Mechanisms underlying resistance to streptozotocin in Mer+ and Mer- human tumor lines

Streptozotocin (STZ) is a monofunctional nitrosourea employed in the treatment of patients with islet cell tumors. To analyze the role of DNA repair mechanisms in causing resistance to STZ, we evaluated the cytotoxicity by this agent in three human tumor lines that differ with respect to their abilities to repair N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) damaged virus (the Mer phenotype). HT-29, A2182, and BE human tumor lines are high, intermediate and low, respectively, with regard to features that define the Mer phenotype. Our results demonstrated that the order of resistance to STZ is HT-29 greater than A2182 greater than BE. The degree of inhibition of DNA synthesis by STZ was in the following order: BE greater than A2182 greater than HT-29. O6-Alkyltransferase activity was increased markedly in HT-29 cells compared to A2182 cells which, in turn, had significantly increased levels compared to the BE line. Other potential factors such as 3-methyladenine DNA glycosylase activity, the induction by STZ of single-stranded DNA breaks, and the kinetics of repair of these breaks do not clearly underlie differences in cytotoxicity among the three tumor lines. However, increased topoisomerase II activity, as well as enhanced sensitivity to agents that interact with topoisomerase II, was present in A2182 cells compared to BE cells. These findings demonstrate that while O6-alkyltransferase contributes to resistance to STZ in some Mer+ tumor lines, other mechanisms may also contribute to resistance to this agent.