɫɬɶ ɢ ɞɪɭɝɢɯ ɬɢɪɨɡɢɧɤɢɧɚɡ, ɨɞɧɚɤɨ ɧɢ ɨɞɢɧ ɢɡ ɧɢɯ ɧɟ ɛɥɨɤɢɪɭɟɬ ɜɫɟ ɫɢɝɧɚɥɶɧɵɟ ɩɭɬɢ, ɫɜɹɡɚɧɧɵɟ ɫ ɬɟɦɢ ɢɥɢ ɢɧɵɦɢ ɚɧɝɢɨɝɟɧɧɵɦɢ ɮɚɤɬɨɪɚɦɢ. ȼ ɫɜɹɡɢ ɫ ɷɬɢɦ, ɩɨɞɚɜɥɟɧɢɟ ɫɢɝɧɚɥɶɧɵɯ ɩɭɬɟɣ, ɫɜɹɡɚɧɧɵɯ ɫ VEGF, ɧɟ ɢɫɤɥɸɱɚɟɬ ɜɨɡɦɨɠɧɨɫɬɶ ɫɬɢɦɭɥɹɰɢɢ ɚɧɝɢɨɝɟɧɟɡɚ ɨɩɭɯɨɥɢ ɞɪɭɝɢɦɢ ɚɧɝɢɨɝɟɧɧɵɦɢ ɮɚɤɬɨɪɚɦɢ. Ɍɚɤ, ɧɚɩɪɢɦɟɪ, ɩɪɢ ɛɥɨɤɢɪɨɜɚɧɢɢ ɚɤɬɢɜɧɨɫɬɢ ɪɟɰɟɩɬɨɪɚ VEGFR2 ɚɧɬɢɬɟɥɚɦɢ ɱɟɪɟɡ ɧɟɤɨɬɨɪɨɟ ɜɪɟɦɹ ɜɧɨɜɶ ɧɚɛɥɸɞɚɥɚɫɶ ɜɚɫɤɭɥɹɪɢɡɚɰɢɹ ɨɩɭɯɨɥɢ [48]. Ȼɨɥɟɟ ɬɨɝɨ, ɩɨɹɜɢɥɢɫɶ ɞɚɧɧɵɟ ɨ ɬɨɦ, ɱɬɨ ɚɧɬɢ-VEGF ɬɟɪɚɩɢɹ ɦɨɠɟɬ ɩɪɢɜɨɞɢɬɶ ɤ ɭɫɢɥɟɧɢɸ ɦɟɬɚɫɬɚɡɢɪɨɜɚɧɢɹ [48, 64, 65]. Ɍɚɤ, ɜ ɪɚɛɨɬɚɯ Casanovas O. ɢ ɫɨɬɪ. [48] ɢ Pàez-Ribes M. ɢ ɫɨɬɪ. [64] ɧɚ ɦɨɞɟɥɢ ɩɟɪɟɜɢɜɚɟɦɨɝɨ ɧɟɣɪɨɷɧɞɨɤɪɢɧɧɨɝɨ ɪɚɤɚ ɩɨɞɠɟɥɭɞɨɱɧɨɣ ɠɟɥɟɡɵ PNET ɛɵɥɨ ɩɪɨɞɟɦɨɧɫɬɪɢɪɨɜɚɧɨ, ɱɬɨ ɩɨɞɚɜɥɟɧɢɟ ɫɜɹɡɚɧɧɨɝɨ ɫ VEGF ɫɢɝɧɚɥɶɧɨɝɨ ɩɭɬɢ, ɧɚɩɪɚɜɥɟɧɧɨɟ ɧɚ ɢɧɝɢɛɢɪɨɜɚɧɢɟ ɚɤɬɢɜɧɨɫɬɢ ɨɫɧɨɜɧɨɝɨ ɮɭɧɤɰɢɨɧɚɥɶɧɨɝɨ ɪɟɰɟɩɬɨɪɚ ɷɬɨɝɨ ɮɚɤɬɨɪɚ ɪɨɫɬɚ VEGFR2 ɫ ɩɨɦɨɳɶɸ ɚɧɬɢɬɟɥ ɢɥɢ ɥɟɤɚɪɫɬɜɟɧɧɨɝɨ ɩɪɟɩɚɪɚɬɚ Sunitinib, ɩɪɢɜɨɞɢɥɨ ɤ ɩɨɜɵɲɟɧɧɨɣ ɢɧɜɚɡɢɜɧɨɫɬɢ ɨɩɭɯɨɥɢ ɢ ɭɫɢɥɟɧɢɸ ɦɟɬɚɫɬɚɡɢɪɨɜɚɧɢɹ. Ⱥɧɚɥɨɝɢɱɧɵɟ ɞɚɧɧɵɟ ɛɵɥɢ ɩɨɥɭɱɟɧɵ ɞɥɹ ɞɪɭɝɨɝɨ ɬɢɩɚ ɨɩɭɯɨɥɢ – ɦɭɥɶɬɢɮɨɪɦɧɨɣ ɝɥɢɨɛɥɚɫɬɨɦɵ [65]. ɂɧɬɟɪɟɫɧɨ, ɱɬɨ ɜ ɫɥɭɱɚɟ ɢɫɩɨɥɶɡɨɜɚɧɢɹ ɨɩɭɯɨɥɟɜɨɝɨ ɲɬɚɦɦɚ ɫ ɧɟɪɚɛɨɬɚɸɳɢɦ ɝɟɧɨɦ Vegf-A ɩɨɜɵɲɚɥɚɫɶ ɢɧɜɚɡɢɜɧɨɫɬɶ ɨɩɭɯɨɥɢ, ɧɨ ɧɟ ɦɟɬɚɫɬɚɡɢɪɨɜɚɧɢɟ. Ɍɟɦ ɧɟ ɦɟɧɟɟ, ɢɧɝɢɛɢɪɨɜɚɧɢɟ ɬɟɦ ɢɥɢ ɢɧɵɦ ɨɛɪɚɡɨɦ VEGF-ɡɚɜɢɫɢɦɨɝɨ ɫɢɝɧɚɥɶɧɨɝɨ ɩɭɬɢ ɜ ɷɬɢɯ ɷɤɫɩɟɪɢɦɟɧɬɚɥɶɧɵɯ ɦɨɞɟɥɹɯ ɩɪɢɜɨɞɢɥɨ ɤ ɭɜɟɥɢɱɟɧɢɸ ɨɛɳɟɣ ɩɪɨɞɨɥɠɢɬɟɥɶɧɨɫɬɢ ɠɢɡɧɢ ɠɢɜɨɬɧɵɯ-ɨɩɭɯɨɥɟɧɨɫɢɬɟɥɟɣ ɩɨ ɫɪɚɜɧɟɧɢɸ ɫ ɤɨɧɬɪɨɥɶɧɵɦɢ ɠɢɜɨɬɧɵɦɢ ɢ ɭɦɟɧɶɲɟɧɢɸ ɨɛɴɟɦɚ ɨɩɭɯɨɥɢ. 25 ɂɧɬɟɪɟɫɧɨ, ɱɬɨ ɞɟɣɫɬɜɢɟ ɩɪɟɩɚɪɚɬɨɜ, ɨɫɧɨɜɚɧɧɵɯ ɧɚ ɢɧɝɢɛɢɪɨɜɚɧɢɢ ɬɢɪɨɡɢɧɤɢɧɚɡɧɨɣ ɚɤɬɢɜɧɨɫɬɢ ɪɟɰɟɩɬɨɪɨɜ, ɬɚɤɢɯ ɤɚɤ Sunitinib, Sorafenib ɢ SU10944, ɤɚɤ ɨɤɚɡɚɥɨɫɶ, ɡɚɜɢɫɢɬ ɨɬ ɫɯɟɦɵ ɢɯ ɩɪɢɦɟɧɟɧɢɹ. ȼ ɨɩɵɬɚɯ ɧɚ ɦɵɲɚɯ ɫ ɢɫɩɨɥɶɡɨɜɚɧɢɟɦ ɩɟɪɟɜɢɜɚɟɦɵɯ ɲɬɚɦɦɨɜ ɪɚɤɚ ɦɨɥɨɱɧɨɣ ɠɟɥɟɡɵ (231/LM2-4) ɢ ɦɟɥɚɧɨɦɵ (MeWo) ɱɟɥɨɜɟɤɚ ɤɪɚɬɤɨɜɪɟɦɟɧɧɨɟ (ɜ ɬɟɱɟɧɢɟ 7 ɞɧɟɣ) ɜɜɟɞɟɧɢɟ ɩɪɟɩɚɪɚɬɚ Sunitinib ɜ ɞɨɡɟ 120 ɦɝ/ɤɝ ɜɟɫɚ ɠɢɜɨɬɧɨɝɨ ɤɚɤ ɩɨɫɥɟ, ɬɚɤ ɢ ɞɨ ɩɪɢɜɢɜɤɢ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ ɩɪɢɜɨɞɢɥɨ ɤ ɫɬɚɬɢɫɬɢɱɟɫɤɢ ɡɧɚɱɢɦɨɦɭ ɭɜɟɥɢɱɟɧɢɸ ɤɨɥɢɱɟɫɬɜɚ ɦɟɬɚɫɬɚɡɨɜ ɢ ɤ ɭɦɟɧɶɲɟɧɢɸ ɦɟɞɢɚɧɵ ɜɵɠɢɜɚɟɦɨɫɬɢ ɩɨ ɫɪɚɜɧɟɧɢɸ ɫ ɠɢɜɨɬɧɵɦɢ, ɧɟ ɩɨɥɭɱɚɜɲɢɦɢ ɷɬɢ ɩɪɟɩɚɪɚɬɵ [66]. Ⱥɧɚɥɨɝɢɱɧɵɟ ɞɚɧɧɵɟ ɛɵɥɢ ɩɨɥɭɱɟɧɵ ɜ ɷɬɨɣ ɪɚɛɨɬɟ ɢ ɞɥɹ ɩɪɟɩɚɪɚɬɨɜ Sorafenib ɢ SU10944. ȼ ɬɨ ɠɟ ɜɪɟɦɹ ɜ ɪɟɡɭɥɶɬɚɬɟ ɞɥɢɬɟɥɶɧɨɝɨ ɩɪɢɦɟɧɟɧɢɹ Sunitinib ɜ ɞɨɡɟ 60 ɦɝ/ɤɝ ɜɟɫɚ ɠɢɜɨɬɧɨɝɨ ɪɨɫɬ ɨɩɭɯɨɥɟɣ ɩɨɞɚɜɥɹɥɫɹ [67]. Ⱥɧɚɥɨɝɢɱɧɵɟ ɞɚɧɧɵɟ ɨ ɩɨɞɚɜɥɟɧɢɢ ɪɨɫɬɚ ɨɩɭɯɨɥɟɣ ɩɪɢ ɢɫɩɨɥɶɡɨɜɚɧɢɢ ɩɪɟɩɚɪɚɬɚ Sunitinib ɛɵɥɢ ɩɨɥɭɱɟɧɵ ɜ ɪɚɛɨɬɟ Christensen J.G. [68]. Ɍɚɤɢɦ ɨɛɪɚɡɨɦ, ɧɚɪɹɞɭ ɫ ɩɨɥɨɠɢɬɟɥɶɧɵɦ ɬɟɪɚɩɟɜɬɢɱɟɫɤɢɦ ɷɮɮɟɤɬɨɦ, ɩɪɨɹɜɥɹɸɳɢɦɫɹ ɜ ɭɦɟɧɶɲɟɧɢɢ ɪɚɡɦɟɪɚ ɢ ɩɨɞɚɜɥɟɧɢɢ ɪɨɫɬɚ ɨɩɭɯɨɥɢ, ɨɞɧɢɦ ɢɡ ɧɟɝɚɬɢɜɧɵɯ ɩɨɫɥɟɞɫɬɜɢɣ ɩɪɢɦɟɧɟɧɢɹ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ ɦɨɠɟɬ ɛɵɬɶ ɫɬɢɦɭɥɹɰɢɹ ɦɟɬɚɫɬɚɡɢɪɨɜɚɧɢɹ, ɢ ɤɪɨɦɟ ɬɨɝɨ, ɧɟɬ ɭɛɟɞɢɬɟɥɶɧɵɯ ɞɚɧɧɵɯ ɨɛ ɭɜɟɥɢɱɟɧɢɢ ɤɚɤ ɨɛɳɟɣ, ɬɚɤ ɢ ɛɟɡɪɟɰɢɞɢɜɧɨɣ ɩɪɨɞɨɥɠɢɬɟɥɶɧɨɫɬɢ ɠɢɡɧɢ ɜ ɪɟɡɭɥɶɬɚɬɟ ɩɪɢɦɟɧɟɧɢɹ ɷɬɢɯ ɥɟɤɚɪɫɬɜɟɧɧɵɯ ɫɪɟɞɫɬɜ. 26 ȼɨɡɦɨɠɧɵɟ ɩɪɢɱɢɧɵ ɧɟɨɞɧɨɡɧɚɱɧɵɯ ɩɨɫɥɟɞɫɬɜɢɣ ɩɪɢɦɟɧɟɧɢɹ ɚɧɬɢɚɧɝɢɨɝɟɧɧɨɣ ɬɟɪɚɩɢɢ ɉɪɢɱɢɧɵ, ɩɪɢɜɨɞɹɳɢɟ ɤ ɭɫɢɥɟɧɢɸ ɢɧɜɚɡɢɜɧɨɫɬɢ ɢ ɦɟɬɚɫɬɚɡɢɪɨɜɚɧɢɹ ɨɩɭɯɨɥɢ ɩɨɫɥɟ ɩɪɨɜɟɞɟɧɢɹ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɨɣ ɬɟɪɚɩɢɢ ɧɟɹɫɧɵ. Ɉɞɢɧ ɢɡ ɜɨɡɦɨɠɧɵɯ ɦɟɯɚɧɢɡɦɨɜ, ɝɢɩɨɤɫɢɹ, ɤɨɬɨɪɚɹ, ɤɚɤ ɩɪɟɞɩɨɥɚɝɚɸɬ, ɦɨɝɥɚ ɛɵ ɨɛɴɹɫɧɢɬɶ ɷɬɢ ɹɜɥɟɧɢɹ, ɨɛɫɭɠɞɚɟɬɫɹ ɜ ɫɬɚɬɶɟ Loges S. ɢ ɫɨɚɜɬ. /69/. ɉɨɫɤɨɥɶɤɭ ɥɟɤɚɪɫɬɜɟɧɧɵɟ ɩɪɟɩɚɪɚɬɵ ɷɬɨɝɨ ɤɥɚɫɫɚ ɧɚɰɟɥɟɧɵ ɧɚ ɩɨɞɚɜɥɟɧɢɟ ɚɧɝɢɨɝɟɧɟɡɚ ɨɩɭɯɨɥɢ, ɨɧɢ ɭɫɢɥɢɜɚɸɬ ɝɢɩɨɤɫɢɸ ɨɩɭɯɨɥɟɜɨɣ ɬɤɚɧɢ, ɭɠɟ ɫɭɳɟɫɬɜɭɸɳɭɸ ɜ ɧɟɣ ɢɡɧɚɱɚɥɶɧɨ. ȼɦɟɫɬɟ ɫ ɬɟɦ, ɤɥɟɬɤɢ ɨɩɭɯɨɥɢ ɥɭɱɲɟ, ɱɟɦ ɧɨɪɦɚɥɶɧɵɟ, ɧɟ ɬɪɚɧɫɮɨɪɦɢɪɨɜɚɧɧɵɟ ɤɥɟɬɤɢ ɩɪɢɫɩɨɫɚɛɥɢɜɚɸɬɫɹ ɤ ɭɫɥɨɜɢɹɦ ɝɢɩɨɤɫɢɢ. ɏɨɪɨɲɨ ɢɡɜɟɫɬɟɧ ɮɚɤɬ, ɨɛɧɚɪɭɠɟɧɧɵɣ ɟɳɟ ɜ 1924 ɝ. ɧɟɦɟɰɤɢɦ ɛɢɨɯɢɦɢɤɨɦ ȼɚɪɛɭɪɝɨɦ, ɱɬɨ ɷɧɟɪɝɟɬɢɤɚ ɨɩɭɯɨɥɟɜɨɣ ɤɥɟɬɤɢ ɨɬɥɢɱɚɟɬɫɹ ɨɬ ɧɨɪɦɚɥɶɧɨɣ. ȿɫɥɢ ɜ ɧɨɪɦɟ ɧɟɨɛɯɨɞɢɦɚɹ ɤɥɟɬɤɚɦ ɷɧɟɪɝɢɹ, ɡɚɩɚɫɚɟɦɚɹ ɜ ɮɨɪɦɟ ɦɨɥɟɤɭɥ ɚɞɟɧɨɡɢɧ-3-ɮɨɫɮɚɬɚ ɦɢɬɨɯɨɧɞɪɢɚɥɶɧɨɝɨ (ȺɌɊ), ɨɤɢɫɥɢɬɟɥɶɧɨɝɨ ɩɪɨɞɭɰɢɪɭɟɬɫɹ ɮɨɫɮɨɪɢɥɢɪɨɜɚɧɢɹ, ɜ ɩɪɨɰɟɫɫɟ ɬɪɟɛɭɸɳɟɝɨ ɩɪɢɫɭɬɫɬɜɢɹ ɤɢɫɥɨɪɨɞɚ, ɬɨ ɨɩɭɯɨɥɟɜɵɟ ɤɥɟɬɤɢ ɞɥɹ ɜɵɪɚɛɨɬɤɢ ȺɌɊ ɩɟɪɟɯɨɞɹɬ ɧɚ ɩɪɨɢɫɯɨɞɹɳɢɣ ɜ ɚɧɚɷɪɨɛɧɵɯ ɭɫɥɨɜɢɹɯ ɝɥɢɤɨɥɢɡ. ɂ ɯɨɬɹ ɷɧɟɪɝɟɬɢɤɚ ɤɥɟɬɤɢ, ɛɚɡɢɪɭɸɳɚɹɫɹ ɧɚ ɝɥɢɤɨɥɢɡɟ, ɦɟɧɟɟ ɷɮɮɟɤɬɢɜɧɚ, ɱɟɦ ɚɷɪɨɛɧɨɟ ɞɵɯɚɧɢɟ, ɜ ɭɫɥɨɜɢɹɯ ɩɨɧɢɠɟɧɧɨɝɨ ɫɨɞɟɪɠɚɧɢɹ ɤɢɫɥɨɪɨɞɚ ɝɥɢɤɨɥɢɬɢɱɟɫɤɢɣ ɬɢɩ ɷɧɟɪɝɟɬɢɤɢ ɦɨɠɟɬ ɞɚɬɶ ɤɥɟɬɤɚɦ ɩɪɟɢɦɭɳɟɫɬɜɨ ɞɥɹ ɜɵɠɢɜɚɧɢɹ. ɉɪɢ ɷɬɨɦ ɢɡɜɟɫɬɧɨ, ɱɬɨ ɚɤɬɢɜɢɪɭɟɦɵɣ ɝɢɩɨɤɫɢɟɣ ɬɪɚɧɫɤɪɢɩɰɢɨɧɧɵɣ ɮɚɤɬɨɪ HIF (Hypoxia-Induced Factor) ɢɝɪɚɟɬ ɧɟɦɚɥɨɜɚɠɧɭɸ ɪɨɥɶ ɜ ɚɤɬɢɜɚɰɢɢ ɮɟɪɦɟɧɬɨɜ, ɫɩɨɫɨɛɫɬɜɭɸɳɢɯ ɩɟɪɟɤɥɸɱɟɧɢɸ ɷɧɟɪɝɟɬɢɤɢ ɤɥɟɬɤɢ ɧɚ ɝɥɢɤɨɥɢɡ [70]. Ɍɚɤɢɦ ɨɛɪɚɡɨɦ, ɜ ɭɫɥɨɜɢɹɯ ɜɨɡɧɢɤɚɸɳɟɣ ɩɪɢ ɪɨɫɬɟ ɨɩɭɯɨɥɢ ɝɢɩɨɤɫɢɢ ɩɪɨɢɫɯɨɞɢɬ ɨɬɛɨɪ ɤɥɟɬɨɤ, ɧɚɢɛɨɥɟɟ ɩɪɢɫɩɨɫɨɛɥɟɧɧɵɯ ɤ ɷɬɢɦ ɭɫɥɨɜɢɹɦ. Ɉɞɧɚɤɨ ɨɫɬɚɟɬɫɹ ɧɟɹɫɧɵɦ ɜɨɩɪɨɫ, ɜɟɞɟɬ ɥɢ ɷɬɨɬ ɨɬɛɨɪ ɜ ɫɬɨɪɨɧɭ ɨɡɥɨɤɚɱɟɫɬɜɥɟɧɢɹ ɨɩɭɯɨɥɢ. 27 Ⱦɚɧɧɵɟ, ɩɨɥɭɱɟɧɧɵɟ ɜ ɪɚɛɨɬɟ Yu J.L. ɢ ɫɨɚɜɬ., ɜ ɤɚɤɨɣ-ɬɨ ɦɟɪɟ ɞɚɸɬ ɨɬɜɟɬ ɧɚ ɷɬɨɬ ɜɨɩɪɨɫ [71]. ȼ ɷɬɨɣ ɪɚɛɨɬɟ ɢɫɫɥɟɞɨɜɚɥɚɫɶ ɡɚɜɢɫɢɦɨɫɬɶ ɱɭɜɫɬɜɢɬɟɥɶɧɨɫɬɢ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ ɤ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɨɣ ɬɟɪɚɩɢɢ ɨɬ ɚɤɬɢɜɧɨɫɬɢ ɝɟɧɚ ɪ53, ɤɨɧɬɪɨɥɢɪɭɸɳɟɝɨ ɤɥɟɬɨɱɧɵɣ ɚɩɨɩɬɨɡ (ɩɪɨɝɪɚɦɦɢɪɭɟɦɭɸ ɝɢɛɟɥɶ ɤɥɟɬɤɢ, ɩɪɨɢɫɯɨɞɹɳɭɸ ɜ ɪɟɡɭɥɶɬɚɬɟ ɜɨɡɧɢɤɧɨɜɟɧɢɹ ɧɚɪɭɲɟɧɢɣ ɜ ɝɟɧɨɦɟ) ɢ ɹɜɥɹɸɳɟɝɨɫɹ ɨɩɭɯɨɥɟɜɵɦ ɫɭɩɪɟɫɫɨɪɨɦ. Ȼɵɥɨ ɩɨɤɚɡɚɧɨ, ɱɬɨ ɦɵɲɢ ɫ ɩɪɢɜɢɬɵɦɢ ɢɦ ɤɥɟɬɤɚɦɢ ɪɚɤɚ ɬɨɥɫɬɨɣ ɤɢɲɤɢ ɱɟɥɨɜɟɤɚ ɇɋɌ116, ɜ ɤɨɬɨɪɵɯ ɝɟɧ ɪ53 ɧɟɚɤɬɢɜɟɧ, ɦɟɧɟɟ ɱɭɜɫɬɜɢɬɟɥɶɧɵ ɤ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɨɣ ɬɟɪɚɩɢɢ, ɱɟɦ ɦɵɲɢ ɫ ɪɚɛɨɬɚɸɳɢɦ ɝɟɧɨɦ ɪ53. Ɍɨ ɟɫɬɶ, ɩɪɢ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɨɣ ɬɟɪɚɩɢɢ ɞɨɥɠɟɧ ɩɪɨɢɫɯɨɞɢɬɶ ɨɬɛɨɪ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ ɫ ɩɨɜɪɟɠɞɟɧɧɵɦ ɝɟɧɨɦ ɪ53. ɂɡɜɟɫɬɧɨ, ɱɬɨ ɝɟɧɨɦ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ ɯɚɪɚɤɬɟɪɢɡɭɟɬɫɹ ɧɟɫɬɚɛɢɥɶɧɨɫɬɶɸ. ɉɪɢ ɪɚɛɨɬɚɸɳɟɦ ɝɟɧɟ ɪ53 ɩɪɨɢɫɯɨɞɢɬ ɨɫɬɚɧɨɜɤɚ ɞɟɥɟɧɢɹ ɢɥɢ ɚɩɨɩɬɨɡ ɜɨɡɧɢɤɚɸɳɢɯ ɜ ɪɟɡɭɥɶɬɚɬɟ ɬɚɤɨɣ ɧɟɫɬɚɛɢɥɶɧɨɫɬɢ ɚɧɨɦɚɥɶɧɵɯ ɤɥɟɬɨɤ. ȼ ɫɥɭɱɚɟ ɠɟ ɢɧɚɤɬɢɜɚɰɢɢ ɝɟɧɚ ɪ53 ɷɥɢɦɢɧɚɰɢɢ ɤɥɟɬɨɤ ɫ ɢɡɦɟɧɟɧɧɵɦ ɝɟɧɨɦɨɦ ɧɟ ɩɪɨɢɫɯɨɞɢɬ, ɭɜɟɥɢɱɢɜɚɟɬɫɹ ɤɨɥɢɱɟɫɬɜɨ ɤɥɟɬɨɤ ɫ ɬɟɦɢ ɢɥɢ ɢɧɵɦɢ ɝɟɧɟɬɢɱɟɫɤɢɦɢ ɚɧɨɦɚɥɢɹɦɢ, ɱɬɨ ɫɩɨɫɨɛɫɬɜɭɟɬ ɩɪɨɝɪɟɫɫɢɢ ɨɩɭɯɨɥɢ. ɗɬɢ ɞɚɧɧɵɟ ɭɤɚɡɵɜɚɸɬ ɧɚ ɬɨ, ɱɬɨ ɩɪɢ ɢɫɩɨɥɶɡɨɜɚɧɢɢ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɯ ɥɟɤɚɪɫɬɜɟɧɧɵɯ ɫɪɟɞɫɬɜ ɦɨɠɟɬ ɩɪɨɢɫɯɨɞɢɬɶ ɨɬɛɨɪ ɤɥɨɧɨɜ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ, ɨɛɥɚɞɚɸɳɢɯ ɛɨɥɶɲɟɣ ɡɥɨɤɚɱɟɫɬɜɟɧɧɨɫɬɶɸ. ɂ ɜ ɬɚɤɨɦ ɫɥɭɱɚɟ ɩɟɪɜɨɧɚɱɚɥɶɧɵɣ ɬɟɪɚɩɟɜɬɢɱɟɫɤɢɣ ɷɮɮɟɤɬ, ɜɵɪɚɠɚɸɳɢɣɫɹ ɜ ɫɞɟɪɠɢɜɚɧɢɢ ɪɨɫɬɚ ɩɟɪɜɢɱɧɨɣ ɨɩɭɯɨɥɢ, ɦɨɠɟɬ ɜ ɞɚɥɶɧɟɣɲɟɦ ɧɢɜɟɥɢɪɨɜɚɬɶɫɹ ɛɨɥɶɲɟɣ ɚɝɪɟɫɫɢɜɧɨɫɬɶɸ ɪɟɡɢɫɬɟɧɬɧɵɯ ɤ ɷɬɨɦɭ ɪɨɞɭ ɬɟɪɚɩɢɢ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ, ɩɪɨɹɜɥɹɸɳɟɣɫɹ ɜ ɭɫɢɥɟɧɢɢ ɢɧɜɚɡɢɢ ɢ ɦɟɬɚɫɬɚɡɢɪɨɜɚɧɢɹ. Ⱥɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɟ ɩɪɟɩɚɪɚɬɵ, ɧɚɩɪɚɜɥɟɧɧɵɟ ɧɚ ɩɨɞɚɜɥɟɧɢɟ VEGFɡɚɜɢɫɢɦɨɝɨ ɫɢɝɧɚɥɢɧɝɚ, ɨɛɥɚɞɚɸɬ ɞɜɨɣɫɬɜɟɧɧɵɦ ɞɟɣɫɬɜɢɟɦ ɧɚ ɨɩɭɯɨɥɟɜɵɟ ɤɥɟɬɤɢ. Ɉɧɢ ɧɟ ɬɨɥɶɤɨ ɫɨɡɞɚɸɬ ɜ ɨɩɭɯɨɥɢ ɭɫɥɨɜɢɹ ɝɢɩɨɤɫɢɢ, ɧɨ ɬɚɤɠɟ ɫɩɨɫɨɛɧɵ ɩɨɞɚɜɥɹɬɶ ɪɚɡɦɧɨɠɟɧɢɟ ɬɟɯ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ, ɤɨɬɨɪɵɟ ɷɤɫɩɪɟɫɫɢɪɭɸɬ ɪɟɰɟɩɬɨɪɵ ɤ ɷɬɢɦ ɮɚɤɬɨɪɚɦ ɪɨɫɬɚ. ȼ ɝɥɚɜɟ «ɗɤɫɩɪɟɫɫɢɹ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ ɜ ɨɩɭɯɨɥɹɯ ɱɟɥɨɜɟɤɚ» ɭɠɟ ɛɵɥɢ ɩɪɢɜɟɞɟɧɵ ɩɨɥɭɱɟɧɧɵɟ ɧɚɦɢ ɞɚɧɧɵɟ ɨ ɬɨɦ, ɱɬɨ ɞɨɛɚɜɥɟɧɢɟ ɜ ɫɪɟɞɭ ɤɭɥɶɬɢɜɢɪɨɜɚɧɢɹ ɪɚɫɬɜɨɪɢɦɨɣ ɮɨɪɦɵ 28 ɪɟɰɟɩɬɨɪɚ VEGFR3 ɩɪɢɜɨɞɢɥɨ ɤ ɡɧɚɱɢɬɟɥɶɧɨɦɭ ɢɧɝɢɛɢɪɨɜɚɧɢɸ ɩɪɨɥɢɮɟɪɚɰɢɢ ɤɭɥɶɬɭɪɵ ɤɥɟɬɨɤ ɤɚɪɰɢɧɨɦɵ ɥɟɝɤɨɝɨ ɱɟɥɨɜɟɤɚ Ⱥ549, ɷɤɫɩɪɟɫɫɢɪɭɸɳɢɯ ɷɬɨɬ ɪɟɰɟɩɬɨɪ. ɗɤɫɩɪɟɫɫɢɹ ɬɟɯ ɢɥɢ ɢɧɵɯ ɪɟɰɟɩɬɨɪɨɜ VEGF ɩɪɨɞɟɦɨɧɫɬɪɢɪɨɜɚɧɚ ɜ ɤɥɟɬɤɚɯ ɨɩɭɯɨɥɟɣ ɪɚɡɥɢɱɧɨɝɨ ɩɪɨɢɫɯɨɠɞɟɧɢɹ [41, 42, 72, 73]. ɂ ɫɥɟɞɨɜɚɬɟɥɶɧɨ, ɧɚɛɥɸɞɚɟɦɨɟ ɩɪɢ ɞɟɣɫɬɜɢɢ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ ɭɦɟɧɶɲɟɧɢɟ ɪɚɡɦɟɪɨɜ ɩɟɪɜɢɱɧɨɣ ɨɩɭɯɨɥɢ ɦɨɠɟɬ ɛɵɬɶ ɫɜɹɡɚɧɨ ɤɚɤ ɫ ɝɢɛɟɥɶɸ ɤɥɟɬɨɤ ɜ ɭɫɥɨɜɢɹɯ ɝɢɩɨɤɫɢɢ, ɬɚɤ ɢ ɫ ɩɨɞɚɜɥɟɧɢɟɦ ɢɯ ɪɚɡɦɧɨɠɟɧɢɹ ɜɫɥɟɞɫɬɜɢɟ ɢɧɝɢɛɢɪɨɜɚɧɢɹ VEGF-ɡɚɜɢɫɢɦɨɣ ɚɭɬɨɤɪɢɧɧɨɣ ɪɟɝɭɥɹɰɢɢ ɞɟɥɟɧɢɹ. ɉɪɢ ɷɬɨɦ, ɤɚɤ ɨɬɦɟɱɚɥɨɫɶ ɜɵɲɟ, ɜ ɭɫɥɨɜɢɹɯ ɝɢɩɨɤɫɢɢ ɩɪɨɢɫɯɨɞɢɬ ɨɬɛɨɪ ɤɥɨɧɨɜ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ, ɨɛɥɚɞɚɸɳɢɯ ɛɨɥɶɲɟɣ ɡɥɨɤɚɱɟɫɬɜɟɧɧɨɫɬɶɸ. Ɂɚɜɢɫɢɬ ɥɢ ɚɤɬɢɜɧɨɫɬɶ VEGF-ɡɚɜɢɫɢɦɵɯ ɫɢɝɧɚɥɶɧɵɯ ɫɢɫɬɟɦ ɨɬ ɫɬɟɩɟɧɢ ɡɥɨɤɚɱɟɫɬɜɟɧɧɨɫɬɢ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ – ɜɨɩɪɨɫ, ɬɪɟɛɭɸɳɢɣ ɜɵɹɫɧɟɧɢɹ, ɜ ɬɨɦ ɱɢɫɥɟ ɢ ɫ ɬɨɱɤɢ ɡɪɟɧɢɹ ɩɪɚɤɬɢɱɟɫɤɨɝɨ ɩɪɢɦɟɧɟɧɢɹ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ ɧɚ ɪɚɡɧɵɯ ɫɬɚɞɢɹɯ ɨɩɭɯɨɥɟɜɨɝɨ ɪɨɫɬɚ. 