Modulation of cytotoxicity of chemotherapeutic drugs by activated H-ras.
Cells from a single MCF-7 clone were transfected with an isopropyl-1-thio-beta-D-galactopyranoside (IPTG)-inducible construct containing activated human H-ras with a Gly12 --> Val12 mutation. Expression of H-ras was induced by the presence of IPTG with low background. MCF-7-ras clones were examined for sensitivity to a wide variety of drugs under both induced and non-induced conditions. When expression of the activated ras was induced, these clones showed markedly increased resistance to cisplatin and mitomycin C, moderately increased resistance to methotrexate and trimetrexate, and no increased resistance to other drugs including taxol, doxorubicin, and etoposide. A DNA fragmentation assay revealed that DNA in MCF-7-ras cells treated with cisplatin under induced conditions was intact, whereas extensive degradation of DNA occurred in similarly treated cells under non-induced conditions. This result, along with the fact that MCF-7-ras cells, upon induction of the activated H-ras, showed increased resistance to drugs that bind DNA, indicates that the activated H-ras may play a role in the DNA repair process.
Fan
J
J
Program for Molecular Pharmacology and Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, U.S.A.
Banerjee
D
D
Stambrook
P J
PJ
Bertino
J R
JR
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics*; D005786:Gene Expression Regulation; D011905:Genes, ras / Q000187:drug effects; D006801:Humans; D007544:Isopropyl Thiogalactoside; D016685:Mitomycin / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D007544:Isopropyl Thiogalactoside; D016685:Mitomycin; D002945:Cisplatin