Îáçîðû ÏÐÎÒÈÂÎÎÏÓÕÎËÅÂÀß ÀÊÒÈÂÍÎÑÒÜ ÃÅÏÀÐÈÍÎÂ: ÄÅÉÑÒÂÈÅ ÍÀ ÎÏÓÕÎËÅÂÛÉ ÐÎÑÒ, ÀÍÃÈÎÃÅÍÅÇ È ÌÅÒÀÑÒÀÇÈÐÎÂÀÍÈÅ Â.È. Ïðîõîðîâà, Ë.Ì. Øèøëî, Í.Í. Êîëÿäêî, Ë.À. Äåðæàâåö, È.À. Êîñåíêî, Î.Ï. Ìàòûëåâè÷ ÐÍÏÖ ÎÌÐ èì. Í.Í. Àëåêñàíäðîâà, ã. Ìèíñê Êëþ÷åâûå ñëîâà: ãåïàðèíû, ðàê, òðîìáîç, ìåòàñòàçèðîâàíèå, àíãèîãåíåç Ãåïàðèí è åãî ïðîèçâîäíûå — íèçêîìîëåêóëÿðíûå ãåïàðèíû, ýôôåêòèâíû ïðè ïðîôèëàêòèêå è ëå÷åíèè òðîìáîýìáîëè÷åñêèõ îñëîæíåíèé â ðàçëè÷íûõ ñôåðàõ ìåäèöèíû. Ïðèìåíåíèå ãåïàðèíîâ â îíêîëîãè÷åñêîé ïðàêòèêå, êàê îêàçûâàåòñÿ, ýôôåêòèâíî â áîðüáå íå òîëüêî ñ ãèïåðêîàãóëÿöèîííûì ñîñòîÿíèåì è òðîìáîçàìè ó îíêîëîãè÷åñêèõ áîëüíûõ, íî è ñ ïðîöåññàìè, ðåãóëèðóþùèìè îïóõîëåâûé ðîñò è ìåòàñòàçèðîâàíèå. Ãëàâíàÿ öåëü ýòîãî îáçîðà — ïðåäñòàâèòü èìåþùèåñÿ äàííûå ìèðîâîé ëèòåðàòóðû î ïðîòèâîîïóõîëåâûõ ñâîéñòâàõ ãåïàðèíîâ. ANTICANCER ACTIVITY OF HEPARINS: EFFECT ON TUMOR GROWTH, ANGIOGENESIS AND METASTATIC DISEASE V.I. Prokhorova, L.M. Shishlo, N.N. Kolyadko, L.A. Derzhavets, I.A. Kosenko, O.P. Matylevich Keywords: heparins, thrombosis, cancer, metastasis, angiogenesis Heparin and its derivatives, low-molecular heparins, are effective in prevention and treatment of tromboembolic complications in various fields of medicine. Application of heparins in oncologic practice appears to be effective not only in the control of a hypercoagulation state and thrombosis in cancer patients, but also in the processes regulating tumor growth and metastatic disease. The principal objective of this review is to present available data of the world literature on antitumor properties of heparins. ÂÅÄÅÍÈÅ Ñâÿçü ìåæäó çëîêà÷åñòâåííûì ïðîöåññîì è ðàçâèòèåì òðîìáîýìáîëè÷åñêèõ îñëîæíåíèé (ÒÝÎ) èçâåñòíà óæå áîëåå ñòà ëåò è ïðåäñòàâëÿåò çíà÷èòåëüíóþ ïðîáëåìó îíêîëîãèè [1, 2]. Ñ öåëüþ ïðîôèëàêòèêè ÒÝÎ ñ ñåðåäèíû ïðîøëîãî âåêà â ìåäèöèíå óñïåøíî ïðèìåíÿëñÿ íåôðàêöèîíèðîâàííûé ãåïàðèí (ÍÔÃ), íà ñìåíó êîòîðîìó ïîçæå ïðèøëè íèçêîìîëåêóëÿðíûå ãåïàðèíû (ÍÌÃ) [3], â íàñòîÿùåå âðåìÿ ïðèìåíÿþùèåñÿ â ñîîòâåòñòâèè ñ ñîâðåìåííûìè ìåæäóíàðîäíûìè ðåêîìåíäàöèÿìè [4, 5].  