Synergistic interaction between acivicin (AT-125) and 6-thioguanine in the murine leukemia L1210. Biochemical and cytokinetic considerations.
The effect of the purine antagonist acivicin (AT-125) on the metabolism and cytotoxicity of 6-thioguanine was examined in the murine leukemia L1210. Cells exposed to 5 X 10(-6) M acivicin for 18 hr followed by 10(-5) M [14C]-6-thioguanine for 2 hr accumulated 2.90 +/- 0.17 nmoles 6-thioguanine/10(6) cells compared to 0.69 +/- 0.07 nmoles 6-thioguanine/10(6) cells in untreated controls. Intracellular accumulation of 6-thioguanine monophosphate, a lethal 6-thioguanine metabolite, increased from 0.27 +/- 0.05 to 1.08 +/- 0.13 nmoles 6-thioguanine monophosphate/10(6) cells following the same acivicin exposure. A similar increment was observed for the formation of 6-thioguanine triphosphate. These alterations in 6-thioguanine metabolism were associated with an increase in the intracellular level of 5-phosphoribosyl-1-pyrophosphate, an obligatory substrate in 6-thioguanine activation (57.9 +/- 7.6 vs 13.4 +/- 2.3 ng 5-phosphoribosyl-1-pyrophosphate/10(6) cells). In contrast, there was a 50% reduction in the amount of 6-thioguanine incorporated into RNA and DNA following acivicin pretreatment. Cytofluorometric analysis revealed that an 18-hr exposure to 5 X 10(6) M acivicin increased the population 5-phase cells, which are more sensitive to the actions of 6-thioguanine, by 50% relative to untreated controls. In both suspension culture growth and soft agar studies, the sequential administration of acivicin followed by 6-thioguanine resulted in substantial growth inhibitory activity; in contrast, the effects of the reverse sequence were subadditive. Pretreatment of L1210 cells with acivicin potentiates the action of subsequently administered 6-thioguanine, and the mechanism may involve both biochemical as well as cytokinetic factors. In vivo studies involving the sequential administration of these agents appear warranted.
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004357:Drug Synergism; D005434:Flow Cytometry; D006150:Guanine Nucleotides / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology*; D007939:Leukemia L1210 / Q000378:metabolism*; D051379:Mice; D010080:Oxazoles / Q000494:pharmacology*; D010754:Phosphoribosyl Pyrophosphate / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013866:Thioguanine / Q000378:metabolism / Q000494:pharmacology*
D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D006150:Guanine Nucleotides; D007555:Isoxazoles; D010080:Oxazoles; D012334:RNA, Neoplasm; D010754:Phosphoribosyl Pyrophosphate; D013866:Thioguanine; C006303:acivicin