Increased expression of gamma-glutamyl transpeptidase in transfected tumor cells and its relationship to drug sensitivity.
To test the hypothesis that elevated expression of the glutathione (GSH) salvage enzyme, gamma-glutamyl transpeptidase (gamma-GT) can confer resistance to chemotherapeutic agents, the cDNA for human gamma-GT was introduced into human prostate carcinoma cells by calcium phosphate precipitation. The sensitivity of a stable clone expressing an 18-fold increase in gamma-GT activity to melphalan (L-PAM), cisplatinum and doxorubicin was compared to that of the parent cell line and a clone transfected with gamma-GT cDNA in the antisense orientation. Despite increased gamma-GT expression and the ability of intact cells to metabolize exogenous GSH, transfection did not result in increased intracellular GSH levels even when an exogenous source of GSH was provided. Furthermore, no change in sensitivity attributable to the transfection and increased expression of gamma-GT was detected with any of the three drugs. Our data indicate that an increase in gamma-GT expression, exceeding that typically associated with resistance phenotypes, is not sufficient to confer resistance to L-PMA, cisplatinum or doxorubicin in the absence of other alterations in GSH homeostasis.
Bailey
H H
HH
Department of Human Oncology, University of Wisconsin Medical School, Madison 53792.
Gipp
J J
JJ
Mulcahy
R T
RT
D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D006801:Humans; D008297:Male; D008558:Melphalan / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured; D005723:gamma-Glutamyltransferase / Q000235:genetics / Q000378:metabolism*
D004317:Doxorubicin; D005723:gamma-Glutamyltransferase; D002945:Cisplatin; D008558:Melphalan