ïîñëåäíåå âðåìÿ ïîÿâëÿþòñÿ äàííûå, óêàçûâàþùèå íà òîò ôàêò, ÷òî ÍÔà è åãî ïðîèçâîäíûå ÍÌà â äîïîëíåíèå ê èõ òðàäèöèîííîìó ïðîòèâîñâåðòûâàþùåìó äåéñòâèþ îáëàäàþò è ïðîòèâîîïóõîëåâûìè ñâîéñòâàìè [6]. Îïóõîëü-àññîöèèðîâàííàÿ ãèïåðêîàãóëÿöèÿ Ôàêò íàëè÷èÿ àêòèâàöèè êîàãóëÿöèîííîãî êàñêàäà ó îíêîëîãè÷åñêèõ áîëüíûõ ñ÷èòàåòñÿ îáùåèçâåñòíûì [7, 8]. Âûñîêàÿ ÷àñòîòà ÒÝÎ ó áîëüíûõ ðàêîì ñâÿçûâàåòñÿ êàê ñî ñïåöèàëüíûì ëå÷åíèåì, òàê è ñ äåéñòâèåì ñàìîé îïóõîëè â êà÷åñòâå èíèöèàòîðà ãèïåðêîàãóëÿöèîííîãî ñîñòîÿíèÿ [9, 10]. Ïàòîãåíåç äàííûõ íàðóøåíèé ñëîæåí è èìååò ìíîãîêîìïîíåíòíûé õàðàêòåð, 78 ïîñêîëüêó íàðÿäó ñ îáùèìè ôàêòîðàìè äåéñòâóþò ñïåöèôè÷åñêèå ìåõàíèçìû [11]. Êëåòêè îïóõîëè ìîãóò àêòèâèðîâàòü ñâåðòûâàíèå êðîâè íåñêîëüêèìè ñïîñîáàìè, ãëàâíûì îáðàçîì, âîâëåêàÿ â ïðîöåññ ïðîêîàãóëÿíòíûå ôàêòîðû, àêòèâèðóÿ ìíîæåñòâî îïóõîëüàññîöèèðîâàííûõ öèòîêèíîâ, à òàêæå ÷åðåç ïðÿìîå âëèÿíèå íà êëåòî÷íûå è ñîñóäèñòûå êîìïîíåíòû [12]. Ïðÿìàÿ ïðîêîàãóëÿíòíàÿ àêòèâíîñòü îïóõîëè ðåàëèçóåòñÿ â âèäå ïðîäóêöèè òêàíåâîãî ôàêòîðà (TF — Tissue Factor) — ïåðâè÷íîãî èíèöèàòîðà âíåøíåãî ïóòè àêòèâàöèè êîàãóëÿöèè, à òàêæå ýêñïðåññèè ðàêîâîãî ïðîêîàãóëÿíòà (CP — Cancer Procoagulant) — öèñòåèíîâîé ïðîòåàçû, àêòèâèðóþùåé Õ-ôàêòîð ñâåðòûâàíèÿ êðîâè. Ïîêàçàíî, ÷òî îïóõîëåâûå êëåòêè ÿâëÿþòñÿ èñòî÷íèêîì è ïðîìîòîðîì ýòèõ ïðîêîàãóëÿíòíûõ âåùåñòâ, ýêñïðåññèðóþùèõñÿ ó îíêîëîãè÷åñêèõ áîëüíûõ ïîñòîÿííî, â îòëè÷èå îò çäîðîâîãî îðãàíèçìà [13, 14]. Íåïðÿìàÿ ïðîêîàãóëÿíòíàÿ àêòèâíîñòü îïóõîëè îïîñðåäóåòñÿ îñíîâíûìè ìåäèàòîðàìè âîñïàëåíèÿ, â ÷àñòíîñòè, ôàêòîðîì íåêðîçà îïóõîëè-a (TNF- a — Tumor Necrosis Factor-a), èíòåðëåéêèíîì-1 (IL-1) è -6 (IL-6), êîòîðûå ïðîäóöèðóþòñÿ ìîíîöèòàìè/ìàêðîôàãàìè õîçÿèíà â îòâåò íà îïóõîëü è ñîçäàþò «èäåàëüíóþ» òðîìáîãåííóþ ïîâåð- Îíêîëîãè÷åñêèé