29 ɗɤɫɩɪɟɫɫɢɹ ɮɚɤɬɨɪɚ ɪɨɫɬɚ VEGF-C ɢ ɟɝɨ ɪɟɰɟɩɬɨɪɚ VEGFR3 ɩɪɢ ɪɚɡɥɢɱɧɵɯ ɩɚɬɨɥɨɝɢɹɯ ɳɢɬɨɜɢɞɧɨɣ ɠɟɥɟɡɵ. Ɇɵ ɢɫɫɥɟɞɨɜɚɥɢ ɷɤɫɩɪɟɫɫɢɸ ɪɟɰɟɩɬɨɪɚ VEGFR3 (FLT4) ɢ ɜɡɚɢɦɨɞɟɣɫɬɜɭɸɳɟɝɨ ɫ ɷɬɢɦ ɪɟɰɟɩɬɨɪɨɦ ɮɚɤɬɨɪɚ ɪɨɫɬɚ VEGF-C ɜ ɨɛɪɚɡɰɚɯ ɬɤɚɧɢ ɛɨɥɶɧɵɯ ɫ ɪɚɡɥɢɱɧɨɣ ɩɚɬɨɥɨɝɢɟɣ ɳɢɬɨɜɢɞɧɨɣ ɠɟɥɟɡɵ [44]. Ȼɵɥɢ ɢɫɫɥɟɞɨɜɚɧɵ ɩɪɨɥɢɮɟɪɚɬɢɜɧɵɟ (ɚɭɬɨɢɦɦɭɧɧɵɟ ɩɚɬɨɥɨɝɢɢ, ɡɚɛɨɥɟɜɚɧɢɹ ɞɢɮɮɭɡɧɵɟ ɢ ɳɢɬɨɜɢɞɧɨɣ ɭɡɥɨɜɵɟ ɡɨɛɵ), ɠɟɥɟɡɵ ɚɞɟɧɨɦɵ ɢ ɚɞɟɧɨɤɚɪɰɢɧɨɦɵ. Ɉɰɟɧɢɜɚɥɚɫɶ ɷɤɫɩɪɟɫɫɢɹ ɤɚɤ ɦɊɇɄ (ɦɟɬɨɞɨɦ ɩɨɥɢɦɟɪɚɡɧɨɣ ɰɟɩɧɨɣ ɪɟɚɤɰɢɢ ɫ ɨɛɪɚɬɧɨɣ ɬɪɚɧɫɤɪɢɩɰɢɟɣ, ɈɌ-ɉɐɊ), ɬɚɤ ɢ ɛɟɥɤɚ (ɦɟɬɨɞɨɦ ɢɦɦɭɧɨɝɢɫɬɨɯɢɦɢɢ). ɂɦɦɭɧɨɝɢɫɬɨɯɢɦɢɱɟɫɤɨɟ ɢɫɫɥɟɞɨɜɚɧɢɟ ɩɨɤɚɡɚɥɨ, ɱɬɨ ɪɟɰɟɩɬɨɪ VEGFR3 ɷɤɫɩɪɟɫɫɢɪɨɜɚɧ ɧɟ ɬɨɥɶɤɨ ɜ ɤɥɟɬɤɚɯ ɷɧɞɨɬɟɥɢɹ ɫɨɫɭɞɨɜ, ɧɨ ɢ ɜ ɤɥɟɬɤɚɯ ɨɩɭɯɨɥɟɣ ɳɢɬɨɜɢɞɧɨɣ ɠɟɥɟɡɵ (ɫɦ. ɪɢɫ.3), ɢ ɬɚɤɢɦ ɨɛɪɚɡɨɦ, VEGF-ɋ, ɜɡɚɢɦɨɞɟɣɫɬɜɭɹ ɫ ɪɟɰɟɩɬɨɪɨɦ VEGFR3, ɫɩɨɫɨɛɟɧ ɪɟɝɭɥɢɪɨɜɚɬɶ ɩɪɨɥɢɮɟɪɚɰɢɸ ɷɬɢɯ ɤɥɟɬɨɤ. ȼ ɫɜɹɡɢ ɫ ɷɬɢɦ ɨɫɨɛɟɧɧɨ ɜɚɠɧɨ ɛɵɥɨ ɨɰɟɧɢɬɶ ɷɤɫɩɪɟɫɫɢɸ ɪɟɰɟɩɬɨɪɚ VEGFR3 ɩɪɢ ɪɚɡɥɢɱɧɵɯ ɩɚɬɨɥɨɝɢɹɯ. Ɉɤɚɡɚɥɨɫɶ, ɱɬɨ ɧɚɢɛɨɥɟɟ ɜɵɪɚɠɟɧɧɨɣ ɷɤɫɩɪɟɫɫɢɹ ɦɊɇɄ VEGFR3 ɛɵɥɚ ɜ ɚɞɟɧɨɦɚɯ ɢ ɜ ɨɛɪɚɡɰɚɯ ɩɪɨɥɢɮɟɪɚɬɢɜɧɵɯ ɩɚɬɨɥɨɝɢɣ, ɝɞɟ ɩɪɚɤɬɢɱɟɫɤɢ ɜɫɟ ɢɫɫɥɟɞɨɜɚɧɧɵɟ ɨɛɪɚɡɰɵ ɷɤɫɩɪɟɫɫɢɪɨɜɚɥɢ ɦɊɇɄ VEGFR3. ȼ ɚɞɟɧɨɤɚɪɰɢɧɨɦɚɯ ɚɤɬɢɜɧɨɫɬɶ ɷɬɨɝɨ ɝɟɧɚ ɛɵɥɚ ɡɚɦɟɬɧɨ ɫɧɢɠɟɧɚ (Ɍɚɛɥɢɰɚ 1). Ɍɚɛɥɢɰɚ 1. ɗɤɫɩɪɟɫɫɢɹ ɦɊɇɄ VEGF-ɋ ɢ VEGFR3 ɜ ɨɛɪɚɡɰɚɯ ɬɤɚɧɢ ɛɨɥɶɧɵɯ ɫ ɪɚɡɥɢɱɧɨɣ ɩɚɬɨɥɨɝɢɟɣ ɳɢɬɨɜɢɞɧɨɣ ɠɟɥɟɡɵ. ɉɚɬɨɥɨɝɢɹ Ʉɨɥɢɱɟɫɬɜɨ ɗɤɫɩɪɟɫɫɢɹ ɨɛɪɚɡɰɨɜ VEGFR3 ɗɤɫɩɪɟɫɫɢɹ VEGF-ɋ ɉɪɨɥɢɮɟɪɚɬɢɜɧɵɟ ɡɚɛɨɥɟɜɚɧɢɹ 17 16/17 14/17 Ⱥɞɟɧɨɦɵ 13 13/13 10/13 Ⱥɞɟɧɨɤɚɪɰɢɧɨɦɵ 8 3/8 4/8 30 Ⱥɧɚɥɨɝɢɱɧɵɟ ɪɟɡɭɥɶɬɚɬɵ ɛɵɥɢ ɩɨɥɭɱɟɧɵ ɞɥɹ ɷɤɫɩɪɟɫɫɢɢ VEGF-ɋ: ɛɨɥɶɲɚɹ ɱɚɫɬɶ ɨɛɪɚɡɰɨɜ ɚɞɟɧɨɦ ɢ ɩɪɨɥɢɮɟɪɚɬɢɜɧɵɯ ɡɚɛɨɥɟɜɚɧɢɣ ɛɵɥɚ ɩɨɥɨɠɢɬɟɥɶɧɨɣ ɩɨ ɷɤɫɩɪɟɫɫɢɢ ɦɊɇɄ ɷɬɨɝɨ ɝɟɧɚ, ɬɨɝɞɚ ɤɚɤ ɜ 50% ɨɛɪɚɡɰɨɜ ɚɞɟɧɨɤɚɪɰɢɧɨɦ ɷɤɫɩɪɟɫɫɢɢ VEGF-ɋ ɨɛɧɚɪɭɠɟɧɨ ɧɟ ɛɵɥɨ (Ɍɚɛɥɢɰɚ 1). ȼ ɧɚɲɟɣ ɪɚɛɨɬɟ ɦɟɬɨɞɨɦ ɢɦɦɭɧɨɝɢɫɬɨɯɢɦɢɢ ɧɚ ɝɢɫɬɨɥɨɝɢɱɟɫɤɢɯ ɫɪɟɡɚɯ ɚɞɟɧɨɦ ɢ ɚɞɟɧɨɤɚɪɰɢɧɨɦ ɳɢɬɨɜɢɞɧɨɣ ɠɟɥɟɡɵ ɱɟɥɨɜɟɤɚ ɬɚɤɠɟ ɢɫɫɥɟɞɨɜɚɥɚɫɶ ɷɤɫɩɪɟɫɫɢɹ ɛɟɥɤɚ VEGFR3. Ɉɤɪɚɲɢɜɚɧɢɟ ɚɧɬɢɬɟɥɚɦɢ ɤ VEGFR3 ɩɨɤɚɡɚɥɨ, ɱɬɨ ɩɨ ɫɪɚɜɧɟɧɢɸ ɫ ɨɤɪɭɠɚɸɳɟɣ ɨɩɭɯɨɥɶ ɨɤɨɥɨɧɨɪɦɚɥɶɧɨɣ ɬɤɚɧɶɸ ɳɢɬɨɜɢɞɧɨɣ ɠɟɥɟɡɵ ɜ ɨɩɭɯɨɥɹɯ (ɤɚɤ ɜ ɚɞɟɧɨɦɚɯ, ɬɚɤ ɢ ɜ ɚɞɟɧɨɤɚɪɰɢɧɨɦɚɯ) ɤɨɥɢɱɟɫɬɜɨ ɷɬɨɝɨ ɛɟɥɤɚ ɡɚɦɟɬɧɨ ɭɜɟɥɢɱɢɜɚɟɬɫɹ (Ɍɚɛɥɢɰɚ 2). ɉɪɢɱɟɦ ɧɚɢɛɨɥɟɟ ɜɵɫɨɤɢɦ ɫɨɞɟɪɠɚɧɢɟ VEGFR3 ɨɤɚɡɚɥɨɫɶ ɜ ɞɨɛɪɨɤɚɱɟɫɬɜɟɧɧɵɯ ɨɩɭɯɨɥɹɯ – ɚɞɟɧɨɦɚɯ, ɬɨɝɞɚ ɤɚɤ ɜ ɚɞɟɧɨɤɚɪɰɢɧɨɦɚɯ ɟɝɨ ɤɨɥɢɱɟɫɬɜɨ ɛɵɥɨ ɫɬɚɬɢɫɬɢɱɟɫɤɢ ɡɧɚɱɢɦɨ ɫɧɢɠɟɧɨ. Ɍɚɛɥɢɰɚ 2. ɗɤɫɩɪɟɫɫɢɹ ɛɟɥɤɚ VEGFR3 ɜ ɚɞɟɧɨɦɚɯ ɢ ɚɞɟɧɨɤɚɪɰɢɧɨɦɚɯ ɳɢɬɨɜɢɞɧɨɣ ɠɟɥɟɡɵ ɱɟɥɨɜɟɤɚ. (ɉɨɞɫɱɢɬɵɜɚɥɨɫɶ ɤɨɥɢɱɟɫɬɜɨ ɩɨɥɨɠɢɬɟɥɶɧɨ ɨɤɪɚɲɟɧɧɵɯ ɧɚ VEGFR3 ɫɬɪɭɤɬɭɪ ɧɚ 1 ɦɦ2 ɩɥɨɳɚɞɢ ɝɢɫɬɨɥɨɝɢɱɟɫɤɨɝɨ ɫɪɟɡɚ). Ʉɨɥɢɱɟɫɬɜɨ ɨɛɪɚɡɰɨɜ ɗɤɫɩɪɟɫɫɢɹ VEGFR3 ɇɨɪɦɚ* 6 11,50 Ⱥɞɟɧɨɦɵ 5 48,26# Ⱥɞɟɧɨɤɚɪɰɢɧɨɦɵ 6 20,30# ɉɚɬɨɥɨɝɢɹ ɋɬɚɬɢɫɬɢɱɟɫɤɚɹ ɡɧɚɱɢɦɨɫɬɶ (ɤɨɥ-ɜɨ VEGFR3+ ɫɬɪɭɤɬɭɪ/ɦɦ2) ɪ = 0,0093 Ɍɚɤɢɦ ɨɛɪɚɡɨɦ, ɜ ɧɚɲɟɦ ɢɫɫɥɟɞɨɜɚɧɢɢ ɨɤɚɡɚɥɨɫɶ, ɱɬɨ ɷɤɫɩɪɟɫɫɢɹ ɤɚɤ ɦɊɇɄ, ɬɚɤ ɢ ɛɟɥɤɚ VEGFR3 ɜ ɚɞɟɧɨɤɚɪɰɢɧɨɦɚɯ ɫɧɢɠɟɧɚ ɩɨ ɫɪɚɜɧɟɧɢɸ ɫ ɚɞɟɧɨɦɚɦɢ. ɗɬɢ ɞɚɧɧɵɟ ɦɨɝɥɢ ɭɤɚɡɵɜɚɬɶ ɧɚ ɫɧɢɠɟɧɢɟ ɷɤɫɩɪɟɫɫɢɢ * ɷɬɨɝɨ ȼ ɤɚɱɟɫɬɜɟ ɧɨɪɦɵ ɢɫɫɥɟɞɨɜɚɥɚɫɶ ɨɤɪɭɠɚɸɳɚɹ ɚɞɟɧɨɤɚɪɰɢɧɨɦɵ ɨɤɨɥɨɧɨɪɦɚɥɶɧɚɹ ɬɤɚɧɶ ɳɢɬɨɜɢɞɧɨɣ ɠɟɥɟɡɵ 31 ɪɟɰɟɩɬɨɪɚ ɩɪɢ ɨɡɥɨɤɚɱɟɫɬɜɥɟɧɢɢ. Ɉɞɧɚɤɨ ɨɛɪɚɳɚɥɨ ɧɚ ɫɟɛɹ ɜɧɢɦɚɧɢɟ ɢɡɦɟɧɟɧɢɟ ɫɚɦɨɣ ɫɬɪɭɤɬɭɪɵ ɬɤɚɧɢ ɳɢɬɨɜɢɞɧɨɣ ɠɟɥɟɡɵ ɜ ɚɞɟɧɨɤɚɪɰɢɧɨɦɚɯ, ɝɞɟ ɭɠɟ ɧɟ ɧɚɛɥɸɞɚɥɚɫɶ ɯɚɪɚɤɬɟɪɧɚɹ ɠɟɥɟɡɢɫɬɚɹ ɫɬɪɭɤɬɭɪɚ. Ɇɨɠɧɨ ɛɵɥɨ ɩɪɟɞɩɨɥɨɠɢɬɶ, ɱɬɨ ɫɧɢɠɟɧɢɟ ɭɪɨɜɧɹ ɷɤɫɩɪɟɫɫɢɢ ɤɚɤ ɦɊɇɄ, ɬɚɤ ɢ ɛɟɥɤɚ VEGFR3 ɦɨɠɟɬ ɛɵɬɶ ɫɜɹɡɚɧɨ ɧɟ ɫɬɨɥɶɤɨ ɫ ɨɡɥɨɤɚɱɟɫɬɜɥɟɧɢɟɦ ɨɩɭɯɨɥɟɜɨɣ ɬɤɚɧɢ, ɫɤɨɥɶɤɨ ɫ ɢɡɦɟɧɟɧɢɟɦ ɟɟ ɫɬɪɭɤɬɭɪɵ. 32 ɗɤɫɩɪɟɫɫɢɹ ɦɊɇɄ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF-A, VEGF-C, VEGF-D ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ VEGFR2 ɢ VEGFR3 ɜ ɨɩɭɯɨɥɹɯ ɦɨɱɟɜɨɝɨ ɩɭɡɵɪɹ ɱɟɥɨɜɟɤɚ ɢ ɜ ɫɚɪɤɨɦɟ Ʉɚɩɨɲɢ. ɋɥɟɞɭɸɳɟɣ ɩɚɬɨɥɨɝɢɟɣ, ɜ ɤɨɬɨɪɨɣ ɦɵ ɢɫɫɥɟɞɨɜɚɥɢ ɷɤɫɩɪɟɫɫɢɸ ɦɊɇɄ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF-A, VEGF-C, VEGF-D ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ VEGFR2 ɢ VEGFR3, ɛɵɥɢ ɨɩɭɯɨɥɢ ɦɨɱɟɜɨɝɨ ɩɭɡɵɪɹ ɱɟɥɨɜɟɤɚ [74]. ɉɨɥɭɱɟɧɧɵɟ ɞɚɧɧɵɟ ɩɪɟɞɫɬɚɜɥɟɧɵ ɧɚ ɪɢɫɭɧɤɚɯ 8 ɢ 9. ɂɡ ɞɚɧɧɵɯ, ɩɪɟɞɫɬɚɜɥɟɧɧɵɯ ɧɚ ɪɢɫɭɧɤɚɯ, ɜɢɞɧɨ, ɱɬɨ ɧɚɢɛɨɥɟɟ ɜɵɫɨɤɚ ɚɤɬɢɜɧɨɫɬɶ ɢɫɫɥɟɞɭɟɦɵɯ ɝɟɧɨɜ ɧɚ ɫɬɚɞɢɹɯ Ɍ1/1-2 – Ɍ1/2. Ɉɫɨɛɟɧɧɨ ɡɚɦɟɬɧɨ ɩɨɜɵɲɟɧɢɟ ɚɤɬɢɜɧɨɫɬɢ ɝɟɧɨɜ ɮɚɤɬɨɪɚ ɪɨɫɬɚ VEGF-A ɢ ɪɟɰɟɩɬɨɪɨɜ VEGFR2 ɢ VEGFR3 (Ɋɢɫ.8). ɉɪɢɱɟɦ, ɧɚɢɛɨɥɟɟ ɜɵɫɨɤɚ ɚɤɬɢɜɧɨɫɬɶ ɷɬɢɯ ɝɟɧɨɜ, ɨɫɨɛɟɧɧɨ ɝɟɧɚ, ɤɨɞɢɪɭɸɳɟɝɨ ɪɟɰɟɩɬɨɪ VEGF2, ɧɚ ɫɬɚɞɢɢ Ɍ1/2. ɂ ɯɨɬɹ ɤɨɥɢɱɟɫɬɜɨ ɨɛɪɚɡɰɨɜ ɪɚɤɚ ɦɨɱɟɜɨɝɨ ɩɭɡɵɪɹ, ɧɚɯɨɞɹɳɢɯɫɹ ɧɚ ɫɬɚɞɢɹɯ Ɍ1/1 ɢ Ɍ1/1-2 ɧɟɜɟɥɢɤɨ, ɦɨɠɧɨ ɨɬɦɟɬɢɬɶ ɬɟɧɞɟɧɰɢɸ ɭɫɢɥɟɧɢɹ ɚɤɬɢɜɧɨɫɬɢ ɝɟɧɨɜ VEGF-A ɢ VEGFR2 ɨɬ ɫɬɚɞɢɢ Ɍ1/1 ɤ ɫɬɚɞɢɢ Ɍ1/2, ɬɨ ɟɫɬɶ, ɩɨ ɦɟɪɟ ɨɡɥɨɤɚɱɟɫɬɜɥɟɧɢɹ. VEGF-A VEGF-C VEGF-D VEGFR2 VEGFR3 ȕ2-M Ɋɢɫ. 8. ɗɤɫɩɪɟɫɫɢɹ ɦɊɇɄ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF-A, VEGF-C, VEGF-D ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ VEGFR2, VEGFR3 ɜ ɨɛɪɚɡɰɚɯ ɪɚɧɧɢɯ ɫɬɚɞɢɣ ɪɚɤɚ ɦɨɱɟɜɨɝɨ ɩɭɡɵɪɹ ɱɟɥɨɜɟɤɚ. 33 Ɉɞɧɚɤɨ ɩɪɢ ɞɚɥɶɧɟɣɲɟɣ ɩɪɨɝɪɟɫɫɢɢ ɡɚɛɨɥɟɜɚɧɢɹ, ɜ ɨɛɪɚɡɰɚɯ Ɍ1/3 – Ɍ4/23, ɩɨɹɜɥɹɟɬɫɹ ɝɟɬɟɪɨɝɟɧɧɨɫɬɶ ɜ ɢɧɬɟɧɫɢɜɧɨɫɬɢ ɫɢɝɧɚɥɨɜ ɦɊɇɄ VEGFR2, ɚ ɜ ɨɬɞɟɥɶɧɵɯ ɨɛɪɚɡɰɚɯ ɧɚɛɥɸɞɚɟɬɫɹ ɡɧɚɱɢɬɟɥɶɧɨɟ ɫɧɢɠɟɧɢɟ ɷɤɫɩɪɟɫɫɢɢ ɨɬɞɟɥɶɧɵɯ ɝɟɧɨɜ ɢɥɢ ɞɚɠɟ ɨɬɫɭɬɫɬɜɢɟ ɢɯ ɷɤɫɩɪɟɫɫɢɢ. ȼ ɰɟɥɨɦ, ɫɪɚɜɧɢɜɚɹ ɷɤɫɩɪɟɫɫɢɸ ɢɫɫɥɟɞɭɟɦɵɯ ɝɟɧɨɜ ɧɚ ɫɬɚɞɢɹɯ Ɍ1/1-Ɍ1/2 ɢ Ɍ1/3-Ɍ4/2-3, ɦɨɠɧɨ ɨɬɦɟɬɢɬɶ ɬɟɧɞɟɧɰɢɸ ɤ ɫɧɢɠɟɧɢɸ ɚɤɬɢɜɧɨɫɬɢ ɝɟɧɨɜ (Ɋɢɫ.9). VEGF-A VEGF-C VEGF-D VEGFR2 VEGFR3 ȕ2-M Ɋɢɫ. 9. ɗɤɫɩɪɟɫɫɢɹ ɦɊɇɄ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF-A, VEGF-C, VEGF-D ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ VEGFR2, VEGFR3 ɜ ɨɛɪɚɡɰɚɯ ɩɨɡɞɧɢɯ ɫɬɚɞɢɣ ɪɚɤɚ ɦɨɱɟɜɨɝɨ ɩɭɡɵɪɹ ɱɟɥɨɜɟɤɚ. Ɍɚɤɢɦ ɨɛɪɚɡɨɦ, ɢ ɩɪɢ ɢɫɫɥɟɞɨɜɚɧɢɢ ɪɚɤɚ ɦɨɱɟɜɨɝɨ ɩɭɡɵɪɹ ɱɟɥɨɜɟɤɚ ɷɤɫɩɪɟɫɫɢɹ ɝɟɧɨɜ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ ɭɫɢɥɢɜɚɥɚɫɶ ɧɚ ɪɚɧɧɢɯ ɫɬɚɞɢɹɯ ɩɪɨɝɪɟɫɫɢɢ ɡɚɛɨɥɟɜɚɧɢɹ, ɬɨɝɞɚ ɤɚɤ ɧɚ ɛɨɥɟɟ ɩɨɡɞɧɢɯ ɫɬɚɞɢɹɯ ɩɪɨɝɪɟɫɫɢɢ ɧɚɛɥɸɞɚɥɨɫɶ ɫɧɢɠɟɧɢɟ ɢɯ ɚɤɬɢɜɧɨɫɬɢ. Ⱥɧɚɥɨɝɢɱɧɵɟ ɪɟɡɭɥɶɬɚɬɵ ɛɵɥɢ ɩɨɥɭɱɟɧɵ ɧɚɦɢ ɢ ɩɪɢ ɢɫɫɥɟɞɨɜɚɧɢɢ ɷɤɫɩɪɟɫɫɢɢ ɷɬɢɯ ɠɟ ɝɟɧɨɜ ɜ ɨɛɪɚɡɰɚɯ ɛɨɥɶɧɵɯ ɫɚɪɤɨɦɨɣ Ʉɚɩɨɲɢ [45]. ɋɚɪɤɨɦɚ Ʉɚɩɨɲɢ ɩɪɟɞɫɬɚɜɥɹɥɚ ɞɥɹ ɧɚɫ ɨɫɨɛɵɣ ɢɧɬɟɪɟɫ, ɩɨɫɤɨɥɶɤɭ ɷɬɚ ɨɩɭɯɨɥɶ, ɩɪɨɢɫɯɨɞɢɬ ɢɡ ɷɧɞɨɬɟɥɢɚɥɶɧɵɯ ɤɥɟɬɨɤ. ȼ ɫɨɨɬɜɟɬɫɬɜɢɢ ɫ ɦɟɠɞɭɧɚɪɨɞɧɨɣ ɤɥɚɫɫɢɮɢɤɚɰɢɟɣ ȼɈɁ, ɫɚɪɤɨɦɚ Ʉɚɩɨɲɢ ɫɱɢɬɚɟɬɫɹ ɡɥɨɤɚɱɟɫɬɜɟɧɧɨɣ ɨɩɭɯɨɥɶɸ ɤɪɨɜɟɧɨɫɧɵɯ ɫɨɫɭɞɨɜ. Ɉɞɧɚɤɨ ɞɨ ɫɢɯ ɩɨɪ ɧɟɬ ɟɞɢɧɨɝɨ ɦɧɟɧɢɹ ɨ ɬɨɦ, 34 ɩɪɨɢɫɯɨɞɢɬ ɥɢ ɷɬɚ ɨɩɭɯɨɥɶ ɢɡ ɤɥɟɬɨɤ ɷɧɞɨɬɟɥɢɹ ɤɪɨɜɟɧɨɫɧɵɯ ɢɥɢ ɥɢɦɮɚɬɢɱɟɫɤɢɯ ɫɨɫɭɞɨɜ. ȼ ɢɫɫɥɟɞɨɜɚɧɧɨɣ ɧɚɦɢ ɝɪɭɩɩɟ ɛɨɥɶɧɵɯ ɷɤɫɩɪɟɫɫɢɪɨɜɚɥɚɫɶ ɤɚɤ ɦɊɇɄ ɝɟɧɚ VEGFR2, ɤɨɞɢɪɭɸɳɟɝɨ ɪɟɰɟɩɬɨɪ, ɫɩɟɰɢɮɢɱɧɵɣ ɞɥɹ ɤɥɟɬɨɤ ɷɧɞɨɬɟɥɢɹ ɤɪɨɜɟɧɨɫɧɵɯ ɫɨɫɭɞɨɜ, ɬɚɤ ɢ ɦɊɇɄ ɝɟɧɚ VEGFR3, ɤɨɞɢɪɭɸɳɟɝɨ ɪɟɰɟɩɬɨɪ, ɥɨɤɚɥɢɡɨɜɚɧɧɵɣ ɩɪɟɢɦɭɳɟɫɬɜɟɧɧɨ ɧɚ ɤɥɟɬɤɚɯ ɷɧɞɨɬɟɥɢɹ ɥɢɦɮɚɬɢɱɟɫɤɢɯ ɫɨɫɭɞɨɜ (Ɋɢɫ. 10). ɗɬɢ ɞɚɧɧɵɟ ɭɤɚɡɵɜɚɥɢ ɧɚ ɜɨɡɦɨɠɧɨɫɬɶ ɩɪɨɢɫɯɨɠɞɟɧɢɹ ɫɚɪɤɨɦɵ Ʉɚɩɨɲɢ ɬɚɤɠɟ ɢ ɢɡ ɤɥɟɬɨɤ ɷɧɞɨɬɟɥɢɹ ɥɢɦɮɚɬɢɱɟɫɤɢɯ ɫɨɫɭɞɨɜ. Ɋɢɫ. 10. ɗɤɫɩɪɟɫɫɢɹ ɦɊɇɄ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF-A, VEGF-C, VEGF-D ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ VEGFR2 ɢ VEGFR3 ɜ ɨɛɪɚɡɰɚɯ ɫɚɪɤɨɦɵ Ʉɚɩɨɲɢ. Ⱥ. ɇɚ ɪɚɧɧɢɯ ɫɬɚɞɢɹɯ ɡɚɛɨɥɟɜɚɧɢɹ. ȼ. ɇɚ ɫɬɚɞɢɹɯ ɩɪɨɝɪɟɫɫɢɢ ɨɩɭɯɨɥɢ. ɇɚ ɫɬɚɞɢɹɯ ɩɪɨɝɪɟɫɫɢɢ ɫɚɪɤɨɦɵ Ʉɚɩɨɲɢ, ɬɚɤ ɠɟ ɤɚɤ ɢ ɜ ɫɥɭɱɚɟ ɪɚɤɚ ɦɨɱɟɜɨɝɨ ɩɭɡɵɪɹ, ɧɚɛɥɸɞɚɥɨɫɶ ɭɫɢɥɟɧɢɟ ɝɟɬɟɪɨɝɟɧɧɨɫɬɢ ɫɢɝɧɚɥɨɜ ɦɊɇɄ ɢ ɩɨɹɜɥɹɥɢɫɶ ɨɛɪɚɡɰɵ, ɜ ɤɨɬɨɪɵɯ ɷɤɫɩɪɟɫɫɢɹ ɦɊɇɄ ɝɟɧɨɜ, ɤɨɞɢɪɭɸɳɢɯ ɪɟɰɟɩɬɨɪɵ, ɨɬɫɭɬɫɬɜɨɜɚɥɚ. Ɇɟɬɨɞɨɦ ɢɦɦɭɧɨɝɢɫɬɨɯɢɦɢɢ ɛɵɥɚ ɢɫɫɥɟɞɨɜɚɧɚ ɷɤɫɩɪɟɫɫɢɹ ɛɟɥɤɚ ɮɚɤɬɨɪɚ ɪɨɫɬɚ VEGF-A ɢ ɜɫɟɯ 3-ɯ ɪɟɰɟɩɬɨɪɨɜ VEGFR ɜ ɨɛɪɚɡɰɚɯ ɫɚɪɤɨɦɵ Ʉɚɩɨɲɢ ɢ ɧɟɤɨɬɨɪɵɯ ɞɨɛɪɨɤɚɱɟɫɬɜɟɧɧɵɯ ɷɧɞɨɬɟɥɢɚɥɶɧɵɯ ɩɚɬɨɥɨɝɢɣ (ɚɧɝɢɨɤɟɪɚɬɨɦɵ, ɩɫɟɜɞɨɫɚɪɤɨɦɚ Ʉɚɩɨɲɢ, ɜɚɫɤɭɥɢɬɵ). ɂ ɟɫɥɢ ɩɪɢ ɢɫɫɥɟɞɨɜɚɧɢɢ ɷɤɫɩɪɟɫɫɢɢ ɦɊɇɄ ɦɟɬɨɞɨɦ ɈɌ-ɉɐɊ ɨɰɟɧɢɜɚɥɫɹ ɫɭɦɦɚɪɧɵɣ ɭɪɨɜɟɧɶ ɚɤɬɢɜɧɨɫɬɢ ɝɟɧɨɜ ɤɚɤ ɜ 35 ɤɥɟɬɤɚɯ ɨɩɭɯɨɥɢ, ɬɚɤ ɢ ɜ ɩɪɨɧɢɡɵɜɚɸɳɢɯ ɨɩɭɯɨɥɶ ɫɨɫɭɞɚɯ, ɬɨ ɢɦɦɭɧɨɝɢɫɬɨɯɢɦɢɱɟɫɤɨɟ ɨɤɪɚɲɢɜɚɧɢɟ ɩɨɡɜɨɥɢɥɨ ɨɩɪɟɞɟɥɢɬɶ ɷɤɫɩɪɟɫɫɢɸ ɛɟɥɤɚ ɧɟɩɨɫɪɟɞɫɬɜɟɧɧɨ ɜ ɜɟɪɟɬɟɧɨɜɢɞɧɵɯ ɤɥɟɬɤɚɯ ɫɚɪɤɨɦɵ Ʉɚɩɨɲɢ. Ɋɟɡɭɥɶɬɚɬɵ, ɩɨɥɭɱɟɧɧɵɟ ɩɪɢ ɢɦɦɭɧɨɝɢɫɬɨɯɢɦɢɱɟɫɤɨɦ ɨɤɪɚɲɢɜɚɧɢɢ, ɩɪɢɜɟɞɟɧɵ ɜ ɬɚɛɥɢɰɟ 3. ɂɡ ɩɪɟɞɫɬɚɜɥɟɧɧɵɯ ɜ ɬɚɛɥɢɰɟ 3 ɞɚɧɧɵɯ ɜɢɞɧɨ, ɱɬɨ, ɩɨ ɫɪɚɜɧɟɧɢɸ ɫ ɧɚɱɚɥɶɧɵɦɢ ɫɬɚɞɢɹɦɢ ɫɚɪɤɨɦɵ Ʉɚɩɨɲɢ, ɧɚ ɫɬɚɞɢɹɯ ɩɪɨɝɪɟɫɫɢɢ ɷɬɨɝɨ ɡɚɛɨɥɟɜɚɧɢɹ ɫɬɚɬɢɫɬɢɱɟɫɤɢ ɞɨɫɬɨɜɟɪɧɨ ɫɧɢɠɟɧɚ ɷɤɫɩɪɟɫɫɢɹ VEGFR3. Ɇɨɠɧɨ ɬɚɤɠɟ ɨɬɦɟɬɢɬɶ ɧɟɡɧɚɱɢɬɟɥɶɧɨɟ ɫɧɢɠɟɧɢɟ ɷɤɫɩɪɟɫɫɢɢ VEGF-A. Ʉɨɥɢɱɟɫɬɜɨ ɨɛɪɚɡɰɨɜ ɫɚɪɤɨɦɵ Ʉɚɩɨɲɢ, ɨɤɪɚɲɟɧɧɵɯ ɧɚ VEGFR1 ɢ VEGFR2 ɛɵɥɨ ɧɟɞɨɫɬɚɬɨɱɧɵɦ ɞɥɹ ɫɬɚɬɢɫɬɢɱɟɫɤɨɣ ɨɰɟɧɤɢ, ɨɞɧɚɤɨ ɡɞɟɫɶ ɬɚɤɠɟ ɧɚɛɥɸɞɚɥɚɫɶ ɬɟɧɞɟɧɰɢɹ ɤ ɫɧɢɠɟɧɢɸ ɱɚɫɬɨɬɵ ɷɤɫɩɪɟɫɫɢɢ ɪɟɰɟɩɬɨɪɚ VEGFR1. Ɍɚɛɥɢɰɚ 3. ɗɤɫɩɪɟɫɫɢɹ ɮɚɤɬɨɪɚ ɪɨɫɬɚ VEGF-A ɢ ɪɟɰɟɩɬɨɪɨɜ VEGFR1, VEGFR2 ɢ VEGFR3 ɜ ɨɛɪɚɡɰɚɯ ɫɚɪɤɨɦɵ Ʉɚɩɨɲɢ ɢ ɩɪɢ ɞɨɛɪɨɤɚɱɟɫɬɜɟɧɧɵɯ ɷɧɞɨɬɟɥɢɚɥɶɧɵɯ ɩɚɬɨɥɨɝɢɹɯ. Ɋɟɡɭɥɶɬɚɬɵ ɢɦɦɭɧɨɝɢɫɬɨɯɢɦɢɱɟɫɤɨɝɨ ɨɤɪɚɲɢɜɚɧɢɹ. ɉɚɬɨɥɨɝɢɹ VEGF-A VEGFR1 VEGFR2 VEGFR3 Ⱦɨɛɪɨɤɚɱɟɫɬɜɟɧɧɵɟ ɷɧɞɨɬɟɥɢɚɥɶɧɵɟ ɩɚɬɨɥɨɝɢɢ 8/9 (88,9%) 2/3 (66,7%) 4/4 (100%) 0/6 (0%) ɇɚɱɚɥɶɧɵɟ ɫɬɚɞɢɢ 9/9 (100%) 2/3 (66,7%) 2/3 (66,7%) 11/11 (100%) ɋɬɚɞɢɢ ɩɪɨɝɪɟɫɫɢɢ 8/10 (80%) 3/7 (42,9%) 4/6 (66,7%) 1/7 (14,3%) ɋɚɪɤɨɦɚ Ʉɚɩɨɲɢ. Ɍɚɤɢɦ ɨɛɪɚɡɨɦ, ɜɨ ɜɫɟɯ 3-ɯ ɢɫɫɥɟɞɨɜɚɧɧɵɯ ɫɥɭɱɚɹɯ ɫɨɥɢɞɧɵɯ ɨɩɭɯɨɥɟɣ ɧɚ ɫɬɚɞɢɹɯ ɩɪɨɝɪɟɫɫɢɢ ɧɚɛɥɸɞɚɥɨɫɶ ɭɫɢɥɟɧɢɟ ɝɟɬɟɪɨɝɟɧɧɨɫɬɢ ɚɤɬɢɜɧɨɫɬɢ ɝɟɧɨɜ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ ɷɧɞɨɬɟɥɢɹ ɫɨɫɭɞɨɜ ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ. ɂ ɜ ɰɟɥɨɦ, ɷɤɫɩɪɟɫɫɢɹ ɦɊɇɄ ɷɬɢɯ ɝɟɧɨɜ ɫɧɢɠɚɥɚɫɶ, ɩɪɢɱɟɦ ɜ ɛɨɥɶɲɟɣ ɫɬɟɩɟɧɢ ɫɧɢɠɟɧɢɟ ɭɪɨɜɧɹ ɷɤɫɩɪɟɫɫɢɢ ɛɵɥɨ ɯɚɪɚɤɬɟɪɧɨ ɞɥɹ ɝɟɧɨɜ, ɤɨɞɢɪɭɸɳɢɯ ɪɟɰɟɩɬɨɪɵ, VEGFR2 ɢ 36 VEGFR3. ɗɤɫɩɪɟɫɫɢɹ ɪɟɰɟɩɬɨɪɨɜ ɜ ɬɤɚɧɢ ɨɩɭɯɨɥɟɣ ɨɫɨɛɟɧɧɨ ɜɚɠɧɚ, ɩɨɫɤɨɥɶɤɭ ɞɚɠɟ ɩɪɢ ɜɵɫɨɤɨɦ ɭɪɨɜɧɟ ɷɤɫɩɪɟɫɫɢɢ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ ɜ ɨɬɫɭɬɫɬɜɢɟ ɪɟɰɟɩɬɨɪɨɜ ɫɢɝɧɚɥ ɩɟɪɟɞɚɜɚɬɶɫɹ ɧɟ ɛɭɞɟɬ. Ⱦɚɧɧɵɟ ɨ ɫɧɢɠɟɧɢɢ ɷɤɫɩɪɟɫɫɢɢ ɪɟɰɟɩɬɨɪɨɜ VEGF ɩɨ ɦɟɪɟ ɨɡɥɨɤɚɱɟɫɬɜɥɟɧɢɹ ɨɩɭɯɨɥɟɣ ɟɫɬɶ ɢ ɜ ɥɢɬɟɪɚɬɭɪɟ. Ɍɚɤ, ɜ ɪɚɛɨɬɟ Ferrer F.A. ɢ ɫɨɬɪ., ɢɫɫɥɟɞɨɜɚɜɲɢɯ ɷɤɫɩɪɟɫɫɢɸ VEGFR2 (FLK-1) ɩɪɢ ɪɚɤɟ ɩɪɨɫɬɚɬɵ ɱɟɥɨɜɟɤɚ, ɜ ɨɩɭɯɨɥɹɯ, ɧɚɯɨɞɹɳɢɯɫɹ ɧɚ ɛɨɥɟɟ ɩɨɡɞɧɢɯ ɫɬɚɞɢɹɯ ɩɪɨɝɪɟɫɫɢɢ, ɷɤɫɩɪɟɫɫɢɹ ɷɬɨɝɨ ɪɟɰɟɩɬɨɪɚ ɛɵɥɚ ɫɢɥɶɧɨ ɫɧɢɠɟɧɚ ɢɥɢ ɨɬɫɭɬɫɬɜɨɜɚɥɚ [73]. Ʉɨɫɜɟɧɧɵɦ ɭɤɚɡɚɧɢɟɦ ɧɚ ɬɨ, ɱɬɨ VEGF-ɡɚɜɢɫɢɦɚɹ ɫɢɝɧɚɥɶɧɚɹ ɫɢɫɬɟɦɚ ɧɟ ɚɤɬɢɜɧɚ ɧɚ ɩɨɡɞɧɢɯ ɫɬɚɞɢɹɯ ɪɚɡɜɢɬɢɹ ɨɩɭɯɨɥɢ, ɦɨɝɭɬ ɫɥɭɠɢɬɶ ɢ ɪɟɡɭɥɶɬɚɬɵ, ɩɨɥɭɱɟɧɧɵɟ ɜ ɪɚɛɨɬɟ Yoshiji H. ɢ ɫɨɬɪ., ɝɞɟ ɢɧɝɢɛɢɪɨɜɚɧɢɟ ɷɤɫɩɪɟɫɫɢɢ VEGF ɩɪɢɜɨɞɢɥɨ ɤ ɬɨɪɦɨɠɟɧɢɸ ɪɨɫɬɚ ɨɩɭɯɨɥɢ ɥɢɲɶ ɜ ɬɨɦ ɫɥɭɱɚɟ, ɟɫɥɢ ɨɩɭɯɨɥɶ ɧɟ ɩɪɟɜɵɲɚɥɚ ɨɩɪɟɞɟɥɟɧɧɵɯ ɪɚɡɦɟɪɨɜ [75]. Ɍɚɤɢɦ ɨɛɪɚɡɨɦ, ɟɫɬɶ ɨɫɧɨɜɚɧɢɹ ɩɪɟɞɩɨɥɚɝɚɬɶ, ɱɬɨ ɨɩɭɯɨɥɶ, ɜ ɤɨɬɨɪɨɣ ɫɧɢɠɟɧɚ ɷɤɫɩɪɟɫɫɢɹ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ, ɧɚɯɨɞɢɬɫɹ ɧɚ ɛɨɥɟɟ ɩɨɡɞɧɟɣ ɫɬɚɞɢɢ ɩɪɨɝɪɟɫɫɢɢ. Ɏɚɤɬɨɪɵ ɪɨɫɬɚ VEGF ɢ ɢɯ ɪɟɰɟɩɬɨɪɵ ɦɨɝɭɬ ɷɤɫɩɪɟɫɫɢɪɨɜɚɬɶɫɹ ɤɚɤ ɜ ɤɥɟɬɤɚɯ ɨɩɭɯɨɥɢ, ɬɚɤ ɢ ɜ ɷɧɞɨɬɟɥɢɢ ɩɪɨɧɢɡɵɜɚɸɳɢɯ ɨɩɭɯɨɥɶ ɫɨɫɭɞɨɜ. ɉɪɢ ɷɬɨɦ ɨɫɧɨɜɧɨɣ ɜɤɥɚɞ ɜ ɷɤɫɩɪɟɫɫɢɸ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF ɜɧɨɫɹɬ ɨɩɭɯɨɥɟɜɵɟ ɤɥɟɬɤɢ; ɷɤɫɩɪɟɫɫɢɹ VEGF ɜ ɤɥɟɬɤɚɯ ɷɧɞɨɬɟɥɢɹ ɧɟɜɵɫɨɤɚ ɢ, ɤɚɤ ɩɨɥɚɝɚɸɬ, ɧɟɨɛɯɨɞɢɦɚ ɞɥɹ ɩɨɞɞɟɪɠɚɧɢɹ ɜɵɠɢɜɚɟɦɨɫɬɢ ɷɬɢɯ ɤɥɟɬɨɤ. ȼ ɨɬɥɢɱɢɟ ɨɬ VEGF, ɷɤɫɩɪɟɫɫɢɹ ɪɟɰɟɩɬɨɪɨɜ VEGFR, ɤɚɤ ɭɠɟ ɨɬɦɟɱɚɥɨɫɶ ɜɵɲɟ, ɩɟɪɜɨɧɚɱɚɥɶɧɨ ɫɱɢɬɚɥɚɫɶ ɞɨɫɬɚɬɨɱɧɨ ɜɵɫɨɤɨɫɩɟɰɢɮɢɱɧɨɣ ɞɥɹ ɤɥɟɬɨɤ ɷɧɞɨɬɟɥɢɹ, ɨɞɧɚɤɨ ɩɨɡɞɧɟɟ ɛɵɥɨ ɩɪɨɞɟɦɨɧɫɬɪɢɪɨɜɚɧɨ, ɱɬɨ ɤɥɟɬɤɢ ɦɧɨɝɢɯ ɨɩɭɯɨɥɟɣ ɬɚɤɠɟ ɦɨɝɭɬ ɷɤɫɩɪɟɫɫɢɪɨɜɚɬɶ ɞɨɜɨɥɶɧɨ ɜɵɫɨɤɢɟ ɭɪɨɜɧɢ VEGFR. ɉɨɷɬɨɦɭ ɩɪɢ ɢɫɫɥɟɞɨɜɚɧɢɢ ɭɪɨɜɧɹ ɷɤɫɩɪɟɫɫɢɢ ɝɟɧɨɜ, ɤɨɞɢɪɭɸɳɢɯ VEGFR, ɜ ɫɨɥɢɞɧɵɯ ɨɩɭɯɨɥɹɯ, ɜ ɫɭɳɧɨɫɬɢ, ɨɰɟɧɢɜɚɟɬɫɹ ɫɭɦɦɚɪɧɚɹ ɷɤɫɩɪɟɫɫɢɹ ɤɥɟɬɨɤ ɨɩɭɯɨɥɢ ɢ ɷɧɞɨɬɟɥɢɹ ɩɪɨɧɢɡɵɜɚɸɳɢɯ ɨɩɭɯɨɥɶ ɫɨɫɭɞɨɜ. 37 ɉɨɥɭɱɟɧɧɵɟ ɧɚɦɢ ɞɚɧɧɵɟ ɨ ɫɧɢɠɟɧɢɢ ɷɤɫɩɪɟɫɫɢɢ ɦɊɇɄ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ ɧɚ ɩɨɡɞɧɢɯ ɫɬɚɞɢɹɯ ɩɪɨɝɪɟɫɫɢɢ ɫɨɥɢɞɧɵɯ ɨɩɭɯɨɥɟɣ, ɞɚɸɬ ɜɨɡɦɨɠɧɨɫɬɶ ɜɵɫɤɚɡɚɬɶ ɩɪɟɞɩɨɥɨɠɟɧɢɟ ɨ ɬɨɦ, ɜ ɩɪɨɰɟɫɫɟ ɪɚɡɜɢɬɢɹ ɡɥɨɤɚɱɟɫɬɜɟɧɧɨɝɨ ɡɚɛɨɥɟɜɚɧɢɹ ɩɪɨɢɫɯɨɞɢɬ ɨɬɛɨɪ ɤɥɨɧɨɜ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ ɫ ɩɨɧɢɠɟɧɧɨɣ ɚɤɬɢɜɧɨɫɬɶɸ ɝɟɧɨɜ ɫɟɦɟɣɫɬɜɚ VEGF ɢ ɝɟɧɨɜ, ɤɨɞɢɪɭɸɳɢɯ ɪɟɰɟɩɬɨɪɵ VEGFR. ȼɚɠɧɵɦ ɮɚɤɬɨɪɨɦ ɨɬɛɨɪɚ, ɤɚɤ ɭɠɟ ɨɬɦɟɱɚɥɨɫɶ ɜɵɲɟ, ɦɨɠɟɬ ɫɥɭɠɢɬɶ ɪɚɡɜɢɜɚɸɳɚɹɫɹ ɩɪɢ ɪɨɫɬɟ ɫɨɥɢɞɧɵɯ ɨɩɭɯɨɥɟɣ ɝɢɩɨɤɫɢɹ, ɩɪɢ ɤɨɬɨɪɨɣ ɩɪɨɢɫɯɨɞɢɬ ɨɬɛɨɪ ɤɥɨɧɨɜ ɤɥɟɬɨɤ ɫ ɢɡɦɟɧɟɧɧɨɣ, ɦɟɧɟɟ ɡɚɜɢɫɢɦɨɣ ɨɬ ɩɪɢɫɭɬɫɬɜɢɹ ɤɢɫɥɨɪɨɞɚ ɷɧɟɪɝɟɬɢɤɨɣ. ɉɪɨɢɫɯɨɞɢɬ ɥɢ ɨɬɛɨɪ ɤɥɨɧɨɜ ɫ ɩɨɧɢɠɟɧɧɨɣ ɷɤɫɩɪɟɫɫɢɟɣ ɝɟɧɨɜ VEGF ɢ VEGFR ɜ ɫɥɭɱɚɟ ɝɟɦɨɛɥɚɫɬɨɡɨɜ, ɞɥɹ ɤɨɬɨɪɵɯ, ɜ ɨɬɥɢɱɢɟ ɨɬ ɫɨɥɢɞɧɵɯ ɨɩɭɯɨɥɟɣ, ɧɟ ɫɬɨɥɶ ɯɚɪɚɤɬɟɪɧɨ ɪɚɡɜɢɬɢɟ ɝɢɩɨɤɫɢɢ? 38 ɗɤɫɩɪɟɫɫɢɹ ɦɊɇɄ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ VEGFR ɭ ɛɨɥɶɧɵɯ ɦɧɨɠɟɫɬɜɟɧɧɨɣ ɦɢɟɥɨɦɨɣ Ɉɞɧɢɦ ɢɡ ɜɢɞɨɜ ɝɟɦɨɛɥɚɫɬɨɡɨɜ ɹɜɥɹɟɬɫɹ ɦɧɨɠɟɫɬɜɟɧɧɚɹ ɦɢɟɥɨɦɚ (ɆɆ) – ɡɥɨɤɚɱɟɫɬɜɟɧɧɨɟ ɥɢɦɮɨɩɪɨɥɢɮɟɪɚɬɢɜɧɨɟ ɡɚɛɨɥɟɜɚɧɢɟ, ɩɪɢ ɤɨɬɨɪɨɦ ɩɪɨɢɫɯɨɞɢɬ ɧɟɤɨɧɬɪɨɥɢɪɭɟɦɨɟ ɪɚɡɦɧɨɠɟɧɢɟ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ, ɩɪɟɞɫɬɚɜɥɹɸɳɢɯ ɫɨɛɨɣ ɤɨɧɟɱɧɭɸ ɫɬɚɞɢɸ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɢ ȼ-ɥɢɦɮɨɰɢɬɨɜ. ȼ ɧɚɲɟɣ ɪɚɛɨɬɟ ɢɫɫɥɟɞɨɜɚɥɚɫɶ ɷɤɫɩɪɟɫɫɢɹ ɦɊɇɄ ɝɟɧɨɜ, ɤɨɞɢɪɭɸɳɢɯ ɮɚɤɬɨɪɵ ɪɨɫɬɚ VEGF-A, VEGF-C, VEGF-D ɢ ɪɟɰɟɩɬɨɪɵ VEGFR1, VEGFR2 ɢ VEGFR3 ɜ ɦɨɧɨɧɭɤɥɟɚɪɧɨɣ ɮɪɚɤɰɢɢ ɚɫɩɢɪɚɬɨɜ ɤɨɫɬɧɨɝɨ ɦɨɡɝɚ ɛɨɥɶɧɵɯ ɆɆ ɗɤɫɩɪɟɫɫɢɹ [76]. ɝɟɧɨɜ ɫɨɩɨɫɬɚɜɥɹɥɚɫɶ ɫ ɬɚɤɢɦɢ ɰɢɬɨɥɨɝɢɱɟɫɤɢɦɢ ɯɚɪɚɤɬɟɪɢɫɬɢɤɚɦɢ ɤɚɤ ɤɨɥɢɱɟɫɬɜɨ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ ɜ ɚɫɩɢɪɚɬɚɯ ɤɨɫɬɧɨɝɨ ɦɨɡɝɚ ɛɨɥɶɧɵɯ ɢ ɫɨɨɬɧɨɲɟɧɢɟ ɤɨɥɢɱɟɫɬɜɚ ɥɢɦɮɨɰɢɬɨɜ ɢ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ. Ɋɚɫɩɪɟɞɟɥɟɧɢɟ ɤɨɥɢɱɟɫɬɜɚ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ ɭ ɢɫɫɥɟɞɨɜɚɧɧɨɣ ɧɚɦɢ ɝɪɭɩɩɵ ɛɨɥɶɧɵɯ ɩɪɟɞɫɬɚɜɥɟɧɨ ɧɚ ɪɢɫɭɧɤɟ 11, ɢɡ ɤɨɬɨɪɨɝɨ ɜɢɞɧɨ, ɱɬɨ ɷɬɨɬ ɩɨɤɚɡɚɬɟɥɶ ɤɨɥɟɛɚɥɫɹ ɜ ɲɢɪɨɤɢɯ ɩɪɟɞɟɥɚɯ, ɨɬ 12% ɞɨ 88%. Ʉɨɥ-ɜɨ ɩɥɚɡɦ. ɤɥ. 100 % 90 80 70 60 50 40 30 20 10 ɆɆ8 ɆɆ10 ɆɆ41 ɆɆ58 ɆɆ11 ɆɆ38 ɆɆ7 ɆɆ36 ɆɆ3 ɆɆ12 ɆɆ13 ɆɆ23 ɆɆ1 ɆɆ34 ɆɆ2 ɆɆ62 ɆɆ35 0 ɇɨɦɟɪɚ ɨɛɪɚɡɰɨɜ ɆɆ Ɋɢɫ. 11. Ɋɚɫɩɪɟɞɟɥɟɧɢɟ ɤɨɥɢɱɟɫɬɜɚ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ ɭ ɛɨɥɶɧɵɯ ɆɆ. 39 Ɋɚɫɩɪɟɞɟɥɟɧɢɟ ɫɨɨɬɧɨɲɟɧɢɹ ɤɨɥɢɱɟɫɬɜɚ ɥɢɦɮɨɰɢɬɨɜ ɢ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ ɩɪɟɞɫɬɚɜɥɟɧɨ ɧɚ ɪɢɫɭɧɤɟ 12. Ɂɧɚɱɟɧɢɹ ɷɬɨɝɨ ɰɢɬɨɥɨɝɢɱɟɫɤɨɝɨ ɩɨɤɚɡɚɬɟɥɹ 0,90 0,80 0,70 0,60 0,50 0,40 0,30 0,20 0,10 ɆɆ19 ɆɆ5 ɆɆ25 ɆɆ23 ɆɆ15 ɆɆ37 ɆɆ18 ɆɆ11 ɆɆ8 ɆɆ57 ɆɆ41 0,00 ɆɆ29 ɋɨɨɬɧɨɲɟɧɢɟ ɤɨɥɢɱɟɫɬɜɚ ɥɢɦɮ. ɩɥɚɡɦ.ɤɥ. ɭ ɨɬɞɟɥɶɧɵɯ ɛɨɥɶɧɵɯ ɬɚɤɠɟ ɛɵɥɢ ɪɚɡɥɢɱɧɵɦɢ ɢ ɜɚɪɶɢɪɨɜɚɥɢ ɨɬ 0,03 ɞɨ 0,80. ɇɨɦɟɪɚ ɨɛɪɚɡɰɨɜ ɆɆ Ɋɢɫ. 12. Ɋɚɫɩɪɟɞɟɥɟɧɢɟ ɫɨɨɬɧɨɲɟɧɢɹ ɥɢɦɮɨɰɢɬɵ/ɩɥɚɡɦɚɬɢɱɟɫɤɢɟ ɤɥɟɬɤɢ ɭ ɛɨɥɶɧɵɯ ɆɆ. Ⱦɥɹ ɚɧɚɥɢɡɚ ɷɤɫɩɪɟɫɫɢɢ ɦɊɇɄ ɢɫɫɥɟɞɭɟɦɵɯ ɝɟɧɨɜ ɢɡ ɚɫɩɢɪɚɬɨɜ ɤɨɫɬɧɨɝɨ ɦɨɡɝɚ ɛɨɥɶɧɵɯ ɦɧɨɠɟɫɬɜɟɧɧɨɣ ɦɢɟɥɨɦɨɣ ɜɵɞɟɥɹɥɚɫɶ ɦɨɧɨɧɭɤɥɟɚɪɧɚɹ ɮɪɚɤɰɢɹ ɤɥɟɬɨɤ, ɫɨɞɟɪɠɚɜɲɚɹ ɨɬ 74,2% ɞɨ 93,6% ɨɩɭɯɨɥɟɜɵɯ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ. ɗɤɫɩɪɟɫɫɢɹ ɦɊɇɄ ɢɫɫɥɟɞɭɟɦɵɯ ɝɟɧɨɜ ɭ ɛɨɥɶɧɵɯ ɆɆ, ɬɚɤ ɠɟ ɤɚɤ ɢ ɰɢɬɨɥɨɝɢɱɟɫɤɢɟ ɯɚɪɚɤɬɟɪɢɫɬɢɤɢ, ɪɚɡɥɢɱɚɥɚɫɶ ɜ ɲɢɪɨɤɨɣ ɫɬɟɩɟɧɢ – ɨɬ ɩɨɥɧɨɫɬɶɸ ɧɟɝɚɬɢɜɧɨɣ ɞɨ ɹɪɤɨ ɜɵɪɚɠɟɧɧɨɣ. ɉɪɢ ɷɬɨɦ ɨɤɚɡɚɥɨɫɶ, ɱɬɨ ɜ ɢɫɫɥɟɞɨɜɚɧɧɨɣ ɧɚɦɢ ɝɪɭɩɩɟ ɛɨɥɶɧɵɯ ɩɪɚɤɬɢɱɟɫɤɢ ɩɨɥɧɨɫɬɶɸ ɨɬɫɭɬɫɬɜɭɟɬ ɷɤɫɩɪɟɫɫɢɹ ɦɊɇɄ ɪɟɰɟɩɬɨɪɚ VEGFR2 – ɫɨɨɬɜɟɬɫɬɜɭɸɳɢɣ ɫɢɝɧɚɥ ɛɵɥ ɜɵɹɜɥɟɧ ɥɢɲɶ ɜ 3/33 ɫɥɭɱɚɟɜ. VEGFR2 – ɟɞɢɧɫɬɜɟɧɧɵɣ ɨɛɳɢɣ ɪɟɰɟɩɬɨɪ ɞɥɹ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF-A, VEGF-C ɢ VEGF-D, ɢ ɜ ɨɬɫɭɬɫɬɜɢɟ VEGFR2 ɭ ɛɨɥɶɲɢɧɫɬɜɚ ɢɫɫɥɟɞɨɜɚɧɧɵɯ ɧɚɦɢ ɛɨɥɶɧɵɯ ɫɢɝɧɚɥɶɧɵɟ ɫɢɫɬɟɦɵ VEGF-A/VEGFR1 ɢ VEGF-C,VEGFD/VEGFR3 ɹɜɥɹɸɬɫɹ ɧɟɡɚɜɢɫɢɦɵɦɢ (ɫɦ. ɪɢɫ. 2). ȼ ɫɜɹɡɢ ɫ ɷɬɢɦ, ɩɪɢ ɞɚɥɶɧɟɣɲɟɦ ɚɧɚɥɢɡɟ ɩɨɥɭɱɟɧɧɵɯ ɪɟɡɭɥɶɬɚɬɨɜ ɛɵɥɢ ɫɮɨɪɦɢɪɨɜɚɧɵ ɝɪɭɩɩɵ 40 ɛɨɥɶɧɵɯ ɜ ɫɨɨɬɜɟɬɫɬɜɢɢ ɫ ɭɪɨɜɧɟɦ ɚɤɬɢɜɧɨɫɬɢ ɬɨɣ ɢɥɢ ɞɪɭɝɨɣ ɫɢɝɧɚɥɶɧɨɣ ɫɢɫɬɟɦɵ. ɂɫɩɨɥɶɡɨɜɚɧɧɵɣ ɜ ɧɚɲɟɣ ɪɚɛɨɬɟ ɩɨɥɭɤɨɥɢɱɟɫɬɜɟɧɧɵɣ ɦɟɬɨɞ ɩɨɥɢɦɟɪɚɡɧɨɣ ɰɟɩɧɨɣ ɪɟɚɤɰɢɢ ɫ ɨɛɪɚɬɧɨɣ ɬɪɚɧɫɤɪɢɩɰɢɟɣ (ɈɌ-ɉɐɊ) ɧɟ ɩɨɡɜɨɥɹɟɬ ɨɰɟɧɢɜɚɬɶ ɤɨɥɢɱɟɫɬɜɟɧɧɵɣ ɭɪɨɜɟɧɶ ɷɤɫɩɪɟɫɫɢɢ ɝɟɧɨɜ, ɩɨɷɬɨɦɭ ɞɥɹ ɫɪɚɜɧɟɧɢɹ ɛɵɥɢ ɜɵɛɪɚɧɵ ɝɪɭɩɩɵ ɛɨɥɶɧɵɯ ɫ ɧɚɢɛɨɥɟɟ ɜɵɫɨɤɢɦ ɭɪɨɜɧɟɦ ɤɨɷɤɫɩɪɟɫɫɢɢ ɦɊɇɄ VEGF-A/VEGFR1 ɢɥɢ VEGF-C,VEGF-D/VEGFR3 ɢ ɝɪɭɩɩɵ ɛɨɥɶɧɵɯ, ɭ ɤɨɬɨɪɵɯ ɤɨ-ɷɤɫɩɪɟɫɫɢɹ ɦɊɇɄ ɷɬɢɯ ɝɟɧɨɜ ɨɬɫɭɬɫɬɜɨɜɚɥɚ. Ɇɨɠɧɨ ɩɪɟɞɩɨɥɨɠɢɬɶ, ɱɬɨ ɭ ɬɟɯ ɛɨɥɶɧɵɯ, ɭ ɤɨɬɨɪɵɯ ɧɟ ɛɵɥɨ ɜɵɹɜɥɟɧɨ ɷɤɫɩɪɟɫɫɢɢ ɦɊɇɄ ɢɫɫɥɟɞɭɟɦɵɯ ɪɟɰɟɩɬɨɪɨɜ ɢɥɢ ɜɡɚɢɦɨɞɟɣɫɬɜɭɸɳɢɯ ɫ ɧɢɦɢ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ, ɫɨɨɬɜɟɬɫɬɜɭɸɳɢɟ ɫɢɝɧɚɥɶɧɵɟ ɫɢɫɬɟɦɵ ɧɟɚɤɬɢɜɧɵ. ɗɬɢ ɛɨɥɶɧɵɟ ɜɨɲɥɢ ɜ ɝɪɭɩɩɵ II ɢ IV. Ƚɪɭɩɩɵ ɛɨɥɶɧɵɯ ɫ ɧɟɚɤɬɢɜɧɨɣ ɫɢɝɧɚɥɶɧɨɣ ɫɢɫɬɟɦɨɣ ɫɪɚɜɧɢɜɚɥɢɫɶ ɫ ɝɪɭɩɩɚɦɢ ɛɨɥɶɧɵɯ ɫ ɧɚɢɛɨɥɟɟ ɜɵɫɨɤɢɦ ɭɪɨɜɧɟɦ ɤɨɷɤɫɩɪɟɫɫɢɢ ɦɊɇɄ ɷɬɢɯ ɠɟ ɝɟɧɨɜ (ɝɪɭɩɩɵ I ɢ III). ɉɨɥɭɱɟɧɧɵɟ ɪɟɡɭɥɶɬɚɬɵ ɩɪɟɞɫɬɚɜɥɟɧɵ ɧɚ ɪɢɫ. 13 ɢ 14. Ɋɢɫ. 13. Ʉɨɷɤɫɩɪɟɫɫɢɹ ɦɊɇɄ ɮɚɤɬɨɪɚ ɪɨɫɬɚ VEGF-A ɢ ɪɟɰɟɩɬɨɪɚ VEGFR1; (VEGFR1 – ɬɪɚɧɫɦɟɦɛɪɚɧɧɚɹ, VEGFR1s – ɪɚɫɬɜɨɪɢɦɚɹ ɮɨɪɦɵ ɪɟɰɟɩɬɨɪɚ). 