153 Бuо логuя СРАВНИТЕЛЬНЫЙ АНАЛИЗ

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1, 2007
Åñòåñòâåííûå íàó-
Ȼɢ ɨ ɥ ɨ ɝ ɢ ɹ
ɍȾɄ 612.014.4.083.36
Ɋ. Ɇ. ȺɊɍɌɘɇəɇ, Ƚ. Ƚ. ɈȽȺɇȿɋəɇ, Ɋ. ȿ. ɆɍɊȺȾəɇ, Ʉ. ɋ. ɆȺɊȽȺɊəɇ
ɋɊȺȼɇɂɌ ȿɅɖɇɕɃ ȺɇȺɅɂɁ ȽȿɇɈɌ ɈɄɋɂɑȿɋɄɂɏ ɗɎɎȿɄɌ Ɉȼ
ɇɈȼɕɏ ɉɈɊɎɂɊɂɇɈȼ ɆȿɌ ɈȾɈɆ ȾɇɄ-ɄɈɆȿɌ IN VIVO
Ɇɟɬɨɞɨɦ ȾɇɄ-ɤɨɦɟɬ ɨɰɟɧɢɜɚɥɚɫɶ ɫɪɚɜɧɢɬɟɥɶɧɚɹ ɝɟɧɨɬɨɤɫɢɱɧɨɫɬɶ
ɧɨɜɨɝɨ ɩɨɪɮɢɪɢɧɚ TOEt4PyP ɢ ɟɝɨ Ag-, Zn- ɢ ɋɨ-ɩɪɨɢɡɜɨɞɧɵɯ ɜ ɥɟɣɤɨɰɢɬɚɯ
ɤɪɨɜɢ ɦɵɲɟɣ in vivo ɜ ɡɚɜɢɫɢɦɨɫɬɢ ɨɬ ɜɪɟɦɟɧɢ ɜɨɡɞɟɣɫɬɜɢɹ. ɉɨɜɵɲɟɧɢɟ
ɭɪɨɜɧɹ ɩɨɜɪɟɠɞɟɧɢɣ ȾɇɄ ɱɟɪɟɡ 24 ɱ ɩɨɫɥɟ ɜɜɟɞɟɧɢɹ ɢɡɭɱɚɟɦɵɯ ɩɨɪɮɢɪɢɧɨɜ
ɩɨ ɫɪɚɜɧɟɧɢɸ ɫ ɭɪɨɜɧɟɦ, ɧɚɛɥɸɞɚɟɦɵɦ ɱɟɪɟɡ 6 ɱɚɫɨɜ, ɫɜɢɞɟɬɟɥɶɫɬɜɭɟɬ ɨ
ɤɭɦɭɥɹɬɢɜɧɨɦ ɷɮɮɟɤɬɟ ɢɯ ɜɨɡɞɟɣɫɬɜɢɹ, ɱɬɨ ɦɨɠɟɬ ɛɵɬɶ ɢɫɩɨɥɶɡɨɜɚɧɨ ɜ
ɯɢɦɢɨɬɟɪɚɩɢɢ ɨɩɭɯɨɥɟɣ.