æóðíàë, Ò.5, ¹2 (18), 2011 õíîñòü ýíäîòåëèÿ. Öèòîêèíû îïóõîëåâûõ êëåòîê è îïóõîëüàññîöèèðîâàííûõ ìàêðîôàãîâ âîâëå÷åíû òàêæå â ýêñïðåññèþ TF, ìîëåêóë àäãåçèè è ôàêòîðîâ ðîñòà ñîñóäîâ [15, 1]. Âàæíàÿ ðîëü â íàðóøåíèÿõ êîàãóëÿöèîííîãî ïîòåíöèàëà êðîâè ó îíêîëîãè÷åñêèõ áîëüíûõ îòâåäåíà àêòèâàöèè ïðîöåññîâ ñâîáîäíîðàäèêàëüíîãî îêèñëåíèÿ, äåñòàáèëèçàöèè áèîëîãè÷åñêèõ ìåìáðàí êëåòîê êðîâè è ñîñóäèñòîé ñòåíêè. Ïðè ýòîì îáíàæàåòñÿ ñóáýíäîòåëèé, ýêñïðåññèðóþòñÿ àäãåçèâíûå ìîëåêóëû, àêòèâèðóåòñÿ âíåøíèé è âíóòðåííèé ìåõàíèçìû ôîðìèðîâàíèÿ ïðîòðîìáèíàçû. Âûáðîñ â êðîâåíîñíîå ðóñëî ëèïîñàõàðèäîâ èç ðàçðóøàþùèõñÿ ìåìáðàí îïóõîëåâûõ êëåòîê ìîæåò àêòèâèðîâàòü òðîìáîöèòû, êîòîðûå, â ñâîþ î÷åðåäü, ãåíåðèðóþò òðîìáîöèòàðíûé ôàêòîð V è ôîñôîëèïèäû, íåîáõîäèìûå äëÿ àêòèâàöèè X ôàêòîðà ñâåðòûâàíèÿ [17]. Òàêèì îáðàçîì, ïðîòðîìáîòè÷åñêèå ñâîéñòâà îïóõîëè îïðåäåëÿþòñÿ, âî-ïåðâûõ, ñèíòåçîì èç îïóõîëåâûõ êëåòîê ðÿäà ïåïòèäíûõ è ïîëèïåïòèäíûõ ìåäèàòîðîâ è, âî-âòîðûõ, ïðÿìûìè ìåæêëåòî÷íûìè âçàèìîäåéñòâèÿìè îïóõîëåâûõ êëåòîê ñ ýíäîòåëèàëüíûìè êëåòêàìè, ìîíîöèòàìè/ìàêðîôàãàìè è òðîìáîöèòàìè, êîòîðûå ðåàëèçóþòñÿ â ïîäàâëåíèè èõ àíòèêîàãóëÿíòíûõ è ñòèìóëÿöèè ïðîêîàãóëÿíòíòûõ ñâîéñòâ. Ñ äðóãîé ñòîðîíû ñîâðåìåííûå íàó÷íûå äàííûå ïîêàçûâàþò, ÷òî ãèïåðêîàãóëÿöèîííîå ñîñòîÿíèå íà ôîíå îïóõîëåâîãî ðîñòà ÿâëÿåòñÿ îäíîé èç ïðè÷èí, ñïîñîáñòâóþùèõ ïðîãðåññèðîâàíèþ íîâîîáðàçîâàíèÿ [18, 19]. À èìåííî, êîìïîíåíòû ñèñòåìû ñâåðòûâàíèÿ êðîâè ñîâìåñòíî ñ îïóõîëåâûìè êëåòêàìè è èõ ìåòàáîëèòàìè ó÷àñòâóþò â ïðîöåññàõ íåîàíãèîãåíåçà, ðîñòà è ìåòàñòàçèðîâàíèÿ îïóõîëè.  ÷àñòíîñòè, ïîâûøåííàÿ ýêñïðåññèÿ îïóõîëüþ TF, CP, ïîâûøåíèå àãðåãàöèîííîé àêòèâíîñòè òðîìáîöèòîâ è êîíöåíòðàöèè àäãåçèîííûõ ôàêòîðîâ ñïîñîáñòâóþò ïðèêðåïëåíèþ îïóõîëåâûõ êëåòîê íà ñîñóäèñòûé ýíäîòåëèé, ôîðìèðîâàíèþ ôèáðèíîâîãî ìàòðèêñà è îáðàçîâàíèþ îïóõîëåâûõ ìèêðîòðîìáîâ. Ôèáðèíîâûé ìàòðèêñ äåéñòâóåò êàê îñíîâà äëÿ àäãåçèè îïóõîëåâûõ êëåòîê, è êàê äåïî àíãèîãåííûõ ðîñòîâûõ ôàêòîðîâ [20–22].  