Lack of a role of glutathione in cellular nonenzymatic activation of BMS-181174, a novel analogue of mitomycin C.
Cancer Res
; 56(15): 3495-8, 1996 Aug 01.
Article
em En
| MEDLINE
| ID: mdl-8758917
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Bexiga Urinária
/
Antineoplásicos Alquilantes
/
Glutationa
/
Mitomicinas
Limite:
Humans
Idioma:
En
Revista:
Cancer Res
Ano de publicação:
1996
Tipo de documento:
Article
País de afiliação:
Estados Unidos