title: Lack of a role of glutathione in cellular nonenzymatic activation of BMS-181174, a novel analogue of mitomycin C.
abstract: Recent studies, using a cell-free system, have suggested that thiol-dependent nonenzymatic bioactivation may be responsible for the superior antitumor activity of the mitomycin C analogue BMS-181174 [N-7-[2-(4-nitrophenyldithio)ethyl]mitomycin C] when compared to the parent compound. If operational in tumor cells, this pathway could have enormous clinical implications since tumor cell resistance to a variety of anticancer agents is often associated with increased glutathione (GSH) levels and BMS-181174 may be used to reverse this mechanism of resistance. The present study was undertaken to determine the role of GSH in cellular activation of BMS-181174 using a pair of well-characterized human bladder cancer cells (J82 and SCaBER) as a model. A 20-h pretreatment of J82 and SCaBER cells with a nontoxic concentration of D,L-buthionine-S,R-sulfoximine (BSO) caused about 80-88% reduction in cellular GSH levels. Surprisingly, the sensitivity of both cells to BMS-181174 was increased, not reduced, by BSO-induced GSH depletion. On the other hand, the cytotoxicity of BMS-181174 was significantly reduced in both cells by a 4-h pretreatment with 1 mM GSH. Like BSO, a 4-h pretreatment with another thiol compound (cysteine) resulted in a statistically significant sensitization of both cells to BMS-181174. Cellular GSH levels were not affected in either of the cell lines by pretreatment with GSH or cysteine. In conclusion, the results or the present study argue against a role of GSH in cellular nonenzymatic activation of BMS-181174 in J82 and SCaBER cells.
authors: Cancer Research Laboratory, Mercy Cancer Institute, Pittsburgh, Pennsylvania 15219, USA.
authors: H
authors: H
authors: Xia
authors: T
authors: T
authors: Pinto
authors: X
authors: X
authors: Hu
authors: P J
authors: PJ
authors: Benson
authors: H A
authors: HA
authors: Zaren
authors: V
authors: V
authors: Gupta
authors: S
authors: S
authors: Singh
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics*; D001711:Biotransformation; D019328:Buthionine Sulfoximine; D003545:Cysteine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D016685:Mitomycin / Q000493:pharmacokinetics / Q000494:pharmacology; D008937:Mitomycins; D014407:Tumor Cells, Cultured / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004791:Enzyme Inhibitors; D008937:Mitomycins; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D016685:Mitomycin; C055172:N-7-(2-(nitrophenyldithio)ethyl)mitomycin C; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D003545:Cysteine