41 Ɋɢɫ. 14. Ʉɨɷɤɫɩɪɟɫɫɢɹ ɦɊɇɄ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF-C, VEGF-D ɢ ɪɟɰɟɩɬɨɪɚ VEGFR3. Ʉɚɤ ɜɢɞɧɨ ɢɡ ɞɚɧɧɵɯ, ɩɪɟɞɫɬɚɜɥɟɧɧɵɯ ɧɚ ɪɢɫɭɧɤɚɯ 13 ɢ 14, ɜ ɝɪɭɩɩɵ I ɢ III ɜɯɨɞɹɬ ɛɨɥɶɧɵɟ, ɭ ɤɨɬɨɪɵɯ ɷɤɫɩɪɟɫɫɢɪɨɜɚɧɚ, ɫɨɨɬɜɟɬɫɬɜɟɧɧɨ, ɦɊɇɄ ɝɟɧɨɜ VEGF-A/VEGFR1 ɢ VEGF-C,VEGF-D/VEGFR3, ɚ ɜ ɝɪɭɩɩɚɯ II ɢ IV ɧɚɯɨɞɹɬɫɹ ɬɟ ɛɨɥɶɧɵɟ, ɭ ɤɨɬɨɪɵɯ ɨɬɫɭɬɫɬɜɭɟɬ ɷɤɫɩɪɟɫɫɢɹ ɦɊɇɄ ɥɢɛɨ ɮɚɤɬɨɪɚ ɪɨɫɬɚ, ɥɢɛɨ ɟɝɨ ɪɟɰɟɩɬɨɪɚ, ɥɢɛɨ ɬɨɝɨ ɢ ɞɪɭɝɨɝɨ. Ⱦɚɥɟɟ ɦɵ ɫɨɩɨɫɬɚɜɢɥɢ ɰɢɬɨɥɨɝɢɱɟɫɤɢɟ ɩɨɤɚɡɚɬɟɥɢ ɛɨɥɶɧɵɯ ɫ ɭɪɨɜɧɹɦɢ ɤɨ-ɷɤɫɩɪɟɫɫɢɢ ɝɟɧɨɜ ɬɨɣ ɢɥɢ ɞɪɭɝɨɣ ɫɢɝɧɚɥɶɧɨɣ ɫɢɫɬɟɦɵ. ȼ ɬɚɛɥɢɰɟ 4 ɛɨɥɶɧɵɟ ɪɚɫɩɨɥɨɠɟɧɵ ɜ ɩɨɫɥɟɞɨɜɚɬɟɥɶɧɨɫɬɢ, ɫɨɨɬɜɟɬɫɬɜɭɸɳɟɣ ɜɨɡɪɚɫɬɚɧɢɸ ɤɨɥɢɱɟɫɬɜɚ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ. ɉɪɢ ɫɨɩɨɫɬɚɜɥɟɧɢɢ ɪɚɫɩɪɟɞɟɥɟɧɢɹ ɛɨɥɶɧɵɯ ɦɧɨɠɟɫɬɜɟɧɧɨɣ ɦɢɟɥɨɦɨɣ ɩɨ ɤɨɥɢɱɟɫɬɜɭ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ ɫ ɪɚɫɩɪɟɞɟɥɟɧɢɟɦ ɩɨ ɝɪɭɩɩɚɦ, ɪɚɡɥɢɱɚɸɳɢɦɫɹ ɩɨ ɭɪɨɜɧɹɦ ɤɨ-ɷɤɫɩɪɟɫɫɢɢ ɝɟɧɨɜ (ɝɪɭɩɩɵ I-IV) ɨɤɚɡɚɥɨɫɶ, ɱɬɨ ɩɪɚɤɬɢɱɟɫɤɢ ɜɫɟ ɛɨɥɶɧɵɟ, ɭ ɤɨɬɨɪɵɯ ɨɬɫɭɬɫɬɜɭɟɬ ɤɨ-ɷɤɫɩɪɟɫɫɢɹ ɦɊɇɄ ɝɟɧɨɜ VEGFR1- ɢɥɢ VEGFR3-ɡɚɜɢɫɢɦɵɯ ɫɢɝɧɚɥɶɧɵɯ ɫɢɫɬɟɦ, ɯɚɪɚɤɬɟɪɢɡɭɸɬɫɹ ɩɨɜɵɲɟɧɧɵɦ ɤɨɥɢɱɟɫɬɜɨɦ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ. 42 Ɍɚɛɥɢɰɚ 4. ɋɨɩɨɫɬɚɜɥɟɧɢɟ ɤɨɥɢɱɟɫɬɜɚ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ ɭ ɛɨɥɶɧɵɯ ɦɧɨɠɟɫɬɜɟɧɧɨɣ ɦɢɟɥɨɦɨɣ ɫ ɭɪɨɜɧɹɦɢ ɤɨ-ɷɤɫɩɪɟɫɫɢɢ ɝɟɧɨɜ VEGFR1- ɢ VEGFR3-ɡɚɜɢɫɢɦɵɯ ɫɢɝɧɚɥɶɧɵɯ ɫɢɫɬɟɦ. ɇɨɦɟɪ ɨɛɪɚɡɰɚ ɆɆ35 ɆɆ4 ɆɆ62 MM5 ɆɆ2 ɆɆ25 ɆɆ1 ɆɆ19 ɆɆ34 ɆɆ40 MM23 ɆɆ37 ɆɆ13 ɆɆ6 ɆɆ3 ɆɆ52 ɆɆ12 Ʉɨɥ-ɜɨ ɩɥ.ɤɥ. (%) 12 13,4 22 22,2 22,8 23 23,3 24,4 25 25,2 31 31,4 34 34,5 35,4 37 39,6 ɗɤɫɩɪɟɫɫɢɹ VEGFR1 ɇɨɦɟɪ ɨɛɪɚɡɰɚ VEGFR3 Ƚɪɭɩɩɚ I Ƚɪɭɩɩɚ II Ƚɪɭɩɩɚ I ɆɆ44 ɆɆ7 ɆɆ39 ɆɆ36 ɆɆ15 ɆɆ38 ɆɆ18 ɆɆ11 ɆɆ17 ɆɆ57 ɆɆ58 ɆɆ41 ɆɆ29 MM8 ɆɆ64 ɆɆ10 Ƚɪɭɩɩɚ III Ƚɪɭɩɩɚ I Ƚɪɭɩɩɚ I Ƚɪɭɩɩɚ II Ƚɪɭɩɩɚ I Ƚɪɭɩɩɚ I Ƚɪɭɩɩɚ III Ƚɪɭɩɩɚ IV Ƚɪɭɩɩɚ III Ƚɪɭɩɩɚ III Ƚɪɭɩɩɚ I Ƚɪɭɩɩɚ I Ʉɨɥ-ɜɨ ɩɥ.ɤɥ. (%) 43,6 44 48 50,8 51,2 53,4 56 56,6 60,6 69 69 69,2 85 85,8 87,8 88 ɗɤɫɩɪɟɫɫɢɹ VEGFR1 VEGFR3 Ƚɪɭɩɩɚ III Ƚɪɭɩɩɚ I Ƚɪɭɩɩɚ I Ƚɪɭɩɩɚ II Ƚɪɭɩɩɚ II Ƚɪɭɩɩɚ III Ƚɪɭɩɩɚ III Ƚɪɭɩɩɚ III Ƚɪɭɩɩɚ IV Ƚɪɭɩɩɚ IV Ƚɪɭɩɩɚ IV Ƚɪɭɩɩɚ II Ƚɪɭɩɩɚ II Ƚɪɭɩɩɚ IV Ƚɪɭɩɩɚ IV Ƚɪɭɩɩɚ III Ʉɚɤ ɜɢɞɧɨ ɢɡ ɬɚɛɥɢɰɵ 4, ɩɪɚɤɬɢɱɟɫɤɢ ɜɫɟ ɛɨɥɶɧɵɟ II ɢ IV ɝɪɭɩɩ ɧɚɯɨɞɹɬɫɹ ɜ ɧɢɠɧɟɣ ɱɚɫɬɢ ɬɚɛɥɢɰɵ, ɝɞɟ ɤɨɥɢɱɟɫɬɜɨ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ ɭ ɛɨɥɶɧɵɯ ɩɪɟɜɵɲɚɟɬ 53,4% ɞɥɹ ɝɪɭɩɩ ɛɨɥɶɧɵɯ, ɪɚɡɥɢɱɚɸɳɢɯɫɹ ɩɨ ɤɨ-ɷɤɫɩɪɟɫɫɢɢ ɦɊɇɄ VEGF-A ɢ VEGFR1 ɢ 60,6% ɞɥɹ ɝɪɭɩɩ ɛɨɥɶɧɵɯ, ɪɚɡɥɢɱɚɸɳɢɯɫɹ ɩɨ ɤɨɷɤɫɩɪɟɫɫɢɢ ɦɊɇɄ VEGF-C, VEGF-D ɢ VEGFR3. ɉɨɞɫɱɟɬ ɰɢɬɨɥɨɝɢɱɟɫɤɢɯ ɩɨɤɚɡɚɬɟɥɟɣ ɜ ɷɬɢɯ 4-ɯ ɝɪɭɩɩɚɯ ɩɨɤɚɡɚɥ, ɱɬɨ ɭ ɛɨɥɶɧɵɯ ɫ ɨɬɫɭɬɫɬɜɢɟɦ ɤɨ-ɷɤɫɩɪɟɫɫɢɢ ɦɊɇɄ ɝɟɧɨɜ ɬɨɣ ɢɥɢ ɞɪɭɝɨɣ VEGFɡɚɜɢɫɢɦɨɣ ɫɢɝɧɚɥɶɧɨɣ ɫɢɫɬɟɦɵ (ɝɪɭɩɩɵ II ɢ IV) ɫɬɚɬɢɫɬɢɱɟɫɤɢ ɞɨɫɬɨɜɟɪɧɨ ɩɨɜɵɲɟɧɨ ɤɨɥɢɱɟɫɬɜɨ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ ɢ ɫɧɢɠɟɧ ɤɨɥɢɱɟɫɬɜɟɧɧɵɣ ɩɨɤɚɡɚɬɟɥɶ ɫɨɨɬɧɨɲɟɧɢɹ ɥɢɦɮɨɰɢɬɵ/ɩɥɚɡɦɚɬɢɱɟɫɤɢɟ ɤɥɟɬɤɢ ɩɨ ɫɪɚɜɧɟɧɢɸ ɫ 43 ɛɨɥɶɧɵɦɢ, ɭ ɤɨɬɨɪɵɯ ɧɚɛɥɸɞɚɟɬɫɹ ɜɵɫɨɤɢɣ ɭɪɨɜɟɧɶ ɤɨ-ɷɤɫɩɪɟɫɫɢɢ ɦɊɇɄ ɷɬɢɯ ɠɟ ɝɟɧɨɜ (ɝɪɭɩɩɵ I ɢ III). ɉɨɥɭɱɟɧɧɵɟ ɞɚɧɧɵɟ ɩɪɢɜɟɞɟɧɵ ɜ ɬɚɛɥɢɰɚɯ 5 ɢ 6. Ɍɚɛɥɢɰɚ 5. ɋɨɩɨɫɬɚɜɥɟɧɢɟ ɰɢɬɨɥɨɝɢɱɟɫɤɢɯ ɯɚɪɚɤɬɟɪɢɫɬɢɤ ɛɨɥɶɧɵɯ ɆɆ ɜ ɝɪɭɩɩɚɯ, ɪɚɡɥɢɱɚɸɳɢɯɫɹ ɩɨ ɤɨ-ɷɤɫɩɪɟɫɫɢɢ ɦɊɇɄ ɝɟɧɨɜ VEGF-A ɢ VEGFR1. Ƚɪɭɩɩɚ I Ƚɪɭɩɩɚ II Ʉɨɥɢɱɟɫɬɜɨ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ 31,94 + 10,53 58,96 + 25,39 ɤɥɟɬɨɤ (%) ɋɨɨɬɧɨɲɟɧɢɟ ɥɢɦɮɨɰɢɬɵ/ 0,48 + 0,17 0,19 + 0,25 ɩɥɚɡɦɚɬɢɱɟɫɤɢɟ ɤɥɟɬɤɢ ɋɬɚɬɢɫɬɢɱɟɫɤɚɹ ɡɧɚɱɢɦɨɫɬɶ ɪ < 0,05 ɪ < 0,05 Ɍɚɛɥɢɰɚ 6. ɋɨɩɨɫɬɚɜɥɟɧɢɟ ɰɢɬɨɥɨɝɢɱɟɫɤɢɯ ɯɚɪɚɤɬɟɪɢɫɬɢɤ ɛɨɥɶɧɵɯ ɆɆ ɜ ɝɪɭɩɩɚɯ, ɪɚɡɥɢɱɚɸɳɢɯɫɹ ɩɨ ɤɨ-ɷɤɫɩɪɟɫɫɢɢ ɦɊɇɄ ɝɟɧɨɜ VEGF-C, VEGF-D ɢ VEGFR3. Ƚɪɭɩɩɚ III Ƚɪɭɩɩɚ IV Ʉɨɥɢɱɟɫɬɜɨ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ 37,05 + 11,88 66,84 + 23,05 ɤɥɟɬɨɤ (%) ɋɨɨɬɧɨɲɟɧɢɟ ɥɢɦɮɨɰɢɬɵ/ 0,28 + 0,14 0,14 + 0,13 ɩɥɚɡɦɚɬɢɱɟɫɤɢɟ ɤɥɟɬɤɢ ɋɬɚɬɢɫɬɢɱɟɫɤɚɹ ɡɧɚɱɢɦɨɫɬɶ ɪ < 0,05 ɪ < 0,05 Ɍɚɤɢɦ ɨɛɪɚɡɨɦ, ɨɤɚɡɚɥɨɫɶ, ɱɬɨ ɞɥɹ ɛɨɥɶɧɵɯ ɆɆ ɫ ɩɨɜɵɲɟɧɧɵɦ ɤɨɥɢɱɟɫɬɜɨɦ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ (ɜ ɧɚɲɟɦ ɫɥɭɱɚɟ Ԩ 60%) ɜ ɚɫɩɢɪɚɬɚɯ ɤɨɫɬɧɨɝɨ ɦɨɡɝɚ ɯɚɪɚɤɬɟɪɧɨ ɫɧɢɠɟɧɢɟ ɚɤɬɢɜɧɨɫɬɢ ɷɤɫɩɪɟɫɫɢɢ ɦɊɇɄ ɝɟɧɨɜ VEGF-ɡɚɜɢɫɢɦɵɯ ɫɢɝɧɚɥɶɧɵɯ ɫɢɫɬɟɦ ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ. ɂ ɫɥɟɞɨɜɚɬɟɥɶɧɨ, ɜ ɤɥɨɧɚɯ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ, ɨɛɥɚɞɚɸɳɢɯ ɛɨɥɟɟ ɜɵɫɨɤɢɦ ɩɪɨɥɢɮɟɪɚɬɢɜɧɵɦ ɩɨɬɟɧɰɢɚɥɨɦ, ɚɤɬɢɜɧɨɫɬɶ VEGF-ɡɚɜɢɫɢɦɵɯ ɫɢɫɬɟɦ ɫɧɢɠɟɧɚ. ɍ ɜɫɟɯ ɢɫɫɥɟɞɨɜɚɧɧɵɯ ɜ ɧɚɲɟɣ ɪɚɛɨɬɟ ɛɨɥɶɧɵɯ ɦɧɨɠɟɫɬɜɟɧɧɨɣ ɦɢɟɥɨɦɨɣ ɛɵɥɚ ɞɢɚɝɧɨɫɬɢɪɨɜɚɧɚ III ɫɬɚɞɢɹ ɪɚɡɜɢɬɢɹ ɡɚɛɨɥɟɜɚɧɢɹ. Ɍɟɦ ɧɟ ɦɟɧɟɟ, ɨɬɞɟɥɶɧɵɟ ɝɪɭɩɩɵ ɛɨɥɶɧɵɯ ɡɧɚɱɢɬɟɥɶɧɨ ɪɚɡɥɢɱɚɥɢɫɶ ɩɨ ɭɪɨɜɧɸ ɤɨ-ɷɤɫɩɪɟɫɫɢɢ ɦɊɇɄ VEGFR1- ɢɥɢ VEGFR3-ɡɚɜɢɫɢɦɵɯ ɫɢɝɧɚɥɶɧɵɯ ɫɢɫɬɟɦ, ɢ ɜ ɷɬɢɯ ɝɪɭɩɩɚɯ 44 ɤɨɥɢɱɟɫɬɜɨ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ ɢ ɫɨɨɬɧɨɲɟɧɢɟ ɤɨɥɢɱɟɫɬɜɚ ɥɢɦɮɨɰɢɬɵ/ ɩɥɚɡɦɚɬɢɱɟɫɤɢɟ ɤɥɟɬɤɢ ɨɤɚɡɚɥɨɫɶ ɪɚɡɥɢɱɧɵɦ. ɉɨɥɭɱɟɧɧɵɟ ɞɚɧɧɵɟ ɭɤɚɡɵɜɚɸɬ ɧɚ ɬɨ, ɱɬɨ ɧɚ ɨɞɧɨɣ ɢ ɬɨɣ ɠɟ ɫɬɚɞɢɢ ɩɪɨɝɪɟɫɫɢɢ ɦɧɨɠɟɫɬɜɟɧɧɨɣ ɦɢɟɥɨɦɵ ɪɚɡɦɧɨɠɚɸɳɢɟɫɹ ɤɥɨɧɵ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ ɦɨɝɭɬ ɡɧɚɱɢɬɟɥɶɧɨ ɨɬɥɢɱɚɬɶɫɹ ɩɨ ɭɪɨɜɧɸ ɷɤɫɩɪɟɫɫɢɢ ɦɊɇɄ VEGF ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ. ɉɪɢ ɷɬɨɦ, ɜɵɫɨɤɢɣ ɭɪɨɜɟɧɶ ɷɤɫɩɪɟɫɫɢɢ ɷɬɢɯ ɝɟɧɨɜ ɫɤɨɪɟɟ ɯɚɪɚɤɬɟɪɟɧ ɞɥɹ ɩɚɰɢɟɧɬɨɜ ɫ ɨɬɧɨɫɢɬɟɥɶɧɨ ɧɟɜɵɫɨɤɢɦ ɩɪɨɰɟɧɬɧɵɦ ɫɨɞɟɪɠɚɧɢɟɦ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ ɢ ɩɨɧɢɠɟɧɧɵɦ ɫɨɨɬɧɨɲɟɧɢɟɦ ɥɢɦɮɨɰɢɬɵ/ɩɥɚɡɦɚɬɢɱɟɫɤɢɟ ɤɥɟɬɤɢ. 45 ɉɪɨɞɭɤɰɢɹ ɩɚɪɚɩɪɨɬɟɢɧɚ ɭ ɛɨɥɶɧɵɯ ɦɧɨɠɟɫɬɜɟɧɧɨɣ ɦɢɟɥɨɦɨɣ, ɪɚɡɥɢɱɚɸɳɢɯɫɹ ɩɨ ɷɤɫɩɪɟɫɫɢɢ ɦɊɇɄ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ. ɏɨɬɹ ɤɨɥɢɱɟɫɬɜɨ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ ɹɜɥɹɟɬɫɹ ɨɞɧɢɦ ɢɡ ɜɚɠɧɵɯ ɩɪɨɝɧɨɫɬɢɱɟɫɤɢɯ ɮɚɤɬɨɪɨɜ ɩɪɢ ɦɧɨɠɟɫɬɜɟɧɧɨɣ ɦɢɟɥɨɦɟ, ɢɯ ɩɨɜɵɲɟɧɧɨɟ ɫɨɞɟɪɠɚɧɢɟ ɜ ɤɨɫɬɧɨɦ ɦɨɡɝɟ ɛɨɥɶɧɵɯ ɧɟ ɜɫɟɝɞɚ ɤɨɪɪɟɥɢɪɭɟɬ ɫ ɬɹɠɟɫɬɶɸ ɡɚɛɨɥɟɜɚɧɢɹ. Ȼɨɥɟɟ ɡɧɚɱɢɦɵɦ ɩɨɤɚɡɚɬɟɥɟɦ ɹɜɥɹɟɬɫɹ ɞɥɹ ɫɟɤɪɟɰɢɹ ɢɦɦɭɧɨɝɥɨɛɭɥɢɧɚ, ɨɩɪɟɞɟɥɹɟɦɨɝɨ ɨɛɳɟɩɪɢɡɧɚɧɧɨɣ ɫɢɫɬɟɦɟ ɨɩɪɟɞɟɥɟɧɢɹ ɩɚɪɚɩɪɨɬɟɢɧɚ, ɜ ɢɥɢ ɫɵɜɨɪɨɬɤɟ ɫɬɚɞɢɪɨɜɚɧɢɹ ɬɹɠɟɫɬɢ ɡɚɛɨɥɟɜɚɧɢɹ ɦɨɧɨɤɥɨɧɚɥɶɧɨɝɨ ɤɪɨɜɢ ɛɨɥɶɧɨɝɨ. ɦɧɨɠɟɫɬɜɟɧɧɨɣ ȼ ɦɢɟɥɨɦɵ, ɩɪɟɞɥɨɠɟɧɧɨɣ Durie ɢ Salmon [77], ɦɚɫɫɚ ɨɩɭɯɨɥɢ, ɨɩɪɟɞɟɥɹɟɦɚɹ ɩɨ ɩɪɨɞɭɤɰɢɢ ɩɚɪɚɩɪɨɬɟɢɧɚ, ɪɚɫɫɦɚɬɪɢɜɚɟɬɫɹ ɜ ɤɚɱɟɫɬɜɟ ɜɚɠɧɟɣɲɟɝɨ ɩɨɤɚɡɚɬɟɥɹ ɨɩɭɯɨɥɟɜɨɣ ɩɪɨɝɪɟɫɫɢɢ ɢ ɩɪɨɝɧɨɡɚ. ȼ ɧɚɲɟɣ ɪɚɛɨɬɟ ɭ ɛɨɥɶɧɵɯ ɬɚɤɠɟ ɨɩɪɟɞɟɥɹɥɚɫɶ ɤɨɧɰɟɧɬɪɚɰɢɹ Ɋɢɦɦɭɧɨɝɥɨɛɭɥɢɧɚ (P-Ig). ɋɨɞɟɪɠɚɧɢɟ P-Ig ɜ ɫɵɜɨɪɨɬɤɟ ɤɪɨɜɢ ɨɬɞɟɥɶɧɵɯ ɛɨɥɶɧɵɯ ɜɚɪɶɢɪɨɜɚɥɨ ɨɬ 1,2 ɝ/ɥ ɞɨ 9,9 ɝ/ɥ (Ɋɢɫ. 15). Ʉɨɧɰɟɧɬɪɚɰɢɹ P-Ig ɜ ɫɵɜɨɪɨɬɤɟ ɤɪɨɜɢ ɛɨɥɶɧɵɯ ɦɧɨɠɟɫɬɜɟɧɧɨɣ ɦɢɟɥɨɦɨɣ ɝ/ɥ 11 10 9 8 7 6 5 4 3 2 1 ɆɆ2 ɆɆ8 ɆɆ11 ɆɆ17 ɆɆ3 ɆɆ41 ɆɆ18 ɆɆ1 ɆɆ23 ɆɆ19 ɆɆ35 ɆɆ58 ɆɆ25 ɆɆ6 0 Ɋɢɫ. 15. ɋɨɞɟɪɠɚɧɢɟ Ɋ-ɢɦɦɭɧɨɝɥɨɛɭɥɢɧɚ ɜ ɫɵɜɨɪɨɬɤɟ ɤɪɨɜɢ ɛɨɥɶɧɵɯ ɦɧɨɠɟɫɬɜɟɧɧɨɣ ɦɢɟɥɨɦɨɣ. 