Effects of cis-diamminedichloroplatinum on DNA incorporation and cytotoxicity of 1-beta-D-arabinofuranosylcytosine.
1-beta-D-Arabinofuranosylcytosine (ara-C) incorporates into replicating cellular DNA and the extent of this incorporation correlates with loss of clonogenic survival. More recent findings have demonstrated that incorporation of ara-C into DNA undergoing repair of damage induced by u.v. light also results in cell lethality. On the basis of previous studies demonstrating a marked synergism between cis-diamminedichloroplatinum (CDDP) and ara-C in LoVo colon carcinoma cells, the present work has examined the interaction of these agents at a biochemical and cellular level in the MCF-7 human breast carcinoma line. The extent of ara-C incorporation into MCF-7 DNA correlated significantly with loss of clonogenic survival in a dose-dependent manner. The effects of CDDP on the formation of MCF-7 (ara-C)DNA were monitored using both cesium sulfate and cesium chloride density centrifugation. The results demonstrate that CDDP had little, if any, detectable effect on incorporation of ara-C into DNA. Furthermore, combinations of CDDP and low concentrations of ara-C (10(-7) and 10(-6) M) decreased MCF-7 clonogenic survival in an additive but not synergistic manner. Modest synergy was detectable with CDDP and higher ara-C concentrations (10(-5) and 10(-4) M). The interaction between CDDP and ara-C was apparently dependent on concentration, duration of exposure and cell type. There was no dramatic synergy between CDDP and ara-C in MCF-7 cells. These findings may be relevant to the design and interpretation of CDDP/ara-C clinical trials.
D001943:Breast Neoplasms / Q000188:drug therapy; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology*; D003561:Cytarabine / Q000378:metabolism* / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D004347:Drug Interactions; D006801:Humans
D003561:Cytarabine; D004247:DNA; D002945:Cisplatin