ðåçóëüòàòå ïîâûøàåòñÿ âûæèâàåìîñòü îïóõîëåâûõ êëåòîê áëàãîäàðÿ çàùèòå îò ìåõàíè÷åñêîãî è èììóííîãî ïîâðåæäåíèÿ, ïðîèñõîäèò ëîêàëüíûé ðîñò îïóõîëè è ìåòàñòàçèðîâàíèå [23]. Òàêèì îáðàçîì, â ïðîöåññå ðàçâèòèÿ íåîïëàçèè è ìåòàñòàçèðîâàíèÿ îïóõîëåâûõ êëåòîê âîçíèêàåò îïðåäåëåííàÿ äèíàìèêà ñîîòíîøåíèé ïðîêîàãóëÿíòíûõ-àíòèêîàãóëÿíòíûõ ìåõàíèçìîâ è ñèñòåìû ôèáðèíîëèçà, îïðåäåëÿþùàÿ ïðîãíîñòè÷åñêè íåáëàãîïðèÿòíûé ôîí äëÿ èñõîäà çàáîëåâàíèÿ, êàê â ïëàíå òðîìáîýìáîëè÷åñêèõ îñëîæíåíèé, òàê è ïðîãðåññèðîâàíèÿ îïóõîëåâîãî ïðîöåññà. Ïðîòèâîîïóõîëåâûå ñâîéñòâà ãåïàðèíîâ Ãåïàðèíû — ýòî ðàçëè÷àþùèåñÿ ïî ìîëåêóëÿðíîé ìàññå ãëèêîçàìèíîãëèêàíû, îáðàçóþùèåñÿ â îðãàíèçìå ÷åëîâåêà è æèâîòíûõ è ñîäåðæàùèåñÿ â îñíîâíîì â òó÷íûõ êëåòêàõ. Âïåðâûå îíè áûëè îáíàðóæåíû â 1916 ã. J. McLean, à êëèíè÷åñêîå ïðèìåíåíèå ãåïàðèíà ñòàëî âîçìîæíûì ïîñëå 1930ã., êîãäà áûëè ïîëó÷åíû åãî íàòðèåâûå ñîëè [24]. Ìåõàíèçì àíòèêîàãóëÿíòíîãî äåéñòâèÿ ãåïàðèíîâ çàâèñèò îò ìîëåêóëÿðíîé ìàññû.  ÍÔà ïðåîáëàäàþò âûñîêîìîëåêóëÿðíûå ôðàêöèè ãëèêîçàìèíîãëèêàíà. Äåéñòâèå ýòèõ ïðåïàðàòîâ ñâÿçàíî ñ òåì, ÷òî îíè îáðàçóþò êîìïëåêñ ñ àíòèòðîìáèíîì III, âåäóùèé ê âîçðàñòàíèþ ñïîñîáíîñòè ïîñëåäíåãî èíãèáèðîâàòü òðîìáèí, ôàêòîð Õàãåìàíà, ôàêòîðû IX, X, XI è äð. ÍÌà — íèçêîìîëåêóëÿðíûå ôðàêöèè ãåïàðèíà, òàêèå êàê íàäðîïàðèí, äàëüòåïàðèí, ýíîêñèïàðèí, ðåâèïàðèí, îáëàäàþò èíûì ìåõàíèçìîì àíòèêîàãóëÿíòíîãî äåéñòâèÿ. Ïîñëåäíèé ñâÿçàí â îñíîâíîì ñ èíãèáèðîâàíèåì àêòèâíîñòè ôàêòîðà Õà.  ìåíüøåé ñòåïåíè ýòè ïðåïàðàòû âëèÿþò íà àêòèâíîñòü ôàêòîðà IIà (òðîìáèíà) è äðóãèõ ôàêòîðîâ ñâåðòûâàíèÿ êðîâè [25]. Íà äàííûé ìîìåíò ñóùåñòâóþò äîñòàòî÷íî âåñêèå äîêàçàòåëüñòâà ïðîòèâîîïóõîëåâûõ ñâîéñòâ ãåïàðèíîâ. Îñíîâíûå âîçìîæíûå ìåõàíèçìû ïðîòèâîîïóõîëåâîé àêòèâíîñòè ãåïàðèíîâ ñâÿçûâàþòñÿ ñ âëèÿíèåì íà êëåòî÷íóþ ïðîëèôåðàöèþ îïóõîëåâûõ êëåòîê, àíãèîãåíåç è ìåòàñòàçèðîâàíèå [26, 27]. Äîêëèíè÷åñêèå èññëåäîâàíèÿ íå