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Lack of a Role of Glutathione in Cellular Nonenzymatic Activation of BMS-181174, a Novel Analogue of Mitomycin C¹

Cancer Research Laboratory, Mercy Cancer Institute, The Mercy Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15219

Recent studies, using a cell-free system, have suggested that thioldependent 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 BSM-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 of the present study argue against a role of GSH in cellular nonenzymatic activation of BMS-181174 in J82 and SCaBER cells.

¹ This investigation was supported in part by USPHS Grant CA 50638, awarded by the National Cancer Institute.

² To whom requests for reprints should be addressed, at Cancer Research Laboratory, The Mercy Hospital of Pittsburgh, 1400 Locust Street, Pittsburgh, PA 15219.

Received 2/29/96. Accepted 5/31/96.