Involvement of the cellular vacuolar system with the cytotoxicity of bleomycin-like agents

The role of acidic cellular organelles in regulating the toxicity of selected antitumor drugs was studied with L1210 cells using modifiers of vesicular pH or function. A 1 hr exposure to a non-toxic concentration of the acidotropic weak base ammonium chloride increased the lethality of bleomycin A2 (BLM A2), demethyl BLM A2, peplomycin, and talisomycin S10b to L1210 cells grown in culture. Enhanced BLM lethality was also seen with the lysosomal disruptive agents verapamil and diltiazem. The increased lethality with verapamil and BLM A2 was schedule dependent, being seen only when cells were exposed to the drugs simultaneously or to BLM A2 first and then verapamil. Non-toxic concentrations of the monovalent cationic ionophore monensin also increased the cytotoxicity of BLM A2 and talisomycin S10b but not doxorubicin. This enhanced cytotoxicity seen with monensin occurred without an increase in either cell associated BLM A2 or single-strand DNA damage as measured by alkaline elution. We propose that acidic cellular organelles or their contents participate in controlling the cytotoxicity of the BLM class of antitumor agents.