óñòàíîâèëè ïðîòèâîîïóõîëåâîãî ýôôåêòà ÍÔà íà ðîñò îïóõîëåâûõ êëåòîê in vitro è ïåðâè÷íîé îïóõîëè â ýêñïåðèìåíòàëüíûõ ìîäåëÿõ [28, 29]. Îäíàêî, â îòëè÷èå îò íèõ, ÍÌà èíãèáèðîâàëè ôîñôîðèëÿöèþ êèíàçû-ERK (Extracellular signal-Regulated Kinase) â êëåòêàõ îïóõîëè è, ñîîòâåòñòâåííî, èõ ïðîëèôåðàöèþ [30], òàê êàê òîðìîæåíèå ïóòè êèíàçû-ERK ÿâëÿåòñÿ öåíòðàëüíûì äëÿ íåêîòîðûõ ïðîòèâîîïóõîëåâûõ ïðåïàðàòîâ, íàïðèìåð, èíãèáèòîðîâ ýïèäåðìàëüíîãî ôàêòîðà ðîñòà [31]. Íî, íåñìîòðÿ íà òî, ÷òî ÍÌà ìîãóò ðåãóëèðîâàòü öåíòðàëüíûå ïðîâîäÿùèå ïóòè ïðîëèôåðàöèè êëåòîê, áîëüøèíñòâî èññëåäîâàíèé íå ïîêàçàëî àíòèïðîëèôåðàòèâíîãî ýôôåêòà íà íåêîòîðûõ ëèíèÿõ îïóõîëåâûõ êëåòîê in vitro. Òàê, óñòàíîâëåíî, ÷òî íè ÍÔÃ, íè ÍÌà íå âëèÿëè íà ðîñò êëåòîê ìåëàíîìû ÷åëîâåêà [32], íå óìåíüøàëè ïðîëèôåðàöèþ êëåòîê ðàêà ëåãêîãî [33] è ìîëî÷íîé æåëåçû [34]. Òàêèì îáðàçîì, ïîëó÷åííûå äàííûå îêàçàëèñü ïðîòèâîðå÷èâûìè.  èññëåäîâàíèè ñ ïîäêîæíî ïåðåâèòûìè êëåòêàìè ðàêà ëåãêîãî ðîñò îïóõîëè áûë çíà÷èòåëüíî ñíèæåí ïðè ïðèìåíåíèè ÍÌà (äàëüòåïàðèí), è â ìåíüøåé ñòåïåíè — ÍÔà [33]. Îäíàêî íè ÍÔÃ, íè äàëüòåïàðèí íå âëèÿëè â åñòåñòâåííûõ óñëîâèÿõ íà ðîñò îïóõîëè ìåëàíîìû [32]. Pross è äð. ïðîâåë ðÿä èññëåäîâàíèé ñ ÍÌà (ðåâèïàðèí) — êîìáèíàöèÿ 79 Îáçîðû èíòðàïåðèòîíåàëüíîãî è ïîäêîæíîãî åãî ââåäåíèÿ íàèáîëåå ìîùíî óìåíüøàëè ðîñò îïóõîëè [35]. Ïðåäâàðèòåëüíûå äàííûå óêàçûâàþò íà òî, ÷òî òèíçàïàðèí òàêæå ïðîÿâëÿåò íåêîòîðûé ïîäàâëÿþùèé ýôôåêò íà ðîñò ïåðâè÷íûõ îïóõîëåé [36]. Èçâåñòíî, ÷òî àíãèîãåíåç ÿâëÿåòñÿ öåíòðàëüíûì ìåõàíèçìîì ðåãóëèðîâàíèÿ, êàê ìåñòíîãî ðîñòà îïóõîëè, òàê è ìåòàñòàçèðîâàíèÿ. Âûçâàííîå ãåïàðèíàìè òîðìîæåíèå àíãèîãåíåçà è ìåõàíèçìû, íà îñíîâå êîòîðûõ ïðîèñõîäèò åãî ðåãóëèðîâàíèå, ÿâëÿëîñü öåëüþ íåêîòîðûõ èññëåäîâàíèé, ïîêàçàâøèõ, ÷òî òîðìîæåíèå ðîñòà îïóõîëè ïîä äåéñòâèåì ãåïàðèíîâ áûëî ñâÿçàíî íåïîñðåäñòâåííî ñî ñíèæåíèåì ïëîòíîñòè ìèêðîñîñóäîâ [37]. Ãåïàðèíû âçàèìîäåéñòâóþò ñî ìíîæåñòâîì ñîñóäèñòûõ ôàêòîðîâ ðîñòà, ñèíòåçèðóåìûõ îïóõîëåâûìè è ýíäîòåëèàëüíûìè êëåòêàìè, âêëþ÷àÿ ñîñóäèñòî- ýíäîòåëèàëüíûé ôàêòîð ðîñòà (VEGF — Vascular Endothelial Growth Factor) è ôàêòîð ðîñòà ôèáðîáëàñòîâ (FGF - Fibroblast Growth Factors ) [38, 39]. ÍÔà è ÍÌà äåìîíñòðèðîâàëè ñíèæåíèå ïðîëèôåðàòèâíîé àêòèâíîñòè ýíäîòåëèàëüíûõ êëåòîê îïóõîëè, âûçâàííîé ôàêòîðàìè ðîñòà FGF è VEGF [40, 41]. Ïðîòèâîîïóõîëåâûå ñâîéñòâà ãåïàðèíà ìîãóò áûòü ñâÿçàíû ñ ýêñïðåññèåé èíãèáèòîðà êîàãóëÿöèè TFPI (Tissue Factor Pathway Inhibitor) ñîñóäèñòûì ýíäîòåëèåì, êîòîðûé â ñâîþ î÷åðåäü ïîäàâëÿåò ïåðåäà÷ó ñèãíàëîâ TF è ðîñò îïóõîëè [42]. Òèíçàïàðèí è ðåêîìáèíàíòíûé TFPI áëîêèðîâàëè íåîàíãèîãåíåç, âûçâàííûé àíãèîãåííûìè ôàêòîðàìè, â òîì ÷èñëå VEGF [43, 44]. Èññëåäîâàíà ñïîñîáíîñòü ÍÔà è ÍÌà èíãèáèðîâàòü ìåòàñòàçèðîâàíèå íà ýêñïåðèìåíòàëüíûõ ìîäåëÿõ.  ìîäåëè ìåòàñòàçèðîâàíèÿ ìåëàíîìû ÍÌà ïîêàçàëè ìîùíîå òîðìîæåíèå ìåòàñòàòè÷åñêîãî ïîðàæåíèÿ ëåãêîãî è ïå÷åíè [45]. Ïðèìåíåíèå òèíçàïàðèíà äî âíóòðèâåííîãî ââåäåíèÿ êëåòîê ìåëàíîìû ñíèæàëî âåðîÿòíîñòü îáðàçîâàíèÿ îïóõîëè â ëåãêîì íà 89 % [46]. Stevenson J.L. è äð. ïîêàçàëè, ÷òî òèíçàïàðèí è ÍÔà èìåëè ñîïîñòàâèìóþ ýôôåêòèâíîñòü îòíîñèòåëüíî ñíèæåíèÿ ìåòàñòàçèðîâàíèÿ â ëåãêîå ïðè âíóòðèâåííîì ââåäåíèè êëåòîê ðàêà òîëñòîé êèøêè è ìåëàíîìû [47]. Áîëüøèíñòâîì èññëåäîâàòåëåé ïðè ýêñïåðèìåíòàëüíîì èçó÷åíèè àíòèìåòàñòàòè÷åñêîãî ýôôåêòà ãåïàðèíîâ èñïîëüçîâàëîñü âíóòðèâåííîå ââåäåíèå îïóõîëåâûõ êëåòîê, îäíàêî íåêîòîðûå äîáèëèñü ïîëîæèòåëüíûõ ðåçóëüòàòîâ è ïðè ïåðèòîíåàëüíîì èõ ïðèìåíåíèè [48]. Áûëî òàêæå ïðåäïîëîæåíî, ÷òî àíòèìåòàñòàòè÷åñêèå ñâîéñòâà ÍÌà îñíîâàíû íà íàðóøåíèè ïðîöåññà àäãåçèè êëåòîê ê ýíäîòåëèþ, à èìåííî íà èíãèáèðîâàíèè ñåëåêòèíîâ [49]. Íàéäåíà êîððåëÿöèîííàÿ çàâèñèìîñòü ìåæäó èíãèáèðîâàíèåì ñåëåêòèíîâ è òîðìîæåíèåì ìåòàñòàòè÷åñêîãî ðàñïðîñòðàíåíèÿ [50]. Âîçìîæíûé ìåõàíèçì ìîæåò âîâëåêàòü P- è L-ñåëåêòèíû, êîòî80 ðûå îïîñðåäóþò çàêðåïëåíèå îïóõîëåâûõ êëåòîê in