ɂɫɫɥɟɞɨɜɚɧɢɹ ɩɨɪɮɢɪɢɧɨɜ ɢ ɢɯ ɚɧɚɥɨɝɨɜ ɡɚ ɩɨɫɥɟɞɧɟɟ ɞɟɫɹɬɢɥɟɬɢɟ
ɫɬɪɟɦɢɬɟɥɶɧɨ ɪɚɡɜɢɜɚɸɬɫɹ. ɉɨɜɵɲɟɧɧɵɣ ɢɧɬɟɪɟɫ ɤ ɭɧɢɤɚɥɶɧɨɣ ɫɬɪɭɤɬɭɪɟ
ɩɨɪɮɢɪɢɧɨɜ ɢ ɦɟɬɚɥɥɨɩɨɪɮɢɪɢɧɨɜ ɨɛɭɫɥɨɜɥɟɧ ɪɟɚɥɶɧɵɦɢ ɩɟɪɫɩɟɤɬɢɜɚɦɢ ɢɯ
ɢɫɩɨɥɶɡɨɜɚɧɢɹ ɜ ɯɢɦɢɨɬɟɪɚɩɢɢ ɨɩɭɯɨɥɟɣ. ȼ ɱɚɫɬɧɨɫɬɢ ɜɟɫɶɦɚ ɩɟɪɫɩɟɤɬɢɜɧɨɣ
ɹɜɥɹɟɬɫɹ ɢɯ ɭɧɢɤɚɥɶɧɚɹ ɫɩɨɫɨɛɧɨɫɬɶ ɫɟɥɟɤɬɢɜɧɨ ɧɚɤɚɩɥɢɜɚɬɶɫɹ ɜ ɨɩɭɯɨɥɟɜɵɯ
ɬɤɚɧɹɯ ɢ ɭɞɟɪɠɢɜɚɬɶɫɹ ɬɚɦ ɞɥɢɬɟɥɶɧɨɟ ɜɪɟɦɹ [1]. Ɏɚɪɦɚɤɨɥɨɝɢɱɟɫɤɢɟ ɢ ɛɢɨɥɨɝɢɱɟɫɤɢɟ ɫɜɨɣɫɬɜɚ ɩɨɪɮɢɪɢɧɨɜ ɜɨ ɦɧɨɝɨɦ ɨɩɪɟɞɟɥɹɸɬɫɹ ɢɯ ɫɬɪɭɤɬɭɪɨɣ.
ɉɨɷɬɨɦɭ ɜɨ ɦɧɨɝɢɯ ɥɚɛɨɪɚɬɨɪɢɹɯ ɡɚɧɢɦɚɸɬɫɹ ɰɟɥɟɧɚɩɪɚɜɥɟɧɧɵɦ ɫɢɧɬɟɡɨɦ
ɧɨɜɵɯ ɩɨɪɮɢɪɢɧɨɜ ɫ ɰɟɥɶɸ ɩɨɥɭɱɟɧɢɹ ɧɚɢɛɨɥɟɟ ɚɤɬɢɜɧɵɯ ɢ ɛɟɡɨɩɚɫɧɵɯ
ɫɨɟɞɢɧɟɧɢɣ. ɉɨɞɨɛɧɵɣ ɩɨɢɫɤ ɩɪɟɞɩɨɥɚɝɚɟɬ ɨɛɹɡɚɬɟɥɶɧɭɸ ɨɰɟɧɤɭ ɢɯ ɝɟɧɨɬɨɤɫɢɱɧɨɫɬɢ ɫ ɭɱɟɬɨɦ ɦɟɯɚɧɢɡɦɨɜ ɞɟɣɫɬɜɢɹ ɢɡɭɱɚɟɦɵɯ ɫɨɟɞɢɧɟɧɢɣ ɧɚ ȾɇɄ ɢ
ɜɨɡɦɨɠɧɨɫɬɢ ɭɦɟɧɶɲɟɧɢɹ ɩɨɛɨɱɧɨɝɨ ɜɨɡɞɟɣɫɬɜɢɹ ɧɚ ɧɨɪɦɚɥɶɧɵɟ ɤɥɟɬɤɢ
ɨɪɝɚɧɢɡɦɚ.
