Enhanced lethality by methylxanthines in human bladder cancer cells treated with thiotepa

Cytotoxicity of thiotepa or doxorubicin hydrochloride in human bladder cancer cells was investigated alone and in combination with methylxanthines. Methylxanthines can potentiate cytotoxicity of some DNA-damaging agents used in cancer therapy by preventing DNA repair. However, the potential clinical utility of these drug combinations has not been defined. Nontoxic concentrations of two methylxanthines, theobromine and caffeine, markedly enhanced lethality in T-24 human bladder cancer cells treated with thiotepa. Thiotepa cytotoxicity was increased over 10-fold by continuous treatment with nontoxic concentrations of methylxanthines (0.5 mM), but the major enhancing effect was observed in the 1st 24 hours after thiotepa exposure. By contrast, no such enhanced lethality was observed using higher methylxanthine concentrations and equal or greater cytotoxic treatments with doxorubicin hydrochloride. The amount of enhanced lethality by methylxanthines correlated directly with growth rate of the cells in culture, suggesting that differential enhanced therapeutic effects could be achieved in the treatment of superficial bladder tumors based on the increased proliferative rate of neoplastic bladder cells compared to normal bladder urothelium.