Action of lycurim and pyrazofurin on hepatoma 3924A cells in culture.
The purpose of this study was to test for a possible synergism in the antitumor action of the antimetabolite pyrazofurin (PF) and the alkylating agent lycurim (LY) [1,4-di(2'-mesyloxy-ethylamino)-1,4-dideoxy-m-erythritol dimethylsulfonate] on proliferating and resting rat hepatoma 3924A cells in tissue culture. Earlier studies showed that PF killed hepatoma cells only in the logarithmic phase of growth as determined by colony-forming ability. Now we report that LY killed hepatoma cells in both the exponential and plateau phases. Treatment of cultures in each phase for 1 or 2 hrs resulted in threshold exponential type dose-response curves, yielding Do values of 3 and 1 microM, respectively. LY is a cycle-specific drug, although fluctuations in cell age-dependent survival were also demonstrated. In synchronized cultures, cells were most sensitive to 0.1 microM LY in early G1 phase, but in higher concentration (5 microM), LY killed the cells during the entire cell cycle, especially in G1, early and mid S phases, and M phase. Lycurim and PF given together in their IC50 concentrations (0.016 and 0.085 microM, respectively) yielded synergistic cell kill in 7-day treatment of proliferating cultures. Two-hour treatment of exponentially growing cells with LY and PF at their IC50 concentrations (1 and 20 microM, respectively) also yielded synergistic killing action, but in plateau-phase cells only summation was observed. Synergistic activity of LY and PF in hepatoma 3924A cells was dependent on drug concentration and incubation time.
D000577:Amides; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D004357:Drug Synergism; D004896:Erythritol / Q000031:analogs & derivatives* / Q000494:pharmacology; D007700:Kinetics; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy*; D011720:Pyrazoles; D051381:Rats; D012263:Ribonucleosides / Q000494:pharmacology*; D012266:Ribose
D000577:Amides; D011720:Pyrazoles; D012263:Ribonucleosides; C002997:pyrazofurin; D012266:Ribose; D004896:Erythritol; C000288:ritrosulfan