ɂɫɫɥɟɞɨɜɚɧɢɹ ɬɨɤɫɢɱɧɨɫɬɢ ɢ ɩɪɨɬɢɜɨɨɩɭɯɨɥɟɜɨɣ ɚɤɬɢɜɧɨɫɬɢ ɧɨɜɵɯ
ɩɨɪɮɢɪɢɧɨɜ, ɫɢɧɬɟɡɢɪɨɜɚɧɧɵɯ ɧɚ ɤɚɮɟɞɪɟ ɮɚɪɦɚɤɨɥɨɝɢɱɟɫɤɨɣ ɯɢɦɢɢ
ȿɪȽɆɍ, ɩɪɨɜɨɞɹɬɫɹ ɜ ɥɚɛɨɪɚɬɨɪɢɢ ɩɪɟɞɤɥɢɧɢɱɟɫɤɨɣ ɬɨɤɫɢɤɨɥɨɝɢɢ ɂɧɫɬɢɬɭɬɚ ɬɨɧɤɨɣ ɨɪɝɚɧɢɱɟɫɤɨɣ ɯɢɦɢɢ ɇȺɇ ɊȺ ɫɨɝɥɚɫɧɨ ɦɟɬɨɞɢɱɟɫɤɢɦ ɪɟɤɨɦɟɧɞɚɰɢɹɦ [2]. Ɉɞɧɨɜɪɟɦɟɧɧɨ ɢɡɭɱɚɸɬɫɹ ɢɯ ɝɟɧɨɬɨɤɫɢɱɟɫɤɢɟ ɫɜɨɣɫɬɜɚ ɦɟɬɨɞɨɦ
ȾɇɄ-ɤɨɦɟɬ. Ɇɟɬɨɞ ɲɢɪɨɤɨ ɢɫɩɨɥɶɡɭɟɬɫɹ ɞɥɹ ɨɰɟɧɤɢ ɩɨɜɪɟɠɞɟɧɢɣ ɢ ɪɟɩɚɪɚɰɢɢ ȾɇɄ ɜ ɥɸɛɵɯ ɩɨɩɭɥɹɰɢɹɯ ɷɭɤɚɪɢɨɬɢɱɟɫɤɢɯ ɤɥɟɬɨɤ in vitro ɢ in vivo [3].
ɐɟɥɶɸ ɧɚɫɬɨɹɳɟɝɨ ɢɫɫɥɟɞɨɜɚɧɢɹ ɹɜɥɹɥɨɫɶ ɢɡɭɱɟɧɢɟ ɝɟɧɨɬɨɤɫɢɱɟɫɤɨɣ
ɚɤɬɢɜɧɨɫɬɢ ɦɟɡɨ-ɬɟɬɪɚ (4-N-ɨɤɫɢɷɬɢɥɩɢɪɢɞɢɥ) ɩɨɪɮɢɧɚ ɬɟɬɪɚɯɥɨɪɢɞɚ ɢ ɟɝɨ
Ag-, Zn- ɢ ɋɨ-ɩɪɨɢɡɜɨɞɧɵɯ ɜ ɤɥɟɬɤɚɯ ɤɪɨɜɢ ɛɟɥɵɯ ɛɟɫɩɨɪɨɞɧɵɯ ɦɵɲɟɣ
153
oT
O
ET
4P
yP
C
4P
yP
Zn
TO
Et
4P
yP
Py
P
Ag
TO
Et
TO
ET
4
Ʉ
ɨɧ
ɬ
ɪɨ
ɥ
ɶ
% ȾɇɄɜ ɯɜɨɫɬ ɟ
in vivo ɜ ɡɚɜɢɫɢɦɨɫɬɢ ɨɬ ɜɪɟɦɟɧɢ ɜɨɡɞɟɣɫɬɜɢɹ ɩɪɟɩɚɪɚɬɨɜ ɦɟɬɨɞɨɦ ȾɇɄɤɨɦɟɬ (ɝɟɥɶ-ɷɥɟɤɬɪɨɮɨɪɟɡ ɟɞɢɧɢɱɧɵɯ ɤɥɟɬɨɤ).
Ɇɚɬɟ ɪɢɚɥ ɢ ɦɟɬɨɞɢɤɚ. ɗɤɫɩɟɪɢɦɟɧɬɵ ɩɪɨɜɨɞɢɥɢ ɧɚ ɛɟɥɵɯ ɛɟɫɩɨɪɨɞɧɵɯ ɦɵɲɚɯ ɜɟɫɨɦ 25–30 ɝ . Ⱦɥɹ ɤɚɠɞɨɝɨ ɷɤɫɩɟɪɢɦɟɧɬɚɥɶɧɨɝɨ ɜɚɪɢɚɧɬɚ ɛɵɥɨ ɢɫɩɨɥɶɡɨɜɚɧɨ ɩɨ 3 ɠɢɜɨɬɧɵɯ. Ɇɵɲɚɦ ɜɜɨɞɢɥɢ ɩɪɟɩɚɪɚɬɵ T OEt4PyP,
ZnT OEt4PyP ɢ CoTOEt4PyP ɜ ɞɨɡɟ 25 ɦɝ /ɤɝ ɢ AgT OET4PyP ɜ ɞɨɡɟ 15 ɦɝ /ɤɝ ,
ɱɬɨ ɫɨɨɬɜɟɬɫɬɜɭɟɬ ½ LD50. Ɂɚɛɨɪ ɨɛɪɚɡɰɨɜ ɰɟɥɶɧɨɣ ɤɪɨɜɢ ɩɪɨɜɨɞɢɥɢ ɱɟɪɟɡ
6 ɢ 24 ɱɚɫɚ ɩɨɫɥɟ ɨɞɧɨɤɪɚɬɧɨɝɨ ɜɜɟɞɟɧɢɹ ɩɪɟɩɚɪɚɬɨɜ. Ⱦɥɹ ɨɰɟɧɤɢ ɢɧɞɭɤɰɢɢ
ɤɨɦɟɬ ɩɪɢɦɟɧɹɥɢ ɦɟɬɨɞɢɤɭ ɉ. ɋɢɧɯɚ ɫ ɫɨɚɜɬɨɪɚɦɢ ɫ ɧɟɛɨɥɶɲɢɦɢ ɦɨɞɢɮɢɤɚɰɢɹɦɢ [4]. Ⱦɥɹ ɩɨɥɭɱɟɧɢɹ ɨɩɬɢɦɚɥɶɧɨɣ ɩɥɨɬɧɨɫɬɢ ɤɥɟɬɨɤ ɧɚ ɩɪɟɞɦɟɬɧɨɟ ɫɬɟɤɥɨ ɧɚɧɨɫɢɥɢ ɫɦɟɫɶ 15 ɦɤɥ ɰɟɥɶɧɨɣ ɤɪɨɜɢ ɦɵɲɟɣ ɢ 85 ɦɤɥ ɪɚɫɬɜɨɪɚ
ɚɝɚɪɨɡɵ. ȼɫɟ ɨɫɬɚɥɶɧɵɟ ɷɬɚɩɵ ɨɫɭɳɟɫɬɜɥɹɥɢ ɩɨ ɫɬɚɧɞɚɪɬɧɨɣ ɦɟɬɨɞɢɤɟ [5].
ɂɡɨɛɪɚɠɟɧɢɹ ɤɨɦɟɬ ɚɧɚɥɢɡɢɪɨɜɚɥɢ ɫ ɩɪɢɦɟɧɟɧɢɟɦ ɩɪɨɝɪɚɦɦɵ ɚɜɬɨɦɚɬɢɱɟɫɤɨɝɨ ɚɧɚɥɢɡɚ Komet 4 (Kinetic Imaging, Liverpool). ȼ ɤɚɠɞɨɦ ɜɚɪɢɚɧɬɟ
ɚɧɚɥɢɡɢɪɨɜɚɥɢ ɩɨ 150 ɤɥɟɬɨɤ. ɍɪɨɜɟɧɶ ɩɨɜɪɟɠɞɟɧɢɣ ȾɇɄ ɨɰɟɧɢɜɚɥɫɹ ɧɚ
ɨɫɧɨɜɟ ɢɡɦɟɪɟɧɢɣ ɩɪɨɰɟɧɬɚ ȾɇɄ ɜ ɯɜɨɫɬɟ.
ɋɬɚɬɢɫɬɢɱɟɫɤɢɣ ɚɧɚɥɢɡ ɩɨɥɭɱɟɧɧɵɯ ɪɟɡɭɥɶɬɚɬɨɜ ɩɪɨɜɨɞɢɥɢ ɫ ɩɨɦɨɳɶɸ
ɩɪɨɝɪɚɦɦ Microsoft EXCEL ɢ ST AT GRAPHICS Plus 5.1 ɫ ɩɪɢɦɟɧɟɧɢɟɦ
ɧɟɩɚɪɚɦɟɬɪɢɱɟɫɤɨɝɨ ɬɟɫɬɚ Mann-Whitney (U-test).