46 ɉɪɢ ɫɪɚɜɧɟɧɢɢ ɝɪɭɩɩ ɛɨɥɶɧɵɯ ɦɧɨɠɟɫɬɜɟɧɧɨɣ ɦɢɟɥɨɦɨɣ ɫ ɧɚɢɛɨɥɟɟ ɜɵɫɨɤɢɦ (> 60%) ɢ ɧɚɢɦɟɧɶɲɢɦ (<30%) ɤɨɥɢɱɟɫɬɜɨɦ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ, ɨɤɚɡɚɥɨɫɶ, ɱɬɨ ɜ ɷɬɢɯ ɝɪɭɩɩɚɯ ɛɨɥɶɧɵɯ ɫɬɚɬɢɫɬɢɱɟɫɤɢ ɞɨɫɬɨɜɟɪɧɨ ɪɚɡɥɢɱɚɟɬɫɹ ɢ ɫɨɞɟɪɠɚɧɢɟ Ɋ-ɢɦɦɭɧɨɝɥɨɛɭɥɢɧɚ, ɢ ɬɚɤɢɦ ɨɛɪɚɡɨɦ, ɜ ɰɟɥɨɦ ɧɚɛɥɸɞɚɟɬɫɹ ɤɨɪɪɟɥɹɰɢɹ ɦɟɠɞɭ ɭɪɨɜɧɟɦ ɩɥɚɡɦɨɰɢɬɨɡɚ ɢ ɤɨɥɢɱɟɫɬɜɨɦ ɩɪɨɞɭɰɢɪɭɟɦɨɝɨ Ɋɢɦɦɭɧɨɝɥɨɛɭɥɢɧɚ (Ɍɚɛɥɢɰɚ 7). Ɍɚɛɥɢɰɚ 7. ɋɨɞɟɪɠɚɧɢɟ Ɋ-ɢɦɦɭɧɨɝɥɨɛɭɥɢɧɚ ɜ ɝɪɭɩɩɚɯ ɛɨɥɶɧɵɯ ɫ ɧɚɢɛɨɥɟɟ ɜɵɫɨɤɢɦ ɢ ɫ ɧɚɢɦɟɧɶɲɢɦ ɭɪɨɜɧɟɦ ɩɥɚɡɦɨɰɢɬɨɡɚ. (N – ɤɨɥɢɱɟɫɬɜɨ ɛɨɥɶɧɵɯ ɜ ɝɪɭɩɩɟ). Ʉɨɥɢɱɟɫɬɜɨ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ (%) <30% (N=8) Ɋ-ɢɦɦɭɧɨɝɥɨɛɭɥɢɧ (ɝ/ɥ) >60% (N=7) 6,16 + 2,36 ɋɬɚɬɢɫɬɢɱɟɫɤɚɹ ɡɧɚɱɢɦɨɫɬɶ ɪ < 0,05 3,02 + 1,69 Ⱦɚɥɟɟ ɦɵ ɫɨɩɨɫɬɚɜɢɥɢ ɫɨɞɟɪɠɚɧɢɟ Ɋ-ɢɦɦɭɧɨɝɥɨɛɭɥɢɧɚ ɜ ɝɪɭɩɩɚɯ ɛɨɥɶɧɵɯ, ɪɚɡɥɢɱɚɜɲɢɯɫɹ ɩɨ ɭɪɨɜɧɸ ɤɨ-ɷɤɫɩɪɟɫɫɢɢ ɝɟɧɨɜ VEGF-A/VEGFR1 ɢ VEGF-C,VEGF-D/VEGFR3 (ɝɪɭɩɩɵ I-II ɢ III-IV) (Ɍɚɛɥ. 8). Ɉɤɚɡɚɥɨɫɶ, ɱɬɨ ɫɪɟɞɧɹɹ ɤɨɧɰɟɧɬɪɚɰɢɹ Ɋ-ɢɦɦɭɧɨɝɥɨɛɭɥɢɧɚ ɜ ɝɪɭɩɩɚɯ III ɢ IV ɩɪɚɤɬɢɱɟɫɤɢ ɫɨɜɩɚɞɚɟɬ, ɧɟɫɦɨɬɪɹ ɧɚ ɫɬɚɬɢɫɬɢɱɟɫɤɢ ɞɨɫɬɨɜɟɪɧɵɟ ɪɚɡɥɢɱɢɹ ɜ ɤɨɥɢɱɟɫɬɜɟ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ ɜ ɷɬɢɯ ɝɪɭɩɩɚɯ. Ɍɚɤɢɦ ɨɛɪɚɡɨɦ, ɞɟɣɫɬɜɢɬɟɥɶɧɨ, ɩɪɨɰɟɧɬɧɨɟ ɫɨɞɟɪɠɚɧɢɟ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ ɜ ɚɫɩɢɪɚɬɚɯ ɤɨɫɬɧɨɝɨ ɦɨɡɝɚ ɛɨɥɶɧɵɯ ɦɧɨɠɟɫɬɜɟɧɧɨɣ ɦɢɟɥɨɦɨɣ ɧɟ ɨɛɹɡɚɬɟɥɶɧɨ ɩɪɢɜɨɞɢɬ ɤ ɩɨɜɵɲɟɧɧɨɣ ɤɨɧɰɟɧɬɪɚɰɢɢ ɩɚɪɚɩɪɨɬɟɢɧɚ ɜ ɫɵɜɨɪɨɬɤɟ ɤɪɨɜɢ ɷɬɢɯ ɛɨɥɶɧɵɯ. ɂ ɩɨɫɤɨɥɶɤɭ ɩɪɢ ɛɨɥɟɟ ɜɵɫɨɤɨɦ ɩɪɨɰɟɧɬɧɨɦ ɫɨɞɟɪɠɚɧɢɢ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ ɜ ɚɫɩɢɪɚɬɚɯ ɤɨɫɬɧɨɝɨ ɦɨɡɝɚ ɛɨɥɶɧɵɯ ɜ ɝɪɭɩɩɟ IV ɩɨ ɫɪɚɜɧɟɧɢɸ ɫ ɛɨɥɶɧɵɦɢ, ɜɨɲɟɞɲɢɦɢ ɜ ɝɪɭɩɩɭ III, ɤɨɧɰɟɧɬɪɚɰɢɹ ɩɚɪɚɩɪɨɬɟɢɧɚ ɜ ɫɵɜɨɪɨɬɤɟ ɤɪɨɜɢ ɭ ɛɨɥɶɧɵɯ ɷɬɢɯ 2-ɯ ɝɪɭɩɩ ɧɟ ɪɚɡɥɢɱɚɟɬɫɹ, ɦɨɠɧɨ ɫɞɟɥɚɬɶ ɜɵɜɨɞ, ɱɬɨ ɩɪɨɞɭɤɰɢɹ 47 ɩɚɪɚɩɪɨɬɟɢɧɚ ɩɥɚɡɦɚɬɢɱɟɫɤɢɦɢ ɤɥɟɬɤɚɦɢ ɛɨɥɶɧɵɯ ɝɪɭɩɩɵ IV ɫɭɳɟɫɬɜɟɧɧɨ ɫɧɢɠɟɧɚ. Ɍɚɛɥɢɰɚ 8. Ʉɨɧɰɟɧɬɪɚɰɢɹ Ɋ-ɢɦɦɭɧɨɝɥɨɛɭɥɢɧɚ ɜ ɝɪɭɩɩɚɯ ɛɨɥɶɧɵɯ ɦɧɨɠɟɫɬɜɟɧɧɨɣ ɦɢɟɥɨɦɨɣ, ɪɚɡɥɢɱɚɸɳɢɯɫɹ ɩɨ ɤɨ-ɷɤɫɩɪɟɫɫɢɢ ɦɊɇɄ VEGF-A/ VEGFR1 ɢ VEGF-C,VEGF-D/VEGFR3. (N – ɤɨɥɢɱɟɫɬɜɨ ɛɨɥɶɧɵɯ ɜ ɝɪɭɩɩɟ). Ʉɨ-ɷɤɫɩɪɟɫɫɢɹ VEGF-A/ VEGFR1 Ƚɪɭɩɩɚ I (N=7) Ƚɪɭɩɩɚ II (N=5) ɋɬɚɬɢɫɬɢɱɟɫɤɚɹ ɡɧɚɱɢɦɨɫɬɶ Ʉɨɥ-ɜɨ ɩɥɚɡɦ. P-Ig ɤɥɟɬɨɤ (%) (ɝ/ɥ) 31,94 + 10,53 3,38 + 1,6 58,96 + 25,39 6,06 + 2,42 ɪ < 0,05 ɪ < 0,05 Ʉɨ-ɷɤɫɩɪɟɫɫɢɹ VEGF-C, VEGF-D/ VEGFR3 Ƚɪɭɩɩɚ III (N=9) Ƚɪɭɩɩɚ IV (N=5) Ʉɨɥ-ɜɨ ɩɥɚɡɦ. P-Ig ɤɥɟɬɨɤ (%) (ɝ/ɥ) 37,05 + 11,88 4,55 + 2,01 65,16 + 23,17 4,96 + 2,17 ɪ < 0,05 ȼ ɨɬɥɢɱɢɟ ɨɬ ɝɪɭɩɩ III ɢ IV, ɜ ɝɪɭɩɩɚɯ I ɢ II, ɪɚɡɥɢɱɚɸɳɢɯɫɹ ɩɨ ɤɨɷɤɫɩɪɟɫɫɢɢ ɦɊɇɄ VEGF-A/VEGFR1, ɛɵɥɢ ɩɨɥɭɱɟɧɵ ɫɬɚɬɢɫɬɢɱɟɫɤɢ ɞɨɫɬɨɜɟɪɧɵɟ ɪɚɡɥɢɱɢɹ ɩɨ ɭɪɨɜɧɸ ɫɨɞɟɪɠɚɧɢɹ ɩɚɪɚɩɪɨɬɟɢɧɚ. ɍ ɛɨɥɶɧɵɯ ɝɪɭɩɩɵ II, ɜ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɤɚɯ ɤɨɬɨɪɵɯ ɧɟ ɛɵɥɨ ɨɛɧɚɪɭɠɟɧɨ ɤɨ-ɷɤɫɩɪɟɫɫɢɢ ɦɊɇɄ VEGF-A/VEGFR1, ɤɨɧɰɟɧɬɪɚɰɢɹ ɩɚɪɚɩɪɨɬɟɢɧɚ ɛɵɥɚ ɜ 2 ɪɚɡɚ ɜɵɲɟ, ɱɟɦ ɭ ɛɨɥɶɧɵɯ ɝɪɭɩɩɵ I, ɝɞɟ ɧɚɛɥɸɞɚɥɫɹ ɜɵɫɨɤɢɣ ɭɪɨɜɟɧɶ ɤɨ-ɷɤɫɩɪɟɫɫɢɢ ɷɬɢɯ ɝɟɧɨɜ. ɂ, ɫɥɟɞɨɜɚɬɟɥɶɧɨ, ɜ ɝɪɭɩɩɟ ɛɨɥɶɧɵɯ ɦɧɨɠɟɫɬɜɟɧɧɨɣ ɦɢɟɥɨɦɨɣ, ɧɟɝɚɬɢɜɧɵɯ ɩɨ ɤɨ-ɷɤɫɩɪɟɫɫɢɢ ɦɊɇɄ VEGF-A/VEGFR1, ɧɟ ɬɨɥɶɤɨ ɩɨɜɵɲɟɧɨ ɩɪɨɰɟɧɬɧɨɟ ɫɨɞɟɪɠɚɧɢɟ ɩɥɚɡɦɚɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ, ɧɨ ɢ ɭɜɟɥɢɱɟɧɚ ɩɪɨɞɭɤɰɢɹ ɩɚɪɚɩɪɨɬɟɢɧɚ. ȼ ɤɚɱɟɫɬɜɟ ɞɨɩɨɥɧɢɬɟɥɶɧɨɣ ɢɥɥɸɫɬɪɚɰɢɢ ɧɚ ɪɢɫɭɧɤɟ 16 ɩɪɟɞɫɬɚɜɥɟɧɨ ɪɚɫɩɪɟɞɟɥɟɧɢɟ ɡɧɚɱɟɧɢɣ ɤɨɧɰɟɧɬɪɚɰɢɢ ɩɚɪɚɩɪɨɬɟɢɧɚ ɭ ɛɨɥɶɧɵɯ I-IV ɝɪɭɩɩ. ɂɡ ɞɚɧɧɵɯ, ɩɪɢɜɟɞɟɧɧɵɯ ɧɚ ɷɬɨɦ ɪɢɫɭɧɤɟ, ɦɨɠɧɨ ɜɢɞɟɬɶ, ɱɬɨ ɪɚɡɥɢɱɢɹ ɩɨ ɫɪɟɞɧɢɦ ɡɧɚɱɟɧɢɹɦ ɤɨɧɰɟɧɬɪɚɰɢɣ ɩɚɪɚɩɪɨɬɟɢɧɚ, ɜɵɹɜɥɟɧɧɵɟ ɦɟɠɞɭ ɨɬɞɟɥɶɧɵɦɢ ɝɪɭɩɩɚɦɢ ɛɨɥɶɧɵɯ, ɫɨɯɪɚɧɹɸɬɫɹ ɢ ɞɥɹ ɦɟɞɢɚɧ ɤɚɠɞɨɝɨ ɢɡ ɪɚɫɩɪɟɞɟɥɟɧɢɣ. 48 Group III Group IV Group I Group II 8 8 P-Ig (g/l) 10 P-Ig (g/l) 10 6 6 4 4 2 2 0 0 B C B X Axis Title C X Axis Title Ɋɢɫ. 16. Ɋɚɫɩɪɟɞɟɥɟɧɢɟ ɡɧɚɱɟɧɢɣ ɤɨɧɰɟɧɬɪɚɰɢɢ ɩɚɪɚɩɪɨɬɟɢɧɚ ɜ ɝɪɭɩɩɚɯ IIV. ɇɚ ɪɢɫɭɧɤɟ ɩɪɟɞɫɬɚɜɥɟɧɵ ɫɪɟɞɧɢɟ ɡɧɚɱɟɧɢɹ, ɫɪɟɞɧɟɤɜɚɞɪɚɬɢɱɧɵɟ ɨɬɤɥɨɧɟɧɢɹ ɢ ɦɟɞɢɚɧɵ ɫɨɨɬɜɟɬɫɬɜɭɸɳɢɯ ɪɚɫɩɪɟɞɟɥɟɧɢɣ. Ɍɚɤɢɦ ɨɛɪɚɡɨɦ, ɝɪɭɩɩɚɦɢ ɛɨɥɶɧɵɯ, ɭ ɤɨɬɨɪɵɯ ɛɵɥɢ ɜɵɹɜɥɟɧɵ ɪɚɡɥɢɱɢɹ ɩɨ ɩɪɨɞɭɤɰɢɢ ɩɚɪɚɩɪɨɬɟɢɧɚ, ɨɤɚɡɚɥɢɫɶ ɝɪɭɩɩɵ I (VEGF-A+/VEGFR1+) ɢ II (VEGF-A-/VEGFR1-), ɩɪɢɱɟɦ ɞɥɹ ɛɨɥɶɧɵɯ ɝɪɭɩɩɵ II ɛɵɥɢ ɯɚɪɚɤɬɟɪɧɵ ɧɚɢɛɨɥɟɟ ɜɵɫɨɤɢɟ ɢɡ ɜɫɟɯ ɝɪɭɩɩ ɛɨɥɶɧɵɯ ɡɧɚɱɟɧɢɹ ɤɨɧɰɟɧɬɪɚɰɢɢ ɩɚɪɚɩɪɨɬɟɢɧɚ. 49 ɉɪɢ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɨɣ ɬɟɪɚɩɢɢ ɦɨɠɟɬ ɩɪɨɢɫɯɨɞɢɬɶ ɨɬɛɨɪ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ, ɧɟ ɷɤɫɩɪɟɫɫɢɪɭɸɳɢɯ ɪɟɰɟɩɬɨɪɵ VEGFR Ɍɚɤɢɟ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɟ ɥɟɤɚɪɫɬɜɟɧɧɵɟ ɩɪɟɩɚɪɚɬɵ ɤɚɤ ɫɜɹɡɵɜɚɸɳɢɣ VEGF-A Avastin ɢ ɫɨɟɞɢɧɟɧɢɹ, ɧɚɩɪɚɜɥɟɧɧɵɟ ɧɚ ɢɧɝɢɛɢɪɨɜɚɧɢɟ ɬɢɪɨɡɢɧɤɢɧɚɡɧɨɣ ɚɤɬɢɜɧɨɫɬɢ ɪɟɰɟɩɬɨɪɨɜ ɷɬɨɝɨ ɮɚɤɬɨɪɚ ɪɨɫɬɚ, ɤɚɤ ɭɠɟ ɨɬɦɟɱɚɥɨɫɶ ɪɚɧɟɟ, ɦɨɝɭɬ ɩɪɢɜɨɞɢɬɶ ɤ ɡɧɚɱɢɬɟɥɶɧɨɦɭ ɩɨɞɚɜɥɟɧɢɸ ɚɤɬɢɜɧɨɫɬɢ ɩɪɨɥɢɮɟɪɚɰɢɢ ɤɥɟɬɨɤ, ɷɤɫɩɪɟɫɫɢɪɭɸɳɢɯ ɪɟɰɟɩɬɨɪɵ VEGFR (ɫɦ. ɪɢɫ. 7). ȼ ɬɨ ɠɟ ɜɪɟɦɹ, ɤɥɟɬɤɢ, ɧɟɝɚɬɢɜɧɵɟ ɩɨ ɷɤɫɩɪɟɫɫɢɢ VEGFR, ɦɨɝɭɬ ɛɵɬɶ ɡɧɚɱɢɬɟɥɶɧɨ ɦɟɧɟɟ ɱɭɜɫɬɜɢɬɟɥɶɧɵ, ɢɥɢ ɫɨɜɫɟɦ ɧɟɱɭɜɫɬɜɢɬɟɥɶɧɵ, ɤ ɬɟɪɚɩɟɜɬɢɱɟɫɤɨɦɭ ɜɨɡɞɟɣɫɬɜɢɸ ɞɚɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ. ȼ ɧɚɲɟɣ ɪɚɛɨɬɟ, ɝɞɟ ɦɵ ɢɫɫɥɟɞɨɜɚɥɢ ɜɥɢɹɧɢɟ ɧɚ ɪɚɡɦɧɨɠɟɧɢɟ ɤɭɥɶɬɭɪ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ ɱɟɥɨɜɟɤɚ ɪɟɤɨɦɛɢɧɚɧɬɧɨɝɨ ɛɟɥɤɚ sFLT4, ɫɜɹɡɵɜɚɸɳɟɝɨ VEGF-ɋ, ɛɵɥɢ ɨɯɚɪɚɤɬɟɪɢɡɨɜɚɧɵ ɩɨ ɤɨ-ɷɤɫɩɪɟɫɫɢɢ ɦɊɇɄ VEGF-C ɢ VEGFR3 ɧɟɫɤɨɥɶɤɨ ɪɚɡɥɢɱɧɵɯ ɥɢɧɢɣ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ ɱɟɥɨɜɟɤɚ [46]. ɗɤɫɩɪɟɫɫɢɹ ɦɊɇɄ ɪɟɰɟɩɬɨɪɚ VEGFR3 ɛɵɥɚ ɜɵɹɜɥɟɧɚ ɥɢɲɶ ɜ ɤɥɟɬɤɚɯ Ⱥ549, ɬɨɝɞɚ ɤɚɤ ɷɤɫɩɪɟɫɫɢɹ ɦɊɇɄ VEGF-C ɛɵɥɚ ɨɛɧɚɪɭɠɟɧɚ ɜ 4/5 ɥɢɧɢɣ ɤɥɟɬɨɤ (Ɋɢɫ. 17). ɇɚɡɜɚɧɢɟ ɉɪɨɢɫɯɨɠɞɟɧɢɟ ɥɢɧɢɢ ɥɢɧɢɢ ɤɥɟɬɨɤ ɤɥɟɬɨɤ 1. LIM 1215 Ʉɚɪɰɢɧɨɦɚ ɬɨɥɫɬɨɣ ɤɢɲɤɢ 2. mS Ɇɟɥɚɧɨɦɚ ɋɢɦɩɫɨɧɚ 3. MCF 7 Ʉɚɪɰɢɧɨɦɚ ɦɨɥɨɱɧɨɣ ɠɟɥɟɡɵ 4. Ⱥ 431 ɗɩɢɞɟɪɦɨɢɞɧɚɹ ɤɚɪɰɢɧɨɦɚ 5. Ⱥ 549 Ʉɚɪɰɢɧɨɦɚ ɥɟɝɤɨɝɨ Ɋɢɫ. 17. ɗɤɫɩɪɟɫɫɢɹ ɦɊɇɄ VEGF-C ɢ VEGFR3 (FLT4) ɜ ɤɭɥɶɬɭɪɚɯ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ ɱɟɥɨɜɟɤɚ. 50 Ⱦɚɥɟɟ ɦɵ ɫɪɚɜɧɢɥɢ ɞɟɣɫɬɜɢɟ ɞɨɛɚɜɥɟɧɢɹ ɪɟɤɨɦɛɢɧɚɧɬɧɨɝɨ ɛɟɥɤɚ sFLT4 ɧɚ ɪɚɡɦɧɨɠɟɧɢɟ ɤɭɥɶɬɭɪ ɤɥɟɬɨɤ ɤɚɪɰɢɧɨɦɵ ɥɟɝɤɨɝɨ Ⱥ549 (VEGF-C+/VEGFR3+) ɢ ɤɥɟɬɨɤ ɷɩɢɞɟɪɦɨɢɞɧɨɣ ɤɚɪɰɢɧɨɦɵ Ⱥ431 (VEGF-C+/VEGFR3-) (Ɋɢɫ. 18). Ʉɨɥɢɱɟɫɬɜɨ ɤɥɟɬɨɤ, % ɨɬ ɤɨɧɬɪɨɥɹ 120 100 80 60 40 20 ɧɝ/ɦɥ 0 0 50 100 A 549 200 A 431 Ɋɢɫ. 18. ȼɥɢɹɧɢɟ ɞɨɛɚɜɥɟɧɢɹ ɛɟɥɤɚ sFLT4 ɧɚ ɪɚɡɦɧɨɠɟɧɢɟ ɤɥɟɬɨɤ Ⱥ549 ɢ Ⱥ435. Ʉɚɤ ɜɢɞɧɨ ɢɡ ɪɢɫ. 18, ɜ ɨɬɥɢɱɢɟ ɨɬ ɷɤɫɩɪɟɫɫɢɪɭɸɳɢɯ ɦɊɇɄ ɪɟɰɟɩɬɨɪɚ VEGFR3 ɤɥɟɬɨɤ ɥɢɧɢɢ Ⱥ 549, ɞɨɛɚɜɥɟɧɢɟ ɪɟɤɨɦɛɢɧɚɧɬɧɨɝɨ ɛɟɥɤɚ sFLT4 ɦɚɥɨ ɫɤɚɡɵɜɚɟɬɫɹ ɧɚ ɪɚɡɦɧɨɠɟɧɢɢ ɤɭɥɶɬɭɪɵ ɤɥɟɬɨɤ Ⱥ 431, ɜ ɤɨɬɨɪɨɣ ɷɤɫɩɪɟɫɫɢɢ ɦɊɇɄ VEGFR3 ɧɟ ɜɵɹɜɥɟɧɨ. ɇɨ ɚɧɚɥɨɝɢɱɧɵɦ ɨɛɪɚɡɨɦ ɞɟɣɫɬɜɭɸɬ ɢ ɛɥɨɤɢɪɭɸɳɢɟ VEGF-ɡɚɜɢɫɢɦɵɟ ɫɢɝɧɚɥɶɧɵɟ ɫɢɫɬɟɦɵ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɟ ɩɪɟɩɚɪɚɬɵ, ɜ ɱɚɫɬɧɨɫɬɢ, Avastin. ɂ ɫɥɟɞɨɜɚɬɟɥɶɧɨ, ɩɪɢɦɟɧɟɧɢɟ ɬɚɤɨɝɨ ɪɨɞɚ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ, ɫ ɨɞɧɨɣ ɫɬɨɪɨɧɵ, ɧɚɪɹɞɭ ɫ ɩɨɞɚɜɥɟɧɢɟɦ ɧɟɨɚɧɝɢɨɝɟɧɟɡɚ ɨɩɭɯɨɥɢ, ɫɞɟɪɠɢɜɚɟɬ ɪɚɡɦɧɨɠɟɧɢɟ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ, ɷɤɫɩɪɟɫɫɢɪɭɸɳɢɯ ɪɟɰɟɩɬɨɪɵ VEGFR, ɧɨ ɩɪɢ ɷɬɨɦ ɧɟ ɨɤɚɡɵɜɚɟɬ ɜɨɡɞɟɣɫɬɜɢɹ ɧɚ ɤɥɟɬɤɢ ɨɩɭɯɨɥɢ, ɧɟɝɚɬɢɜɧɵɟ ɩɨ ɷɤɫɩɪɟɫɫɢɢ ɷɬɢɯ ɪɟɰɟɩɬɨɪɨɜ. Ɍɚɤɢɦ ɨɛɪɚɡɨɦ, ɜ ɤɚɱɟɫɬɜɟ ɨɞɧɨɝɨ ɢɡ ɩɨɫɥɟɞɫɬɜɢɣ ɩɪɢɦɟɧɟɧɢɹ ɚɧɬɢɚɧɝɢɨɝɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ ɦɨɠɟɬ ɩɪɨɢɫɯɨɞɢɬɶ ɨɬɛɨɪ ɤɥɨɧɨɜ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ, ɧɟ ɷɤɫɩɪɟɫɫɢɪɭɸɳɢɯ ɪɟɰɟɩɬɨɪɵ VEGFR. ɉɨɥɭɱɟɧɧɵɟ ɜ ɧɚɲɢɯ ɪɚɛɨɬɚɯ ɞɚɧɧɵɟ 51 ɭɤɚɡɵɜɚɸɬ ɧɚ ɬɨ, ɱɬɨ ɧɟɝɚɬɢɜɧɵɟ ɩɨ ɷɤɫɩɪɟɫɫɢɢ VEGFR ɤɥɟɬɤɢ ɱɚɳɟ ɜɫɬɪɟɱɚɸɬɫɹ ɧɚ ɛɨɥɟɟ ɩɨɡɞɧɢɯ ɫɬɚɞɢɹɯ ɩɪɨɝɪɟɫɫɢɢ ɨɩɭɯɨɥɟɣ. ȼɨɡɦɨɠɧɨ, ɱɬɨ ɬɚɤɨɣ ɨɬɛɨɪ ɹɜɥɹɟɬɫɹ ɨɞɧɨɣ ɢɡ ɩɪɢɱɢɧ ɧɟɤɨɬɨɪɵɯ ɧɟɛɥɚɝɨɩɪɢɹɬɧɵɯ ɩɨɫɥɟɞɫɬɜɢɣ ɩɪɢɦɟɧɟɧɢɹ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɯ ɩɪɨɬɢɜɨɨɩɭɯɨɥɟɜɵɯ ɩɪɟɩɚɪɚɬɨɜ, ɬɚɤɢɯ ɤɚɤ ɧɚɛɥɸɞɚɸɳɟɟɫɹ ɜ ɨɬɞɟɥɶɧɵɯ ɫɥɭɱɚɹɯ ɭɱɚɳɟɧɢɟ ɦɟɬɚɫɬɚɡɢɪɨɜɚɧɢɹ. ɍɱɢɬɵɜɚɹ ɜɨɡɦɨɠɧɨɫɬɶ ɨɬɛɨɪɚ VEGFR-ɧɟɝɚɬɢɜɧɵɯ ɤɥɨɧɨɜ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ, ɩɨ-ɜɢɞɢɦɨɦɭ, ɩɪɢɦɟɧɟɧɹɬɶ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɟ ɩɪɟɩɚɪɚɬɵ ɠɟɥɚɬɟɥɶɧɨ ɜ ɤɨɦɛɢɧɚɰɢɢ ɫ ɯɢɦɢɨɩɪɟɩɚɪɚɬɚɦɢ, ɨɫɧɨɜɚɧɧɵɦɢ ɧɚ ɞɪɭɝɢɯ ɦɟɯɚɧɢɡɦɚɯ ɜɨɡɞɟɣɫɬɜɢɹ ɧɚ ɤɥɟɬɤɢ. Ɍɚɤ, ɧɚɩɪɢɦɟɪ, ɜ ɧɚɲɟɣ ɪɚɛɨɬɟ ɦɟɬɨɞɨɦ ɆɌɌ ɛɵɥɚ ɢɫɫɥɟɞɨɜɚɧɚ ɜɵɠɢɜɚɟɦɨɫɬɶ 3-ɯ ɥɢɧɢɣ ɤɥɟɬɨɤ ɦɧɨɠɟɫɬɜɟɧɧɨɣ ɦɢɟɥɨɦɵ IM9, RPMI 1640 ɢ RPMI 8226 ɩɪɢ ɜɨɡɞɟɣɫɬɜɢɢ ɧɚ ɧɢɯ ɥɟɤɚɪɫɬɜɟɧɧɨɝɨ ɩɪɟɩɚɪɚɬɚ «ȼɟɥɤɟɣɞ» (ɛɨɪɬɟɡɨɦɢɛ), ɹɜɥɹɸɳɟɝɨɫɹ ɩɪɨɬɟɚɫɨɦɧɵɦ ɢɧɝɢɛɢɬɨɪɨɦ [78]. ȿɞɢɧɫɬɜɟɧɧɨɣ ɢɡ ɷɬɢɯ 3-ɯ ɥɢɧɢɣ ɤɥɟɬɨɤ, ɜ ɤɨɬɨɪɨɣ ɧɚɛɥɸɞɚɥɚɫɶ ɤɨ-ɷɤɫɩɪɟɫɫɢɹ ɦɊɇɄ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ, ɛɵɥɚ ɤɭɥɶɬɭɪɚ ɤɥɟɬɨɤ IM9, ɝɞɟ ɛɵɥɚ ɜɵɹɜɥɟɧɚ ɦɊɇɄ VEGF-A ɢ VEGFR1 (Ɋɢɫ. 19). Ɋɢɫ. 19. ɗɤɫɩɪɟɫɫɢɹ ɦɊɇɄ ɝɟɧɨɜ ɫɟɦɟɣɫɬɜɚ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ ɜ ɤɭɥɶɬɭɪɚɯ ɤɥɟɬɨɤ ɆɆ ɱɟɥɨɜɟɤɚ. 52 Ʉɚɤ ɨɤɚɡɚɥɨɫɶ, ɤɥɟɬɤɢ ɥɢɧɢɢ IM9, ɤɨ-ɷɤɫɩɪɟɫɫɢɪɭɸɳɢɟ ɦɊɇɄ VEGF-A ɢ VEGFR1, ɛɵɥɢ ɦɟɧɟɟ ɱɭɜɫɬɜɢɬɟɥɶɧɵɦɢ ɤ ɞɨɛɚɜɥɟɧɢɸ ɛɨɪɬɟɡɨɦɢɛɚ, ɱɟɦ ɤɥɟɬɤɢ ɥɢɧɢɣ RPMI 1640 ɢ RPMI 8226, ɜ ɤɨɬɨɪɵɯ ɤɨ-ɷɤɫɩɪɟɫɫɢɹ ɦɊɇɄ ɷɬɢɯ ɝɟɧɨɜ ɨɬɫɭɬɫɬɜɨɜɚɥɚ (Ɋɢɫ. 20). 