Tumor-inhibitory effects of combinations of the vinca alkaloids with actinomycin D

Abstract

Combinations of vinblastine and actinomycin D exhibited synergistic tumor-inhibitory activity against the ascitic form of Ehrlich carcinoma and sarcoma-180 when given daily to mice by intraperitoneal injection for 6 to 10 days. Against L1210 ascites tumor the combination produced approximately additive increases in survival time. Single large doses of vinblastine were much less effective than chronic treatment. Antitumor effects of combinations of single doses of vinblastine and actinomycin D were not significantly greater than those produced by actinomycin D alone, unless the drugs were administered in a sequence, 24 hr apart, initiated with vinblastine. Vincristine was not a very effective inhibitor of the three tumors examined, and in combination with actinomycin D, showed additive or subadditive effects against L1210 and sarcoma-180 ascites tumors. Biochemical studies using the Ehrlich ascites carcinoma indicated that therapy with vinblastine produced an increase in cell size coupled with elevation of the cellular contents of DNA, RNA, and protein. Super-imposition of actinomycin D did not affect the increases in protein or cell size, but largely prevented the increase in DNA per cell and reduced the level of RNA. Incorporation of 3H-uridine into RNA was depressed by treatment with actinomycin D; further reduction in the uptake of isotope by superimposing single doses of vinblastine was achieved only if treatment with the vinca alkaloid preceded actinomycin therapy by 24 hr.