Ɋɟ ɡɭɥɶɬɚɬɵ ɢ ɨɛɫɭɠɞɟ ɧɢɟ . ɑɟɪɟɡ 6 ɱɚɫɨɜ ɩɨɫɥɟ ɜɜɟɞɟɧɢɹ ɩɪɟɩɚɪɚɬɨɜ
ɧɚɛɥɸɞɚɥɨɫɶ ɞɨɫɬɨɜɟɪɧɨɟ (p<0,05) ɩɨɜɵɲɟɧɢɟ % ȾɇɄ ɜ ɯɜɨɫɬɟ ɤɨɦɟɬ ɞɥɹ
T OEt4PyP (10,41%), AgT OEt4PyP (9,32%) ɢ ZnTOEt4PyP (8,20%) ɩɨ ɫɪɚɜɧɟɧɢɸ ɫ ɤɨɧɬɪɨɥɟɦ (5,86 %). ɑɟɪɟɡ 24 ɱɚɫɚ ɩɨɫɥɟ ɜɜɟɞɟɧɢɹ ɬɚɤɠɟ ɛɵɥɨ ɨɬɦɟɱɟɧɨ ɞɨɫɬɨɜɟɪɧɨɟ (p<0,05) ɩɨɜɵ14
ɲɟɧɢɟ % ȾɇɄ ɜ ɯɜɨɫɬɟ ɞɥɹ
12
2
ɜɫɟɯ ɢɡɭɱɟɧɧɵɯ ɩɨɪɮɢɪɢɧɨɜ:
10
T OEt4PyP (12,18%), ZnT OEt4PyP
8
(11,94%), CoTOEt4PyP (10,58%)
1
6
ɢ AgT OEt4PyP (10,47%) ɩɨ ɫɪɚɜ4
ɧɟɧɢɸ ɫ ɤɨɧɬɪɨɥɟɦ (5,90 %).
2
ɍɪɨɜɧɢ ɩɨɜɪɟɠɞɟɧɢɣ ȾɇɄ
0
ɱɟɪɟɡ 24 ɱɚɫɚ ɩɨɫɥɟ ɜɜɟɞɟɧɢɹ
ɩɨɪɮɢɪɢɧɨɜ ɛɵɥɢ ɞɨɫɬɨɜɟɪɧɨ
ɜɵɲɟ, ɱɟɦ ɱɟɪɟɡ 6 ɱɚɫɨɜ (ɫɦ. ɪɢɫɭɧɨɤ).
ɇɄ ɜ ɯɜɨɫɬɟ ɤɨɦɟɬ ɜ ɥɟɣɤɨɰɢɬɚɯ ɦɵɲɟɣ ɩɨɫɥɟ
Ɍ ɚɤɢɦ ɨɛɪɚɡɨɦ, ɩɨɥɭɱɟɧɜɜɟɞɟɧɢɹ ɩɨɪɮɢɪɢɧɨɜ TOEt4PyP, AgTOEt4PyP,
ɧɵɟ
ɧɚɦɢ
ɪɟɡɭɥɶɬɚɬɵ ɫɜɢɞɟɬɟɥɶZnTOEt4PyP ɢ CoTOEt4PyP: 1 – ɱɟɪɟɡ 6 ɱ ɩɨɫɥɟ
ɫɬɜɭɸɬ
ɨ
ɤɭɦɭɥɹɬɢɜɧɨɦ
ɷɮɮɟɤɬɟ
ɜɜɟɞɟɧɢɹ; 2 – ɱɟɪɟɡ 24 ɱ.
ɢɡɭɱɟɧɧɵɯ ɩɨɪɮɢɪɢɧɨɜ ɩɪɢ ɨɰɟɧɤɟ ɢɯ ɝɟɧɨɬɨɤɫɢɱɧɨɫɬɢ, ɱɬɨ ɫɨɡɞɚɟɬ ɩɪɟɞɩɨɫɵɥɤɢ ɞɥɹ ɢɯ ɜɨɡɦɨɠɧɨɝɨ ɩɪɢɦɟɧɟɧɢɹ ɜ ɯɢɦɢɨɬɟɪɚɩɢɢ ɨɩɭɯɨɥɟɣ.
Ɋɚɛɨɬɚ ɜɵɩɨɥɧɟɧɚ ɩɪɢ ɩɨɞɞɟɪɠɤɟ ɝɪɚɧɬɚ Ⱥ-301.2.