vitro [51]. Ãåïàðèíû, êàê áûëî ïîêàçàíî âûøå, èíãèáèðóþò íåêîòîðûå çâåíüÿ â êàñêàäå êîàãóëÿöèè, íî, â êîíå÷íîì ñ÷åòå, ïðîòèâîäåéñòâóþò àêòèâíîñòè òðîìáèíà, â äàëüíåéøåì îáðàçîâàíèþ ôèáðèíà, êîòîðûé ñïîñîáñòâóåò ïðîãðåññèðîâàíèþ îïóõîëåâîãî ïðîöåññà. Ïîêàçàíî, ÷òî ãåïàðèíû, èíãèáèðóÿ îáðàçîâàíèå ôèáðèíà, ñíèæàåò äåïîíèðîâàíèå òðîìáîöèòîâ âîêðóã îïóõîëåâûõ êëåòîê, à, ñëåäîâàòåëüíî, è îáðàçîâàíèå âîêðóã íèõ çàùèòíîé òðîìáîöèòàðíî-ôèáðèíîãåííîé îáîëî÷êè, ÷òî äåëàåò çëîêà÷åñòâåííûå êëåòêè áîëåå óÿçâèìûìè ïåðåä èììóííîé ñèñòåìîé [52]. Îòìå÷åíî èíãèáèðóþùåå âëèÿíèå ãåïàðèíîâ íà õåìîòàêñèñ ïîñðåäñòâîì áëîêèðîâàíèÿ îïðåäåëåííûõ ëèãàíäîâ ðåöåïòîðîâ õåìîêèíîâ, âàæíûõ äëÿ ìåòàñòàòè÷åñêîãî ðàñïðîñòðàíåíèÿ îïóõîëè [34]. Èíâàçèÿ è ìåòàñòàçèðîâàíèå, êàê áûëî ïîêàçàíî [53], çàâèñÿò îò ïðîòåîëèòè÷åñêèõ ôåðìåíòîâ, íàïðèìåð, òàêèõ êàê, ãåïàðàíàçà, êîòîðàÿ ðàñùåïëÿåò ãåïàðàíñóëüôàò è ó÷àñòâóåò â äåãðàäàöèè è ðåêîíñòðóêöèè âíåêëåòî÷íîãî ìàòðèêñà. Ïîâûøåííàÿ âûðàáîòêà ãåïàðàíàçû, ñïîñîáñòâóþùàÿ îïóõîëåâîé ïðîãðåññèè, îáíàðóæåíà â çëîêà÷åñòâåííûõ îïóõîëÿõ. Ãåïàðàíàçà âîâëå÷åíà â ñèíòåç ôàêòîðîâ ðîñòà, ñâÿçàííûõ ñ ãåïàðàíñóëüôàòîì è ýêñïðåññèåé TF íà ýíäîòåëèàëüíûõ è îïóõîëåâûõ êëåòêàõ [54]. Ãåïàðèíû ìîùíî èíãèáèðóþò ãåïàðàíàçó, ÷òî ñîäåéñòâóåò çíà÷èòåëüíîìó ïðîòèâîîïóõîëåâîìó ýôôåêòó [55]. Íàïðîòèâ, óñèëåííûé ñèíòåç ãåïàðàíàçû ìîæåò ðàñùåïëÿòü ãåïàðèíû è ÷àñòè÷íî íåéòðàëèçîâûâàòü èõ àíòèêîàãóëÿíòíûå ñâîéñòâà [56]. Ïåðñïåêòèâû ïðèìåíåíèå ãåïàðèíîâ â òåðàïèè ðàêà  íàñòîÿùåå âðåìÿ ÍÌà èñïîëüçóþòñÿ â îíêîëîãè÷åñêîé ïðàêòèêå èñêëþ÷èòåëüíî â êà÷åñòâå ïðîôèëàêòèêè ÒÝÎ ïðè îïåðàòèâíîì ëå÷åíèè îíêîëîãè÷åñêèõ áîëüíûõ. Îäíàêî èçâåñòíî, ÷òî âñå áîëüíûå çëîêà÷åñòâåííûìè íîâîîáðàçîâàíèÿìè âõîäÿò â ãðóïïó âûñîêîãî ðèñêà ðàçâèòèÿ ÒÝÎ, îñîáåííî ïðè ïðîâåäåíèè ëó÷åâîãî è õèìèîòåðàïåâòè÷åñêîãî ëå÷åíèÿ, ñîïðîâîæäàþùåãîñÿ öèòîëèçîì. Ïðåäâàðèòåëüíûå ýêñïåðèìåíòàëüíûå äàííûå ïî ïðèìåíåíèþ ãåïàðèíîâ â êà÷åñòâå