Differential response to 1,3-bis (2-chloroethyl)-1-nitrosourea in drug-resistant and -sensitive 9L rat brain tumor cells pretreated with alpha-difluoromethylornithine and 6-thioguanine.

Pretreatment of 9L cells with either alpha-difluoromethylornithine (DFMO), which depletes intracellular levels of polyamines, or 6-thioguanine (6TG), which substitutes for guanine in DNA, potentiates the cytotoxic effects of 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU). We examined the effects of these 2 agents in combination on the cytotoxicity of BCNU in sensitive (9L) and resistant (BTRC-19) rat brain tumor cell lines. 9L cells were incubated with 0.2 microM 6TG for 72 hr; during the last 48 hr, 1 mM DFMO was added to cell cultures. The cytotoxicity of BCNU in pretreated cells was increased in an additive manner compared with the effects of each agent alone. Results of experiments in which the BCNU-resistant BTRC-19 cell line was treated similarly showed that only 6TG enhanced BCNU cytotoxicity. Flow cytometry studies showed that these effects are not related to cell-cycle processes.