ɉɨɫɬɭɩɢɥɨ 13.02.2007
Ʉɚɮɟɞɪɚ ɝɟɧɟɬɢɤɢ ɢ ɰɢɬɨɥ ɨɝɢɢ
Ʌ ɂ Ɍȿ Ɋ Ⱥ Ɍ ɍɊ Ⱥ
1. Vicente MG .H. – Current Med. Chem., Anti-Cancer Agents, 2001, v.1, p. 175–194.
154
2. ɋɬɟɩɚɧɨɜ Ⱥ.ȼ . Ⱦɨɤɥɢɧɢɱɟɫɤɢɟ ɢɫɫɥɟɞɨɜɚɧɢɹ ɥɟɤɚɪɫɬɜɟɧɧɵɯ ɫɪɟɞɫɬɜ. Ɇɟɬɨɞɢɱɟɫɤɢɟ ɪɟɤɨɦɟɧɞɚɰɢɢ. Ʉɢɟɜ, 2002.
3. T ice R.R., Agurell E., Anderson D., Burlinson B., Hartman A., Kobayashi H., Miyamae Y.,
Royas E., Ryu J.C., Sasaki Y.F. – Environ. Mol. Mutagen., 2000, v. 35, p. 206–221.
4. Singh N.P. et al. – Exp. Cell Research, 1988, v. 175, p. 184–191.
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è. Ø. вðàôÂÚàôÜÚ²Ü, ¶. ¶. ÐàìвÜÜÆ êÚ²Ü, è. º. Øàôð²¸Ú²Ü,
ø. ê. زð¶²ðÚ²Ü
Üàð äàðüÆðÆÜܺðÆ ¶ºÜàîàøêÆÎ ¾üºÎîܺðÆ
вغزî²Î²Ü ²Ü²ÈƼÀ ¸ÜÂ-¶Æê²êîÔºðÆ ØºÂà¸àì IN VIVO
²Ù ÷ á ÷ á õÙ
¸ÜÂ-·Çë³ëïÕ»ñÇ Ù»Ãá¹áí ·Ý³Ñ³ïí»É ¿ Ýáñ åáñýÇñÇÝ` T OEt4PyP Ç ¨ Ýñ³ Ag-, Zn- ¨ Co-³Í³ÝóÛ³ÉÝ»ñÇ Ñ³Ù»Ù³ï³Ï³Ý ·»ÝáïáùëÇÏáõÃÛáõÝÁ ÙÏÝ»ñÇ ³ñÛ³Ý É»ÛÏáóÇïÝ»ñáõÙ in vivo ` ϳËí³Í ³½¹Ù³Ý ųٳݳÏÇó:
¸ÜÂ-Ç íݳëí³ÍùÝ»ñÇ Ù³Ï³ñ¹³ÏÇ μ³ñÓñ³óáõÙÁ áõëáõÙݳëÇñíáÕ åáñýÇñÇÝÝ»ñÇ Ý»ñ³ñÏáõÙÇó 24 ų٠³Ýó (Ý»ñ³ñÏáõÙÇó 6 ų٠³Ýó íݳëí³ÍùÝ»ñÇ
ٳϳñ¹³ÏÇ Ñ³Ù»Ù³ïáõÃÛ³Ùμ) íϳÛáõÙ ¿ Ýñ³Ýó ÏáõÙáõÉÛ³ïÇí ¿ý»ÏïÇ
Ù³ëÇÝ, ÇÝãÁ ϳñáÕ ¿ ÏÇñ³éí»É áõéáõóùÝ»ñÇ ùÇÙÇáûñ³ådzÛáõÙ:
R. M. HAROUTYUNIAN, G. G. HOVHANNISYAN, R.Ye. MURADYAN, K. S. MARGARYAN
COMPARAT IVE ANALYSIS OF GENOT OXIC EFFECT S OF NEW
PORPHYRINS IN COMET ASSAY IN VIVO
S u m ma r y
Comparative genotoxicity of new porphyrins TOEt4PyP and their Ag-,
Zn- and Co derivatives was estimated by Comet-assay in mice leukocytes
in vivo, depending on time of treatment. The increase of level of DNA
damage after 24 hours in comparison with 6 hours of porphyrins
administration confirms their cumulative effect, that can be applied in
chemotherapy of tumors.
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