Expression of human glutathione S-transferases in Saccharomyces cerevisiae confers resistance to the anticancer drugs adriamycin and chlorambucil.
Adaptation and resistance to chemicals in the environment is a critical part of the evolutionary process. As a result, a wide variety of defence systems that protect cells against chemical insult have evolved. Such chemical resistance mechanisms appear to play a central role in determining the sensitivity of human tumours to treatment with chemotherapeutic drugs. The glutathione S-transferases (GST) are important detoxification enzymes whose over-expression has been associated with drug-resistance. In order to evaluate this possibility we have expressed the human Alpha-class and Pi-class GST cDNAs that encode GST B1B1 and GST pi in the yeast Saccharomyces cerevisiae. The expression of GST B1B1 or GST pi resulted in a marked reduction in the cytotoxic effects of chlorambucil, a bifunctional alkylating agent, and an anthracycline, adriamycin. These data provide direct evidence that the over-expression of GST in cells can confer resistance to anticancer drugs.
Black
S M
SM
Imperial Cancer Research Fund, University of Edinburgh Department of Biochemistry.
Beggs
J D
JD
Hayes
J D
JD
Bartoszek
A
A
Muramatsu
M
M
Sakai
M
M
Wolf
C R
CR
D000477:Alkylating Agents / Q000494:pharmacology*; D002699:Chlorambucil / Q000494:pharmacology*; D004271:DNA, Fungal / Q000096:biosynthesis; D004274:DNA, Recombinant / Q000096:biosynthesis; D004317:Doxorubicin / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D004926:Escherichia coli / Q000235:genetics; D015870:Gene Expression; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000235:genetics*; D008826:Microbial Sensitivity Tests; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*
D000477:Alkylating Agents; D004271:DNA, Fungal; D004274:DNA, Recombinant; D002699:Chlorambucil; D004317:Doxorubicin; D005982:Glutathione Transferase