Theophylline reversal of alkylator-induced replicon initiation inhibition: no correlation with DDP-induced cytotoxicity.
The synergistic cytotoxic activity exhibited by bifunctional alkylating agents in the presence of methylxanthines has been associated with methylxanthine-induced reversal of alkylator-induced DNA replicon initiation inhibition. This has also been seen with methylxanthines and ionizing irradiation. Methylxanthines do not appear exacerbate drug or ionizing radiation-induced damage. We report here a situation in which methylxanthine-induced reversal of DNA replicon initiation inhibition is not associated with increased cytotoxicity of the alkylator. Murine L1210 leukemia cells were assayed for cytotoxicity following treatment with either L-PAM or cis-DDP in the presence or absence of theophylline. Theophylline increased the cytotoxicity seen after L-PAM treatment but failed to increase the cis-DDP induced cytotoxicity. Analysis of pulse-labeled DNA on alkaline sucrose gradients revealed the expected decrease in DNA replicon initiation in L1210 cells treated with either L-PAM or cis-DDP. Theophylline had no effect on replicon initiation in untreated cells. Theophylline reversed the replicon initiation inhibition in cells treated with either L-PAM or cis-DDP. The reason for the apparent lack of added toxicity of the replicon initiation inhibition reversal in L1210 cells treated with theophylline and DDP is unknown.
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004261:DNA Replication / Q000187:drug effects*; D004357:Drug Synergism; D007939:Leukemia L1210 / Q000235:genetics; D008558:Melphalan / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051379:Mice; D013806:Theophylline / Q000494:pharmacology* / Q000633:toxicity
D013806:Theophylline; D002945:Cisplatin; D008558:Melphalan