120,00 Ʉɨɥɢɱɟɫɬɜɨ ɤɥɟɬɨɤ, % 100,00 80,00 60,00 40,00 20,00 IM9 RPMI 1640 3,3ɯ10-8 2,4ɯ10-8 1,7ɯ10-8 1,2ɯ10-8 8,6ɯ10-9 6,1ɯ10-9 4,4ɯ10-9 3,1ɯ10-9 2,4ɯ10-9 Ʉɨɧɬɪɨɥɶ 0,00 Ⱦɨɡɵ (Ɇ) RPMI 8226 Ɋɢɫ. 20. ɑɭɜɫɬɜɢɬɟɥɶɧɨɫɬɶ ɤɥɟɬɨɱɧɵɯ ɤɭɥɶɬɭɪ ɦɧɨɠɟɫɬɜɟɧɧɨɣ ɦɢɟɥɨɦɵ ɱɟɥɨɜɟɤɚ ɤ ɩɪɨɬɟɚɫɨɦɧɨɦɭ ɢɧɝɢɛɢɬɨɪɭ ɛɨɪɬɟɡɨɦɢɛɭ. ɆɌɌ-ɬɟɫɬ. Ɍɚɤɢɦ ɨɛɪɚɡɨɦ, ɩɨ-ɜɢɞɢɦɨɦɭ, ɧɚɢɛɨɥɟɟ ɷɮɮɟɤɬɢɜɧɨɣ ɦɨɝɥɚ ɛɵ ɛɵɬɶ ɤɨɦɛɢɧɚɰɢɹ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɯ ɥɟɤɚɪɫɬɜɟɧɧɵɯ ɫɨɟɞɢɧɟɧɢɣ, ɧɚɰɟɥɟɧɧɵɯ ɧɚ ɩɨɞɚɜɥɟɧɢɟ VEGF-ɡɚɜɢɫɢɦɵɯ ɫɢɝɧɚɥɶɧɵɯ ɫɢɫɬɟɦ, ɢ ɯɢɦɢɨɩɪɟɩɚɪɚɬɨɜ, ɩɪɟɢɦɭɳɟɫɬɜɟɧɧɨ ɜɨɡɞɟɣɫɬɜɭɸɳɢɯ ɧɚ ɤɥɟɬɤɢ, ɜ ɤɨɬɨɪɵɯ ɪɟɰɟɩɬɨɪɵ VEGF ɧɟ ɷɤɫɩɪɟɫɫɢɪɨɜɚɧɵ, ɧɚɩɪɢɦɟɪ, ɬɚɤɢɯ ɩɪɟɩɚɪɚɬɨɜ ɤɚɤ ɛɨɪɬɟɡɨɦɢɛ. 53 Ɂɚɤɥɸɱɟɧɢɟ ɗɤɫɩɪɟɫɫɢɹ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ ɧɚɛɥɸɞɚɟɬɫɹ ɜ ɛɨɥɶɲɢɧɫɬɜɟ ɡɥɨɤɚɱɟɫɬɜɟɧɧɵɯ ɨɩɭɯɨɥɟɣ. ȼ ɫɨɥɢɞɧɵɯ ɨɩɭɯɨɥɹɯ ɭɠɟ ɧɚ ɪɚɧɧɢɯ ɫɬɚɞɢɹɯ ɨɡɥɨɤɚɱɟɫɬɜɥɟɧɢɹ ɩɨɞ ɞɟɣɫɬɜɢɟɦ ɝɢɩɨɤɫɢɢ ɩɪɨɢɫɯɨɞɢɬ ɚɤɬɢɜɚɰɢɹ ɷɤɫɩɪɟɫɫɢɢ VEGF, ɩɪɢɜɨɞɹɳɚɹ ɤ ɫɬɢɦɭɥɹɰɢɢ ɪɨɫɬɚ ɩɢɬɚɸɳɢɯ ɨɩɭɯɨɥɶ ɧɨɜɵɯ ɫɨɫɭɞɨɜ ɢ ɬɟɦ ɫɚɦɵɦ ɫɩɨɫɨɛɫɬɜɭɸɳɚɹ ɭɜɟɥɢɱɟɧɢɸ ɪɚɡɦɟɪɨɜ ɨɩɭɯɨɥɢ. Ʉɪɨɦɟ ɬɨɝɨ, ɫɚɦɢ ɤɥɟɬɤɢ ɨɩɭɯɨɥɢ ɧɚɱɢɧɚɸɬ ɷɤɫɩɪɟɫɫɢɪɨɜɚɬɶ ɪɟɰɟɩɬɨɪɵ VEGF, ɜ ɪɟɡɭɥɶɬɚɬɟ ɱɟɝɨ ɜɨɡɧɢɤɚɟɬ ɚɭɬɨɤɪɢɧɧɚɹ ɫɬɢɦɭɥɹɰɢɹ ɢɯ ɪɚɡɦɧɨɠɟɧɢɹ. Ɉɞɧɚɤɨ ɩɪɢ ɞɚɥɶɧɟɣɲɟɣ ɩɪɨɝɪɟɫɫɢɢ ɨɩɭɯɨɥɢ ɷɤɫɩɪɟɫɫɢɹ VEGF ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ ɦɨɠɟɬ ɫɧɢɠɚɬɶɫɹ. ɂɞɟɹ ɩɨɞɚɜɥɟɧɢɹ ɧɟɨɚɧɝɢɨɝɟɧɟɡɚ ɨɩɭɯɨɥɢ ɫɬɢɦɭɥɢɪɨɜɚɥɚ ɪɚɡɪɚɛɨɬɤɭ ɧɨɜɨɝɨ ɧɚɩɪɚɜɥɟɧɢɹ ɜ ɯɢɦɢɨɬɟɪɚɩɢɢ – ɩɪɢɦɟɧɟɧɢɹ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ, ɧɚɰɟɥɟɧɧɵɯ ɧɚ ɢɧɝɢɛɢɪɨɜɚɧɢɟ ɚɤɬɢɜɧɨɫɬɢ VEGF-ɡɚɜɢɫɢɦɵɯ ɫɢɝɧɚɥɶɧɵɯ ɫɢɫɬɟɦ ɢ ɬɟɦ ɫɚɦɵɦ ɩɪɟɩɹɬɫɬɜɭɸɳɢɯ ɜɨɡɧɢɤɧɨɜɟɧɢɸ ɜ ɨɩɭɯɨɥɢ ɧɨɜɵɯ ɫɨɫɭɞɨɜ. ȼ ɬɨ ɠɟ ɜɪɟɦɹ, ɭɠɟ ɩɟɪɜɵɟ ɪɟɡɭɥɶɬɚɬɵ ɩɪɢɦɟɧɟɧɢɹ ɥɟɤɚɪɫɬɜɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ ɷɬɨɝɨ ɤɥɚɫɫɚ, ɧɚɪɹɞɭ ɫ ɩɨɞɚɜɥɟɧɢɟɦ ɪɨɫɬɚ ɩɟɪɜɢɱɧɨɣ ɨɩɭɯɨɥɢ, ɜɵɹɜɢɥɢ ɢ ɧɟɛɥɚɝɨɩɪɢɹɬɧɵɟ ɩɨɫɥɟɞɫɬɜɢɹ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɨɣ ɬɟɪɚɩɢɢ – ɜ ɪɹɞɟ ɫɥɭɱɚɟɜ ɧɚɛɥɸɞɚɥɨɫɶ ɭɫɢɥɟɧɢɟ ɦɟɬɚɫɬɚɡɢɪɨɜɚɧɢɹ. ɉɪɢɱɢɧɵ ɷɬɨɝɨ ɧɟɛɥɚɝɨɩɪɢɹɬɧɨɝɨ ɹɜɥɟɧɢɹ ɜ ɧɚɫɬɨɹɳɟɟ ɜɪɟɦɹ ɧɟ ɹɫɧɵ. ȼɨɡɦɨɠɧɨ, ɱɬɨ ɜɚɠɧɵɦ ɮɚɤɬɨɪɨɦ ɹɜɥɹɟɬɫɹ ɫɬɚɞɢɹ, ɧɚ ɤɨɬɨɪɨɣ ɩɪɢɦɟɧɹɸɬɫɹ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɟ ɩɪɟɩɚɪɚɬɵ. Ɍɚɤ, ɧɚɩɪɢɦɟɪ, Hanahan D. ɢ Folkman J., ɨɫɧɨɜɵɜɚɹɫɶ ɧɚ ɞɨɤɥɢɧɢɱɟɫɤɢɯ ɢɫɫɥɟɞɨɜɚɧɢɹɯ ɩɪɢɦɟɧɟɧɢɹ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ, ɜɵɫɤɚɡɚɥɢ ɩɪɟɞɩɨɥɨɠɟɧɢɟ ɨ ɬɨɦ, ɱɬɨ ɧɚɢɛɨɥɟɟ ɷɮɮɟɤɬɢɜɧɵɦ ɹɜɥɹɟɬɫɹ ɢɫɩɨɥɶɡɨɜɚɧɢɟ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɨɣ ɬɟɪɚɩɢɢ ɧɚ ɫɚɦɵɯ ɪɚɧɧɢɯ ɫɬɚɞɢɹɯ ɪɚɡɜɢɬɢɹ ɨɩɭɯɨɥɢ, ɩɨɤɚ ɪɚɡɦɟɪ ɨɩɭɯɨɥɢ ɟɳɟ ɧɟɜɟɥɢɤ [79]. ɇɚ ɪɚɧɧɢɯ ɫɬɚɞɢɹɯ «ɜɤɥɸɱɟɧɢɹ» ɚɧɝɢɨɝɟɧɟɡɚ ɨɩɭɯɨɥɢ, ɤɚɤ ɩɨɥɚɝɚɸɬ ɚɜɬɨɪɵ, ɥɟɝɱɟ ɨɫɬɚɧɨɜɢɬɶ ɢɥɢ ɩɨɜɟɪɧɭɬɶ ɜɫɩɹɬɶ ɷɬɨɬ ɩɪɨɰɟɫɫ. 54 ȿɳɟ ɨɞɧɢɦ ɢɡ ɜɨɡɦɨɠɧɵɯ ɨɛɴɹɫɧɟɧɢɣ ɦɨɠɟɬ ɫɥɭɠɢɬɶ ɩɪɨɢɫɯɨɞɹɳɢɣ ɩɨɞ ɞɟɣɫɬɜɢɟɦ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ ɨɬɛɨɪ ɤɥɨɧɨɜ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ, ɨɛɥɚɞɚɸɳɢɯ ɩɨɜɵɲɟɧɧɨɣ ɫɩɨɫɨɛɧɨɫɬɶɸ ɤ ɦɟɬɚɫɬɚɡɢɪɨɜɚɧɢɸ. Ⱦɚɧɧɵɟ ɥɢɬɟɪɚɬɭɪɵ ɢ ɪɟɡɭɥɶɬɚɬɵ ɧɚɲɢɯ ɢɫɫɥɟɞɨɜɚɧɢɣ ɞɚɸɬ ɨɫɧɨɜɚɧɢɟ ɩɪɟɞɩɨɥɚɝɚɬɶ, ɱɬɨ ɟɫɥɢ ɧɚ ɪɚɧɧɢɯ ɫɬɚɞɢɹɯ ɜ ɛɨɥɶɲɟɦ ɤɨɥɢɱɟɫɬɜɟ ɩɪɢɫɭɬɫɬɜɭɸɬ ɤɥɨɧɵ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ ɷɤɫɩɪɟɫɫɢɪɭɸɳɢɟ VEGF ɢ ɪɟɰɟɩɬɨɪɵ, ɬɨ ɧɚ ɛɨɥɟɟ ɩɨɡɞɧɢɯ ɫɬɚɞɢɹɯ ɩɪɟɢɦɭɳɟɫɬɜɨ ɩɨɥɭɱɚɸɬ ɤɥɨɧɵ, ɧɟɝɚɬɢɜɧɵɟ ɩɨ ɷɤɫɩɪɟɫɫɢɢ ɷɬɢɯ ɝɟɧɨɜ. Ʌɟɤɚɪɫɬɜɟɧɧɵɟ ɩɪɟɩɚɪɚɬɵ, ɧɚɩɪɚɜɥɟɧɧɵɟ ɧɚ ɛɥɨɤɢɪɨɜɚɧɢɟ VEGFɡɚɜɢɫɢɦɵɯ ɫɢɝɧɚɥɶɧɵɯ ɫɢɫɬɟɦ, ɜ ɫɥɭɱɚɟ ɢɯ ɩɪɢɦɟɧɟɧɢɹ ɧɟ ɬɨɥɶɤɨ ɩɨɞɚɜɥɹɸɬ ɧɟɨɚɧɝɢɨɝɟɧɟɡ ɨɩɭɯɨɥɢ, ɧɨ ɢ ɢɧɝɢɛɢɪɭɸɬ ɪɚɡɦɧɨɠɟɧɢɟ VEGF-ɩɨɥɨɠɢɬɟɥɶɧɵɯ ɤɥɨɧɨɜ ɤɥɟɬɨɤ, ɱɬɨ ɩɪɢɜɨɞɢɬ ɤ ɩɨɞɚɜɥɟɧɢɸ ɪɨɫɬɚ ɨɩɭɯɨɥɢ. ȼɦɟɫɬɟ ɫ ɬɟɦ, ɭɦɟɧɶɲɟɧɢɟ ɤɨɥɢɱɟɫɬɜɚ VEGF-ɩɨɥɨɠɢɬɟɥɶɧɵɯ ɤɥɨɧɨɜ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ ɞɚɟɬ ɞɨɩɨɥɧɢɬɟɥɶɧɨɟ ɩɪɟɢɦɭɳɟɫɬɜɨ ɤɥɟɬɤɚɦ ɫ ɧɟɚɤɬɢɜɧɵɦɢ VEGF-ɡɚɜɢɫɢɦɵɦɢ ɫɢɝɧɚɥɶɧɵɦɢ ɫɢɫɬɟɦɚɦɢ, ɤɨɬɨɪɵɟ ɩɨ ɧɟɤɨɬɨɪɵɦ ɩɪɢɡɧɚɤɚɦ ɦɨɝɭɬ ɛɵɬɶ ɛɨɥɟɟ ɡɥɨɤɚɱɟɫɬɜɟɧɧɵɦɢ. ȼ ɩɨɫɥɟɞɧɟɟ ɜɪɟɦɹ ɛɨɥɶɲɨɣ ɢɧɬɟɪɟɫ ɭ ɢɫɫɥɟɞɨɜɚɬɟɥɟɣ ɜɵɡɵɜɚɸɬ ɫɬɜɨɥɨɜɵɟ ɨɩɭɯɨɥɟɜɵɟ ɤɥɟɬɤɢ, ɧɚɡɜɚɧɧɵɟ ɬɚɤ ɩɨ ɚɧɚɥɨɝɢɢ ɫɨ ɫɬɜɨɥɨɜɵɦɢ ɤɥɟɬɤɚɦɢ ɝɟɦɨɩɨɷɡɚ. ɗɬɢ ɤɥɟɬɤɢ ɫɨɫɬɚɜɥɹɸɬ ɥɢɲɶ ɧɟɡɧɚɱɢɬɟɥɶɧɵɣ ɩɪɨɰɟɧɬ ɨɬ ɜɫɟɣ ɨɩɭɯɨɥɟɜɨɣ ɦɚɫɫɵ, ɧɨ ɤɚɤ ɩɪɟɞɩɨɥɚɝɚɟɬɫɹ, ɢɦɟɧɧɨ ɷɬɢ ɤɥɟɬɤɢ ɩɨɞɞɟɪɠɢɜɚɸɬ ɪɨɫɬ ɢ ɪɚɡɜɢɬɢɟ ɨɩɭɯɨɥɢ. ɉɪɨɛɥɟɦɚ ɫɬɜɨɥɨɜɵɯ ɤɥɟɬɨɤ ɨɩɭɯɨɥɢ ɩɨɤɚ ɟɳɟ ɦɚɥɨ ɢɡɭɱɟɧɚ, ɜ ɧɚɫɬɨɹɳɟɟ ɜɪɟɦɹ ɚɤɬɢɜɧɨ ɜɟɞɭɬɫɹ ɩɨɢɫɤɢ ɦɨɥɟɤɭɥɹɪɧɵɯ ɦɚɪɤɟɪɨɜ, ɫ ɩɨɦɨɳɶɸ ɤɨɬɨɪɵɯ ɦɨɠɧɨ ɛɵɥɨ ɛɵ ɨɬɥɢɱɚɬɶ ɨɩɭɯɨɥɟɜɵɟ ɤɥɟɬɤɢ ɨɬ ɫɬɜɨɥɨɜɵɯ ɤɥɟɬɨɤ ɞɚɧɧɨɝɨ ɜɢɞɚ ɨɩɭɯɨɥɢ. Ɇɨɞɟɥɶ ɜɨɡɧɢɤɧɨɜɟɧɢɹ ɡɥɨɤɚɱɟɫɬɜɟɧɧɵɯ ɨɩɭɯɨɥɟɣ, ɨɫɧɨɜɚɧɧɚɹ ɧɚ ɫɭɳɟɫɬɜɨɜɚɧɢɢ ɫɬɜɨɥɨɜɵɯ ɤɥɟɬɨɤ, ɩɪɟɞɩɨɥɚɝɚɟɬ ɢɟɪɚɪɯɢɱɟɫɤɭɸ ɨɪɝɚɧɢɡɚɰɢɸ ɨɩɭɯɨɥɢ, ɩɪɢ ɤɨɬɨɪɨɣ ɩɨɬɨɦɤɚɦɢ ɫɬɜɨɥɨɜɵɯ ɤɥɟɬɨɤ ɹɜɥɹɸɬɫɹ ɧɟ ɬɨɥɶɤɨ ɛɨɥɟɟ ɞɢɮɮɟɪɟɧɰɢɪɨɜɚɧɧɵɟ ɤɥɟɬɤɢ ɨɩɭɯɨɥɢ, ɧɨ ɢ ɦɚɥɨ ɞɢɮɮɟɪɟɧɰɢɪɨɜɚɧɧɵɟ ɫɬɜɨɥɨɜɵɟ ɤɥɟɬɤɢ [80]. ȼ ɬɚɤɨɦ ɫɥɭɱɚɟ, ɦɚɪɤɟɪɚɦɢ ɫɬɜɨɥɨɜɵɯ ɤɥɟɬɨɤ ɨɩɭɯɨɥɢ ɦɨɝɭɬ ɛɵɬɶ ɩɨɜɟɪɯɧɨɫɬɧɵɟ ɦɚɪɤɟɪɵ ɤɥɟɬɨɤ, ɧɚɯɨɞɹɳɢɯɫɹ ɧɚ ɛɨɥɟɟ ɪɚɧɧɢɯ ɫɬɚɞɢɹɯ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɢ. 55 ȼɨɡɦɨɠɧɨ, ɱɬɨ ɤ ɫɬɜɨɥɨɜɵɦ ɨɩɭɯɨɥɟɜɵɦ ɤɥɟɬɤɚɦ ɦɨɝɭɬ ɨɬɧɨɫɢɬɶɫɹ ɢ ɤɥɨɧɵ ɤɥɟɬɨɤ ɨɩɭɯɨɥɢ, ɧɟ ɷɤɫɩɪɟɫɫɢɪɭɸɳɢɟ ɮɚɤɬɨɪɵ ɪɨɫɬɚ VEGF ɢ ɢɯ ɪɟɰɟɩɬɨɪɵ. Ɍɚɤ, ɧɚɩɪɢɦɟɪ, ɜ ɨɞɧɨɣ ɢɡ ɪɚɛɨɬ ɢɡɭɱɚɥɚɫɶ ɷɤɫɩɪɟɫɫɢɹ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF-A, VEGF-B, VEGF-C, VEGF-D ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ ɜ ɩɪɨɰɟɫɫɟ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɢ ɨɫɬɟɨɛɥɚɫɬɨɜ [81]. Ɉɤɚɡɚɥɨɫɶ, ɱɬɨ ɷɤɫɩɪɟɫɫɢɹ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF-A, VEGF-B ɢ VEGF-D, ɚ ɬɚɤɠɟ ɪɟɰɟɩɬɨɪɚ VEGFR2 ɭɫɢɥɢɜɚɥɚɫɶ ɩɨ ɦɟɪɟ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɢ ɨɫɬɟɨɛɥɚɫɬɨɜ. ɗɤɫɩɪɟɫɫɢɹ VEGF-C ɢ ɪɟɰɟɩɬɨɪɚ VEGFR1 ɩɨɹɜɥɹɥɚɫɶ ɧɚ ɩɨɡɞɧɢɯ ɫɪɨɤɚɯ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɢ. ɗɤɫɩɪɟɫɫɢɹ VEGFR3 ɨɬɫɭɬɫɬɜɨɜɚɥɚ. ɂɫɯɨɞɹ ɢɡ ɷɬɢɯ ɞɚɧɧɵɯ, ɦɨɠɧɨ ɩɪɟɞɩɨɥɨɠɢɬɶ, ɱɬɨ ɤɥɨɧɵ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ, ɧɟ ɷɤɫɩɪɟɫɫɢɪɭɸɳɢɟ ɮɚɤɬɨɪɵ ɪɨɫɬɚ VEGF ɢ ɢɯ ɪɟɰɟɩɬɨɪɵ, ɧɚɯɨɞɹɬɫɹ ɧɚ ɛɨɥɟɟ ɪɚɧɧɢɯ ɫɬɚɞɢɹɯ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɢ ɢ, ɫɨɨɬɜɟɬɫɬɜɟɧɧɨ, ɫɯɨɞɧɵ ɫɨ ɫɬɜɨɥɨɜɵɦɢ ɤɥɟɬɤɚɦɢ ɨɩɭɯɨɥɢ. Ɍɚɤɢɦ ɨɛɪɚɡɨɦ, ɨɞɧɚ ɢɡ ɜɨɡɦɨɠɧɵɯ ɩɪɢɱɢɧ ɭɫɢɥɟɧɢɹ ɦɟɬɚɫɬɚɡɢɪɨɜɚɧɢɹ ɜ ɪɟɡɭɥɶɬɚɬɟ ɩɪɢɦɟɧɟɧɢɹ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɯ ɩɪɟɩɚɪɚɬɨɜ, ɧɚɰɟɥɟɧɧɵɯ ɧɚ ɛɥɨɤɢɪɨɜɚɧɢɟ VEGF-ɡɚɜɢɫɢɦɵɯ ɫɢɝɧɚɥɶɧɵɯ ɩɭɬɟɣ, ɦɨɠɟɬ ɡɚɤɥɸɱɚɬɶɫɹ ɜ ɨɬɛɨɪɟ ɧɟɝɚɬɢɜɧɵɯ ɩɨ ɷɤɫɩɪɟɫɫɢɢ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ VEGF, ɢ ɨɫɨɛɟɧɧɨ, ɢɯ ɪɟɰɟɩɬɨɪɨɜ ɤɥɨɧɨɜ ɨɩɭɯɨɥɟɜɵɯ ɤɥɟɬɨɤ, ɤɨɬɨɪɵɟ ɩɨ ɫɜɨɢɦ ɛɢɨɥɨɝɢɱɟɫɤɢɦ ɯɚɪɚɤɬɟɪɢɫɬɢɤɚɦ, ɜɨɡɦɨɠɧɨ, ɹɜɥɹɸɬɫɹ ɛɨɥɟɟ ɡɥɨɤɚɱɟɫɬɜɟɧɧɵɦɢ. ɉɨɥɨɠɢɬɟɥɶɧɵɣ ɷɮɮɟɤɬ ɩɪɢɦɟɧɟɧɢɹ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɵɯ ɥɟɤɚɪɫɬɜɟɧɧɵɯ ɫɪɟɞɫɬɜ, ɩɪɨɹɜɥɹɸɳɢɣɫɹ ɜ ɩɨɞɚɜɥɟɧɢɢ ɪɨɫɬɚ ɩɟɪɜɢɱɧɨɣ ɨɩɭɯɨɥɢ, ɩɨɞɬɜɟɪɠɞɟɧ ɜ ɤɥɢɧɢɱɟɫɤɢɯ ɢɫɩɵɬɚɧɢɹɯ ɞɥɹ ɪɹɞɚ ɨɩɭɯɨɥɟɣ ɱɟɥɨɜɟɤɚ. Ɉɞɧɚɤɨ, ɜ ɧɚɫɬɨɹɳɟɟ ɜɪɟɦɹ ɚɤɬɭɚɥɶɧɨɣ ɹɜɥɹɟɬɫɹ ɩɪɨɛɥɟɦɚ ɩɨɢɫɤɚ ɬɚɤɨɣ ɤɨɦɛɢɧɚɰɢɢ ɥɟɤɚɪɫɬɜɟɧɧɵɯ ɫɪɟɞɫɬɜ, ɤɨɬɨɪɚɹ ɛɭɞɟɬ ɫɨɱɟɬɚɬɶ ɩɪɟɢɦɭɳɟɫɬɜɚ ɚɧɬɢ-ɚɧɝɢɨɝɟɧɧɨɣ ɬɟɪɚɩɢɢ ɜ ɫɞɟɪɠɢɜɚɧɢɢ ɪɨɫɬɚ ɩɟɪɜɢɱɧɨɣ ɨɩɭɯɨɥɢ ɢ ɜ ɬɨ ɠɟ ɜɪɟɦɹ ɩɨɞɚɜɥɹɬɶ ɦɟɬɚɫɬɚɡɢɪɨɜɚɧɢɟ, ɜɨɡɧɢɤɚɸɳɟɟ ɩɨɞ ɞɟɣɫɬɜɢɟɦ ɩɪɟɩɚɪɚɬɨɜ, ɧɚɩɪɚɜɥɟɧɧɵɯ ɧɚ ɛɥɥɨɤɢɪɨɜɚɧɢɟ VEGF-ɡɚɜɢɫɢɦɵɯ ɫɢɝɧɚɥɶɧɵɯ ɫɢɫɬɟɦ. 56 ɋɩɢɫɨɤ ɥɢɬɟɪɚɬɭɪɵ 1. Greene H.S.N. Heterologous transplantation of mammalian tumors. I. The transfer of rabbit tumors to alien species. J. Exp. Med., 1941, 73, 461-473. 2. Greene H.S.N. Heterologous transplantation of mammalian tumors. II. The transfer of human tumors to alien species. J. Exp. Med., 1941, 73, 475-485. 3. Folkman J. Tumor angiogenesis: Therapeutic implications. N. Engl. J. Med., 1971, 285, 1182-1186. 4. Folkman J. Tumor angiogenesis factor. Cancer Res., 1974, 34, 2109-2113. 5. Brem S.S., Jensen H.M., Gullino P.M. Angiogenesis as a marker of preneoplastic lesions of the human breast. Cancer, 1978, 41, 239-244. 6. Brem S.S., Gullino P.M., Medina D. Angiogenesis: a marker for neoplastic transformation of mammary papillary hyperplasia. Science, 1977, 195 (4281), 880-882. 7. Gimbrone M.A., Gullino P.M. Neovascularization induced by intraocular xenografts of normal, preneoplastic, and neoplastic mouse mammary tissues. J.Natl. Cancer Inst., 1976, 56, 305-318. 