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Effect of DNA-repair-enzyme modulators on cytotoxicity ofl-phenylalanine mustard andcis-diamminedichloroplatinum (II) in mammary carcinoma cells resistant to alkylating drugs

  • Original Articles
  • Tumor cells, Alkylating Drugs, Resistance, Repair inhibitors
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Abstract

We investigated the effect of DNA-repair-enzyme inhibitors onl-phenylalanine mustard (L-PAM) andcis-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 byl-buthionine-(S,R)-sulfoximine (BSO). This was also associated with a significant increase in DNA-DNA interstrand crosslinks. 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.

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Abbreviations

3-AB:

3-Aminobenzamide

ADP:

adenosine diphosphate

APD:

aphidicolin

Ara-C:

arabinofuranosylcytosine

BSO:

1-β-d-l-buthionine-(S,R)-sulfoximine

CDDP:

cis-diamminedichloroplatinum (II) (cisplatin)

GSH:

glutathione

GST:

glutathione-S-transferase

HU:

hydroxyurea

L-PAM:

l-phenylalanine mustard (melphalan)

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Authors and Affiliations

  1. Paul Brousse Hospital-CNRS, Villejuif, France

    Haim Tapiero

  2. Lady Davis Institute, for Medical Research, and McGill University, Room 523, 3755 Cote-Ste Catherine Road, H3T 1E2, Montreal, Canada

    Moulay Alaoui-Jamali, Bel-Baraka Loubaba, Schecter Robyn & Gerald Batist

Authors
  1. Moulay Alaoui-Jamali
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  2. Bel-Baraka Loubaba
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  3. Schecter Robyn
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  4. Haim Tapiero
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  5. Gerald Batist
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This work was supported in part by the Quebec Lung Association and the National Cancer Institute of Canada

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Alaoui-Jamali, M., Loubaba, BB., Robyn, S. et al. Effect of DNA-repair-enzyme modulators on cytotoxicity ofl-phenylalanine mustard andcis-diamminedichloroplatinum (II) in mammary carcinoma cells resistant to alkylating drugs. Cancer Chemother. Pharmacol. 34, 153–158 (1994). https://doi.org/10.1007/BF00685933

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  • DOI: https://doi.org/10.1007/BF00685933

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