Phase III comparison of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) vs. doxorubicin and cisplatin (AC) in women with advanced primary or recurrent metastatic carcinoma of the uterine endometrium
Harry J. LongRobert A. NelimarkKarl C. PodratzVera J. SumanGary L. KeeneyDaniel A. NikcevichJohn W. KuglerKendrith M. RowlandCarl G. KardinalEdward J. Wos
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Gynecologic oncology
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In two hamster cell lines that differed 100-fold in their vinblastine sensitivity, dissolution of the mitotic spindle by vinblastine in living cells correlated with cytotoxicity from vinblastine expressed as suppression of colony formation. The effect on the spindle apparatus occurred in 30 sec or less and thus provides a rapid assay for determining the cytotoxic effects of the Vinca alkaloids, as well as the potential for quantitative assay of solutions of Vinca derivatives.
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Microtubule-associated protein
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The strong depressive effect of vinblastine on the rat sarcoma 45 growth and intensification of this effect by the combination of vinblastine treatment with the activation of the blood anticoagulating system (BAS) were found. Vinblastine had no negative effect on the BAS activation process and induced no persistent changes in the qualitative content of leucocytes in the peripheral blood.
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A series of disubstituted C20'-urea derivatives of vinblastine were prepared from 20'-aminovinblastine that was made accessible through a unique Fe(III)/NaBH4- mediated alkene functionalization reaction of anhydrovinblastine. Three analogs were examined across a panel of 15 human tumor cell lines, displaying remarkably potent cell growth inhibition activity (avg. IC50 = 200-300 pM), being 10-200-fold more potent than vinblastine (avg. IC50 = 6.1 nM). Significantly, the analogs also display further improved activity against the vinblastine-resistant HCT116/VM46 cell line that bears the clinically relevant overexpression of Pgp, exhibiting IC50 values on par with that of vinblastine against the sensitive HCT116 cell line, 100-200-fold greater than the activity of vinblastine against the resistant HCT116/VM46 cell line, and display a reduced 10-20-fold activity differential between the matched sensitive and resistant cell lines (vs 100-fold for vinblastine).
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The possibility of reducing toxicity of Vinblastine by fixing it in polybutyl-2-cyanoacrylate nanoparticles was studied. A significant reduction of mortality of mice was recorded after a single intraperitoneal (i. p.) injection of nanoparticle-associated Vinblastine. A wide range of doses of Vinblastine (1.04-6.25 mg/kg) were used. There was a considerable decrease of leucopenia caused by Vinblastine-loaded polybutyl-2-cyanoacrylate nanoparticles as compared to that induced by free Vinblastine.
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Vinblastine arrests cells in the G2/M phase of the cell cycle and subsequently induces cell death by apoptosis. We found that treatment of cells with vinblastine induced phosphorylation of Bcl‐2, resulting in the dissociation of Bcl‐2 and Bax. Moreover, vinblastine‐induced apoptosis was suppressed by an inhibitor of caspase‐3, Ac‐DEVD‐CHO; and a 17‐kDa active fragment of caspase‐3 was detected following vinblastine treatment, suggesting that caspase‐3 is involved in vinblastine‐induced apoptosis. However, Ac‐DEVD‐CHO affected neither vinblastine‐induced Bcl‐2 phosphorylation nor vinblastine‐induced G2/M arrest. Vinblastine caused G2/M arrest prior to apoptosis, whereas vinblastine‐induced apoptosis was not dependent on the duration of the G2/M phase. Thus, vinblastine‐induced apoptosis might be mediated by the phosphorylation of Bcl‐2, resulting in Bcl‐2 inactivation, and by subsequent activation of caspase‐3.
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An early, transient drop in peripheral blood platelets to a mean nadir value of 49% (range 31–83%) of the pretreatment value was seen in 31 patients during chemotherapy with cis‐platinum, vinblastine and bleomycin (PVB). The mean number of platelets dropped by 22% during the first 24 h after the start of chemotherapy, nadir value was seen after 3 d, with recovery to 107% of pretreatment level on d 14–15. Platelet survival studies during PVB chemotherapy showed shortened platelet survival time and indicated increased destruction of platelets. Identical patterns of early, transient thrombocytopenia were seen in 6 patients treated with vinblastine only. The early fall in circulating platelets did not predict subsequent serious thrombocytopenia. There were no bleeding episodes in the 37 patients studied here, but the early thrombocytopenia seen after vinblastine therapy may possibly be of clinical importance in critically ill patients at risk for bleeding episodes. In rats, an early drop in circulating platelets occurred after a high dose of vinblastine, but not after bleomycin. Addition of bleomycin to vinblastine did not increase the vinblastine‐induced thrombocytopenia. It is concluded that the early drop in peripheral blood platelets during chemotherapy with PVB is due to vinblastine.
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