8. Nagy J.A., Chang S.H., Shih S.C., Dvorak A.M., Dvorak H.F. Heterogeneity of the tumor vasculature. Semin Thromb Hemost, 2010, 36, 321–331. 9. Morikawa S., Baluk P., Kaidoh T., Haskell A., Jain R.K., McDonald D.M. Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol, 2002, 160, 985–1000. 10. Denekamp J., Hobson B. Endothelial-cell proliferation in experimental tumours. Br J Cancer, 1982, 46, 711–720. 11. Hida K., Hida Y., Amin D.N., Flint A.F., Panigrahy D., Morton C.C., Klagsbrun M. Tumor-associated endothelial cells with cytogenetic abnormalities. Cancer Res, 2004, 64, 8249–8255. 12. Gasparini G., Harris A.L. Clinical importance of the determination of tumor angiogenesis in breast carcinoma: much more than a new prognostic tool. J Clin Oncol, 1995, 13, 765-782. 13. Senger D.R., Galli S.J., Dvorak A.M., Perruzzi C.A., Harvey V.S., Dvorak H.F. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science, 1983, 219, 983-985. 14. Senger D.R., Perruzzi C.A., Feder J., Dvorak H.F. A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res., 1986, 46, 5629-5632. 57 15. Gospodarowicz D., Abraham J.A., Schilling J. Isolation and characterization of a vascular endothelial cell mitogen produced by pituitary-derived folliculo stellate cells. PNAS USA, 1989, 86 (19), 7311-7315. 16. Tisher E., Gospodarowicz D., Mitchell R., Silva M., Schilling J., Lau K., Crisp T., Fiddes J.C., Abraham J.A. Vascular endothelial growth factor: a new member of the platelet-derived growth factor gene family. Biochem. Biophys.Res.Comm., 1989, 165, 1198-1206. 17. Keck J.P., Hauser S.D., Krivi G., Sanzo K., Warren T., Feder J., Connolly D.T. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science, 1989, 246, 1309-1312. 18. Leung D.W., Cachianes G., Kuang W.J., Goeddel D.V., Ferrara N. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science, 1989, 246, 1306-1309. 19. Olofsson B., Pajusola K., Kaipainen A., von Euler G., Joukov V., Saksela O., Orpana A., Petterson R., Alitalo K., Eriksson U. Vascular endothelial growth factor B, a novel growth factor for endothelial cells. PNAS USA, 1996, 93, 2576-2581. 20. Grimmond S., Lagercrantz J., Drinkwater C., Silins G., Towson S., Pollock P., Gotley D., Carson E., Rakar S., Nordenskjold M., Ward L., Hayward N., Weber G. Cloning and characterization of a novel human gene related to vascular endothelial growth factor. Genome Res., 1996, 6, 124-131. 21. Joukov V., Pajusola K., Kaipainen A., Chilov D., Lahtinen I., Kukk E., Saskela O., Kalkkinen N., Alitalo K. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J., 1996, 15, 290-298. 22. Lee J., Gray A., Yuan J., Luoh S.M., Avraham H., Wood W.I. Vascular endothelial growth factor-related protein: A ligand and specific activator of the tyrosine kinase receptor Flt4. PNAS USA, 1996, 93, 1988-1992. 23. Yamada Y., Nezu J., Shimane M., Hirata Y. Molecular cloning of a novel vascular endothelial growth factor, VEGF-D. Genomics, 1997, 42, 483-488. 24. Achen M.G., Jeltsch M., Kukk E., Makinen T., Vitali A., Wilks A.F., Alitalo K., Stacker S.A. Vascular endothelial growth factor D (VEGF-D) is a ligand for the thyrosine kinase receptor 2 (Flk1) and VEGF receptor 3 (Flt4). PNAS USA, 1998, 95, 548-553. 25. Ogawa S., Oku A., Sawano A., Yamaguchi S., Yasaki Y., Shibuya M. A novel type of vascular endothelial growth factor: VEGF-E (NZ-7 VEGF) preferentially utilizes KDR/Flk-1 receptor and carries a potent mitotic activity without heparin-binding domain. J.Biol.Chem., 1998, 273, 31273-31282. 26. Maglione D., Guerriero V., Viglietto G., Delli-Bovi P., Persico M.G. Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. PNAS USA, 1991, 88, 9267-9271. 58 27. De Vries C., Escobedo J.A., Ueno H., Houck K., Ferrara N., Williams L.T. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science, 1992, 255, 989-991. 28. Terman B.I., Dougher-Vermazen M., Carrion M.E., Dimitrov D., Armeltno D.C., Gospodarowicz D., Bolen P. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial growth factor. Biochem.Biophys.Res. Commun., 1992, 187, 1579-1586. 29. Matthews W., Jordan C.T., Gavin M. Jenkins N.A., Copeland N.G., Lemischka I.R. A receptor tyrosine kinase cDNA isolated froma population of enriched promitive hematopoietic cells and exhibiting close genetic linkage to c-kit. PNAS USA, 1991, 88, 9026-9030. 30. Aprelikova O., Pajusola K., Partanen J., Armstrong E., Alitalo R., Bailey S., McMahon J., Wasmuth J., Alitalo K. FLT4, a novel class III receptor tyrosine kinase in chromosome 5q33-qter. Cancer Res., 1992, 52, 746-748. 31. Galland F., Karamysheva A., Mattei M.G., Rosnet O., Marchetto S., Birnbaum D. Chromosomal localization of FLT4, a novel receptor-type tyrosine kinase gene. Genomics, 1992, 13, 465-478. 32. Carmeliet P. Angiogenesis in health and disease. Nat Med, 2003, 9, 653–660. 33. Barleon B., Sozzani S., Zhou D., Weich H.A., Martovani A., Marme D. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood, 1996, 87, 3336–3343. 34. Clauss M., Weich H., Breier G., Knies U., Rockl W., Waltenberger J., Risau W. The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis. J Biol Chem, 1996, 271, 17629–17634. 35. Yoshiji H., Gomez D.E., Shibuya M., Thorgeirsson U.P. Expression of vascular endothelial growth factor, its receptor, and other angiogenic factors in human breast cancer. Cancer Research, 1996, 56, 2013-2016. 36. Maeda K., Ogawa Y., Takatsuka S., Kang S., Ogawa M., Sawada T., Chung Y., Sowa M. Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer, 1996, 77 (5), 858-863. 37. Inoue K., Ozeki Y., Suganuma T., Sugiura Y., Tanaka S. Vascular endothelial growth factor expression in primary esophageal squamous cell carcinoma. association with angiogenesis and tumor progression. Cancer, 1997, 79, 206– 213. 38. Salven P., Heikkila P., Joensuu H. Enhanced expression of vascular endothelial growth factor in metastatic melanoma. British Journal of Cancer, 1997, 76(7), 930-934. 59 39. Gasparini G. Prognostic value of vascular endothelial growth factor in breast cancer. The Oncologist, 2000, 5 (suppl 1), 37-44. 40. Takahashi Y., Kitadai Y., Bucana C.D., Cleary K.R., Ellis L.M. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res., 1995, 55, 3964-3968. 41. Boocock C.A., Charnock-Jones D.S., Sharkey A.M., McLaren J., Barker P.J., Wright K.A., Twentyman P.R., Smith S.K. Expression of vascular endothelial growth factor and its receptors flt and KDR in ovarian carcinoma. J Natl Cancer Inst., 1995, 87(7), 506-516. 42. Masood R., Cai J., Zheng T., Smith D.L., Naidu Y., Gill P.S. Vascular endothelial growth factor/vascular permeability factor is an autocrine growth factor for AIDS-Kaposi sarcoma. PNAS USA, 1997, 94(3), 979-984. 43. Herold-Mende C., Steiner H.H., Andl T., Riede D., Buttler A., Reisser C., Fusenig N.E., Mueller M.M. Expression and functional significance of vascular endothelial growth factor receptors in human tumor cells. Lab Invest., 1999, 79(12), 1573-1582. 44. Shushanov S.S., Bronstein M.I., Adelaide J., Jussila L., Tchipysheva T., Jacquemier J., Stavrovskaya A., Birnbaum D., Karamysheva A. VEGFc and VEGFR3 expression in human thyroid pathologies. Int. J. Cancer, 2000, 86, 47-52. 45. Shishkin A., Kadyrova E., Lukashina M., Vavilov A., Stavrovskaya A., Karamysheva A., Gurtsevitch V. Comparative analysis of angiogenic cell markers expression in Kaposi’s sarcoma at different stages of progression and in some other pathologies. Ɋɭɫɫɤɢɣ ɠɭɪɧɚɥ ɋɉɂȾ, ɪɚɤ ɢ ɨɛɳɟɫɬɜɟɧɧɨɟ ɡɞɨɪɨɜɶɟ, 2005, 9(1), 41-49. 46. ɋɚɛɥɢɧɚ ɘ.Ⱥ., Ʉɚɤɩɚɤɨɜɚ ȿ.ɋ., Ʉɚɪɚɦɵɲɟɜɚ Ⱥ.Ɏ. Ɋɟɝɭɥɹɰɢɹ ɷɤɫɩɪɟɫɫɢɢ ɝɟɧɚ ɮɚɤɬɨɪɚ ɪɨɫɬɚ ɷɧɞɨɬɟɥɢɹ ɫɨɫɭɞɨɜ VEGF-C ɦɟɠɤɥɟɬɨɱɧɵɦɢ ɜɡɚɢɦɨɞɟɣɫɬɜɢɹɦɢ ɜ ɩɨɩɭɥɹɰɢɢ ɤɥɟɬɨɤ. Ȼɢɨɥɨɝɢɱɟɫɤɢɟ ɦɟɦɛɪɚɧɵ, 2005, 22(4), 300-307. 