Неодъювантная химолучевая терапия у больных

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 ÍÌÃ
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]. Â 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. Â ÍÔÃ 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.
ÍÌÃ — íèçêîìîëåêóëÿðíûå ôðàêöèè ãåïàðèíà, òàêèå êàê íàäðîïàðèí, äàëüòåïàðèí, ýíîêñèïàðèí,
ðåâèïàðèí, îáëàäàþò èíûì ìåõàíèçìîì àíòèêîàãóëÿíòíîãî äåéñòâèÿ. Ïîñëåäíèé ñâÿçàí â îñíîâíîì
ñ èíãèáèðîâàíèåì àêòèâíîñòè ôàêòîðà Õà. Â 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, ÍÌÃ 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 ÍÌÃ 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 ÍÌÃ 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 ÍÌÃ (äàëüòåïàðèí), è â
ìåíüøåé ñòåïåíè — ÍÔÃ [33]. Îäíàêî íè ÍÔÃ, íè
äàëüòåïàðèí íå âëèÿëè â åñòåñòâåííûõ óñëîâèÿõ íà
ðîñò îïóõîëè ìåëàíîìû [32]. Pross è äð. ïðîâåë ðÿä
èññëåäîâàíèé ñ ÍÌÃ (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]. ÍÔÃ è ÍÌÃ 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 ÍÔÃ è ÍÌÃ èíãèáèðîâàòü ìåòàñòàçèðîâàíèå íà ýêñïåðèìåíòàëüíûõ
ìîäåëÿõ. Â 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 ÍÔÃ 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
ÍÌÃ 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.
Òàêèì îáðàçîì, îáçîð ìèðîâîé ëèòåðàòóðû
ïîêàçàë, ÷òî ãåïàðèí-èíäóöèðîâàííîå ñíèæåíèå
ðîñòà îïóõîëè è åå ìåòàñòàçèðîâàíèÿ ïðåäñòàâëÿåò
îáøèðíóþ îáëàñòü äëÿ äàëüíåéøåãî èçó÷åíèÿ.
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