Effect of DNA-repair-enzyme modulators on cytotoxicity of L-phenylalanine mustard and cis-diamminedichloroplatinum (II) in mammary carcinoma cells resistant to alkylating drugs.
We investigated the effect of DNA-repair-enzyme inhibitors on L-phenylalanine mustard (L-PAM) and cis-diamminedichloroplatinum (II) (CDDP) cytotoxicity in rat mammary-carcinoma MatB cells sensitive (WT) and resistant (MLNr) to bifunctional alkylating drugs. Among the modulators tested, the combination of arabinofuranosylcytosine (Ara-C) and hydroxyurea (HU) significantly increased the sensitivity of the cells to CDDP and, to a lesser extent, L-PAM as compared with cells treated with drug alone. The modulation effect of HU+Ara-C on CDDP and L-PAM cytotoxicity was more effective when intracellular glutathione (GSH) was depleted by L-buthionine-(S,R)-sulfoximine (BSO). This was also associated with a significant increase in DNA-DNA interstrand cross-links. Caffeine also sensitized both WT and MLNr cells to the cytotoxic effect of L-PAM and CDDP, and this effect was potentiated in GSH-depleted cells. No significant effect was observed with other repair modulators such as aphidicolin, 3-aminobenzamide, novobiocin, or etoposide. These results show (a) that inhibition of DNA repair by HU+Ara-C or caffeine could be a target for modulation of bifunctional alkylating-drug resistance and (b) that GSH depletion renders resistant cells more susceptible to the repair-enzyme modulators, suggesting that intracellular GSH may be involved in the regulation of some of these enzymes. Our results also indicate that a combination of a number of modulators may offer an advantage over the use of a single modulator in tumor resistance that may be associated with multifactorial mechanisms.
Alaoui-Jamali
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Lady Davis Institute for Medical Research, Montreal, Canada.
Loubaba
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Robyn
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Tapiero
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Batist
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D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000477:Alkylating Agents; D000818:Animals; D002945:Cisplatin / Q000627:therapeutic use*; D003432:Cross-Linking Reagents; D004260:DNA Repair / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000378:metabolism; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D008558:Melphalan / Q000627:therapeutic use*; D051381:Rats; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D000477:Alkylating Agents; D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D005978:Glutathione; D002945:Cisplatin; D008558:Melphalan