47. Inoue M., Hager J.H., Ferrara N., Gerber H.P., Hanahan D. VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis. Cancer Cell, 2002, 1, 193–202. 48. Casanovas O., Hicklin D.J., Bergers G., Hanahan, D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell, 2005, 8, 299–309. 49. Rosen LS. VEGF-targeted therapy: therapeutic potential and recent advances (Review). Oncologist, 2005, 10, 382–391. 50. Kerbel R., Folkman J. Clinical translation of angiogenesis inhibitors (Review). Nat Rev Cancer, 2002, 2, 727–739. 60 51. Holmes K., Roberts O.L., Thomas A.M., Cross M.J. Vascular endothelial growth factor receptor-2: Structure, function, intracellular signalling and therapeutic inhibition. Cellular Signalling, 2007, 19, 2003-2012. 52. Thomas A.L., Morgan B., Drevs J., Unger C., Wiedenmann B., Vanhoefer U., Laurent D., Dugan M., Steward W.P. Vascular endothelial growth factor receptor tyrosine kinase inhibitors: PTK787/ZK 222584. Semin Oncol, 2003, 30 (suppl 6), 32 r38. 53. Mendel D.B., Laird A.D., Xin X., Louie S.G., Christensen J.G., Li G., Schreck R.E., Abrams T.J., Ngai T.J., Lee L.B., Murray L.J., Carver J., Chan E., Moss K.G., Haznedar J.Ö., Sukbuntherng J., Blake R.A., Sun L., Tang C., Miller T., Shirazian S., McMahon G., Cherrington J.M. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res, 2003, 9, 327 r337. 54. Wedge S.R., Ogilvie D.J., Dukes M., Kendrew J., Chester R., Jackson J.A., Boffey S.J., Valentine P.J., Curwen J.O., Musgrove H.L., Graham G.A., Hughes G.D., Thomas A.P., Stokes E.S.E., Curry B., Richmond G.H.P., Wadsworth P.F., Bigley A.L., Hennequin L.F. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res, 2002, 62, 4645 r4655. 55. Jain R.K., Duda D.G., Clark J.W., Loeffler J.S. Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nature Clinical Practice Oncology, 2006, 3(1), 24–40. 56. Steward W.P., Thomas A., Morgan B. et al. Expanded phase I/II study of PTK787/ZK 222584 (PTK/ZK), a novel, oral angiogenesis inhibitor, in combination with FOLFOX-4 as first-line treatment for patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol, 2004, 23, 259. 57. Trarbach T., Schleucher N., Riedel U. et al. Phase I study of the oral vascular endothelial growth factor (VEGF) receptor inhibitor PTK787/ZK 222584 (PTK/ZK) in combination with irinotecan/5-fluorouracil/leucovorin in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol, 2003, 22, 285. 58. News in Brief. Nat Rev Drug Discov, 2005, 4, 448–449. 59. Meadows K.L., Hurwitz H.I. Anti-VEGF therapies in the clinic. Cold Spring Harb Perspect Med, 2012, 2:a006577. 60. Allegra C.J., Yothers G. O’Connell M.J., Sharif S., Petrelli N.J., Colangelo L.H., Atkins J.N., Seay T.E., Fehrenbacher L., Goldberg R.M., et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: Results of NSABP protocol C-08. J Clin Oncol, 2011, 29, 11–16. 61 61. Brufsky A., Bondarenko I., Smirnov V., Hurvitz S., Perez E., Ponomarova O., Vynnychenko I., Swamy R., Mu H., Rivera R. RIBBON-2: A randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of HER2-negative metastatic breast cancer. Cancer Res, 2009, 69, 942. 62. Burger R.A., Brady M.F., Bookman M.A., Walker J.L., Homesley H.D., Fowler J., Monk B.J., Greer B.E., Boente M., Liang S.X. Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): A Gynecologic Oncology Group study. J Clin Oncol, 2010, 28, 18. 63. Miles D.W., Chan A., Dirix L.Y., Cortes J., Pivot X., Tomczak P., Delozier T., Sohn J.H., Provencher L., Puglisi F., Harbeck N., Steger G.G., Schneeweiss A., Wardley A.M., Chlistalla A., Romieu G. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol, 2010, 28, 3239–3247. 64. Pàez-Ribes M., Allen E., Hudock J., Takeda T., Okuyama H., Vinals F., Inoue M., Bergers G., Hanahan D., Casanovas O. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell, 2009, 15, 220–231. 65. De Groot J.F., Fuller G., Kumar A.J., Piao Y., Eterovic K., Ji Y., Conrad C.A. Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro Oncol, 2010, 12(3), 233–242. 66. Ebos J.M.L., Lee C.R., Cruz-Munoz W., Bjarnason G.A., Christensen J.G., Kerbel R.S. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell, 2009, 15, 232–239. 67. Ebos J.M., Lee C.R., Christensen J.G., Mutsaers A.J., Kerbel R.S. Multiple circulating proangiogenic factors induced by sunitinib malate are tumorindependent and correlate with antitumor efficacy. PNAS USA, 2007, 104, 17069–17074. 68. Christensen J.G. A preclinical review of sunitinib, a multitargeted receptor tyrosine kinase inhibitor with anti-angiogenic and antitumour activities. Ann. Oncol., 2007, 18 (Suppl 10), x3–x10. 69. Loges S., Mazzone M., Hohensinner P., Carmeliet P. Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited. Cancer Cell, 2009, 15, 167-170. 70. Brahimi-Horn M.C., Chiche J., Pouysségur J. Hypoxia and cancer. J Mol Med, 2007, 85, 1301–1307. 62 71. Yu, J.L. Rak, J.W., Coomber B.L., Hicklin D.J., Kerbel R.S. Effect of p53 status on tumor response to antiangiogenic therapy. Science, 2002, 295, 1526– 1528. 72. Graeven U., Fiedler W., Karpinski S., Ergün S., Kilic N., Rodeck U., Schmiegel W., Hossfeld D.K. Melanoma-associated expression of vascular endothelial growth factor and its receptors FLT-1 and KDR. J Cancer Res Clin Oncol., 1999, 125(11), 621-629. 73. Ferrer F.A., Miller L.J., Lindquist R., Kowalczyk P., Laudone V.P., Albertsen P.C., Kreutzer D.L. Expression of vascular endothelial growth factor receptors in human prostate cancer. Urology, 1999, 54(3), 567-572. 74. Ʉɚɪɚɦɵɲɟɜɚ Ⱥ.Ɏ., ɒɢɲɤɢɧ Ⱥ.Ⱥ., Ⱦɪɭɠɢɧɢɧ Ʉ.ȼ., ɋɬɚɜɪɨɜɫɤɚɹ Ⱥ.Ⱥ. ɂɡɦɟɧɟɧɢɟ ɷɤɫɩɪɟɫɫɢɢ ɝɟɧɨɜ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ ɷɧɞɨɬɟɥɢɹ ɫɨɫɭɞɨɜ VEGF ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ ɩɪɢ ɩɪɨɝɪɟɫɫɢɢ ɪɚɤɚ ɦɨɱɟɜɨɝɨ ɩɭɡɵɪɹ ɱɟɥɨɜɟɤɚ. Ɇɚɬɟɪɢɚɥɵ IV ɋɴɟɡɞɚ ɨɧɤɨɥɨɝɨɜ ɢ ɪɚɞɢɨɥɨɝɨɜ ɋɇȽ, 2006, Ȼɚɤɭ, 43. 75. Yoshiji H., Harris S.R., Thorgeirsson U.P. Vascular endothelial growth factor is essential for initial but not continued in vivo growth of human breast carcinoma cells. Cancer Research, 1997, 57, 3924-3928. 76. Ȼɭɪɚɜɰɨɜɚ ɂ.ȼ., Ʉɚɥɢɬɢɧ ɇ.ɇ., ɋɚɛɥɢɧɚ ɘ.Ⱥ., Ʉɚɤɩɚɤɨɜɚ ȿ.ɋ., Ʉɚɪɚɦɵɲɟɜɚ Ⱥ.Ɏ., ɋɬɚɜɪɨɜɫɤɚɹ Ⱥ.Ⱥ., Ƚɨɥɟɧɤɨɜ Ⱥ.Ʉ. ɗɤɫɩɪɟɫɫɢɹ ɦɊɇɄ ɝɟɧɨɜ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ ɫɟɦɟɣɫɬɜɚ VEGF ɢ ɢɯ ɪɟɰɟɩɬɨɪɨɜ ɭ ɛɨɥɶɧɵɯ ɦɧɨɠɟɫɬɜɟɧɧɨɣ ɦɢɟɥɨɦɨɣ: ɋɨɩɨɫɬɚɜɥɟɧɢɟ ɫ ɰɢɬɨɥɨɝɢɱɟɫɤɢɦɢ ɯɚɪɚɤɬɟɪɢɫɬɢɤɚɦɢ ɤɨɫɬɧɨɝɨ ɦɨɡɝɚ. Ɋɨɫɫɢɣɫɤɢɣ ɛɢɨɬɟɪɚɩɟɜɬɢɱɟɫɤɢɣ ɠɭɪɧɚɥ, 2009, 8(4), 17-24. 77. Durie B.G.M., Salmon S.E. Cancer, 1975, 36, 842-854. 78. Ʉɚɥɢɬɢɧ ɇ.ɇ., Ʉɨɫɬɸɤɨɜɚ Ɇ.ɇ., Ʉɚɤɩɚɤɨɜɚ ȿ.ɋ., Ɍɭɩɢɰɵɧ ɇ.ɇ., Ʉɚɪɚɦɵɲɟɜɚ Ⱥ.Ɏ. ɗɤɫɩɪɟɫɫɢɹ ɪɟɰɟɩɬɨɪɚ ɮɚɤɬɨɪɨɜ ɪɨɫɬɚ ɷɧɞɨɬɟɥɢɹ ɫɨɫɭɞɨɜ VEGFR1 ɜ ɤɭɥɶɬɭɪɚɯ ɤɥɟɬɨɤ ɦɧɨɠɟɫɬɜɟɧɧɨɣ ɦɢɟɥɨɦɵ: ɤɨɪɪɟɥɹɰɢɹ ɫ ɢɦɦɭɧɨɮɟɧɨɬɢɩɨɦ ɢ ɥɟɤɚɪɫɬɜɟɧɧɨɣ ɭɫɬɨɣɱɢɜɨɫɬɶɸ. Ȼɸɥɥ. ɗɤɫɩ. Ȼɢɨɥ. Ɇɟɞ., 2012, 153 (6), 865-869. 79. Hanahan D., Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell, 1996, 86, 353–364. 80. Reya T., Morrison S.J., Clarke M.F., Weissman I.L. Stem cells, cancer, and cancer stem cells. Nature, 2001, 414, 105-111. 81. Deckers M.M.L., Karperien M., van der Bent C., Yamashita T., Papapoulos S.E., Löwik C.W.G.M. Expression of vascular endothelial growth factors and their receptors during osteoblast differentiation. Endocrinology, 2000, 141, 1667–1674. 63 Покупайте Ваши книги быстро и без посредников он-лайн – в одном из самых быстрорастущих книжных он-лайн магазинов! окружающей среде благодаря технологии Печати-на-Заказ. Покупайте Ваши книги на www.more-books.ru Buy your books fast and straightforward online - at one of world’s fastest growing online book stores! Environmentally sound due to Print-on-Demand technologies. Buy your books online at www.get-morebooks.com VDM Verlagsservicegesellschaft mbH Heinrich-Böcking-Str. 6-8 D - 66121 Saarbrücken Telefon: +49 681 3720 174 Telefax: +49 681 3720 1749 info@vdm-vsg.de www.vdm-vsg.de
