Rescue from enhanced alkylator-induced cell death with low molecular weight sulfur-containing chemoprotectants

Modulation of glutathione has been proposed as a mechanism to alter the eff icacy and toxicity of chemotherapeutic agents. We investigated in vitro cyt oenhancement of chemotherapy toxicity by reducing cellular glutathione leve ls with L-buthionine-[S,R]-sulfoximine (BSO), and chemoprotection with smal l molecular weight sulfur-containing agents that mimic or replace glutathio ne. Cytotoxicity, caspase-2 enzymatic activity, and in situ DNA staining fo r apoptosis were assessed in cultured human small cell lung carcinoma cells and fibroblasts. BSO treatment reduced the half-maximal cytotoxic dose of the alkylating chemotherapeutics melphalan, carboplatin, and cisplatin, and increased the total magnitude of cell death. Melphalan was more sensitive than carboplatin or cisplatin to BSO. The chemoprotective agents sodium thi osulfate, N-acetylcysteine, and glutathione ethyl ester reduced the cytotox icity of all three alkylating chemotherapeutics regardless of BSO treatment , but D-methionine was effective only against the platinum agents. N-Acetyl cysteine was the most effective protectant tested. Chemoprotection against melphalan toxicity was maximally effective only if administered concurrent with chemotherapy, whereas chemoprotection for the platinum agents remained effective if delayed 4 h after chemotherapy. BSO enhancement and N-acetylc ysteine chemoprotection for melphalan toxicity occurred at least partially through an apoptotic mechanism. Modulation of glutathione levels will be va luable in the clinical setting if chemotherapy and chemoprotectant can be p hysically and/or temporally separated. Cytoenhancement and chemoprotection may be particularly useful in the central nervous system where the blood-br ain barrier of the cerebral vasculature creates two compartments, for cytoe nhancement in brain tumors and systemic chemoprotection.