ïðîòèâîîïóõîëåâûõ ñðåäñòâ ÿâëÿþòñÿ ïåðñïåêòèâíûìè è ìíîãîîáåùàþùèìè, íî íóæíû äàëüíåéøèå èññëåäîâàíèÿ â êëèíè÷åñêîé îíêîëîãèè äëÿ óáåäèòåëüíîñòè èõ ïðîòèâîîïóõîëåâûõ ñâîéñòâ. Êëèíè÷åñêèå èñïûòàíèÿ îáÿçàíû ïðîäåìîíñòðèðîâàòü òåðàïåâòè÷åñêèé ïðîòèâîîïóõîëåâûé ýôôåêò ãåïàðèíîâ ïðè ìîíîòåðàïèè, ëèáî â êîìáèíàöèè ñ äðóãèìè ìåòîäàìè ïðîòèâîîïóõîëåâîãî ëå÷åíèÿ îíêîëîãè÷åñêèõ áîëüíûõ. Îæèäàíèå ïîëîæèòåëüíûõ ðåçóëüòàòîâ ÿâëÿåòñÿ âåñüìà îáîñíîâàííûì, òàê êàê ïî ïðåäâàðèòåëüíûì äàííûì âåäóùèõñÿ ìåòà-èññëåäîâàíèé ïðè Îíêîëîãè÷åñêèé æóðíàë, Ò.5, ¹2 (18), 2011 ïðèìåíåíèè ÍÌà è ÍÔà óñòàíîâëåíî óâåëè÷åíèå âûæèâàåìîñòè áîëüíûõ çëîêà÷åñòâåííûìè íîâîîáðàçîâàíèÿìè, èíãèáèðîâàíèå ðîñòà îïóõîëè è ìåòàñòàçèðîâàíèÿ [57–59].  íåêîòîðûõ ðàáîòàõ â êà÷åñòâå ðåêîìåíäàöèé ïî ïðèìåíåíèþ ÍÌà ó îíêîëîãè÷åñêèõ ïàöèåíòîâ óêàçûâàåòñÿ âûñîêèé ðèñê ìåòàñòàçèðîâàíèÿ è ÒÝÎ. Ýôôåêòèâíîñòü, áåçîïàñíîñòü è ïðîñòîòà ïðèìåíåíèÿ ÍÌà â îòëè÷èå îò ÍÔà ïîäõîäèò äëÿ äëèòåëüíîé ïðîòèâîîïóõîëåâîé òåðàïèè.  íàñòîÿùåå âðåìÿ ïðîâîäèòñÿ ðÿä èññëåäîâàíèé ñ ïðèìåíåíèåì ÍÌà â îíêîëîãèè. Ýòî òàêèå èññëåäîâàíèÿ êàê TILT (òåñòèðîâàíèå òèíçàïàðèíà ó ïàöèåíòîâ ñ ðàêîì ëåãêèõ ïîñëå õèðóðãè÷åñêîãî ëå÷åíèÿ), FRAGMATIC è PROSPECT-CONKO 004 (ïðèìåíåíèå äàëüòåïàðèíà è ýíîêñàïàðèíà â êîìáèíàöèè ñ õèìèîòåðàïèåé ïðè ðàêå ëåãêèõ è ïîäæåëóäî÷íîé æåëåçû) [60–61]. Èñõîäÿ èç òîãî, ÷òî íåêîòîðûå ìåòà-àíàëèçû óêàçûâàþò íà ïîâûøåíèå âûæèâàåìîñòè îíêîëîãè÷åñêèõ áîëüíûõ ïðè ïðèìåíåíèè ÍÌÃ, ìîæíî ñäåëàòü âûâîä îá àêòóàëüíîñòè áîëåå ïîäðîáíûõ èññëåäîâàíèé â ýòîé îáëàñòè, òàê êàê ïîêà îòñóòñòâóåò îäíîçíà÷íûé îòâåò íà íåêîòîðûå âîïðîñû, â ÷àñòíîñòè, îáëàäàþò ëè ÍÌà íåïîñðåäñòâåííûì ïðîòèâîîïóõîëåâûì ýôôåêòîì â êëèíè÷åñêîé ïðàêòèêå, â îòëè÷èå îò ýêñïåðèìåíòà, èìååòñÿ ëè ïðåèìóùåñòâî êàêîãî-ëèáî ïðåïàðàòà èç ãðóïïû ÍÌÃ, îïòèìàëüíàÿ äëèòåëüíîñòü ïðèåìà è äîçû äëÿ íàèëó÷øåãî ïðîòèâîîïóõîëåâîãî äåéñòâèÿ. 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