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Lack of cross-resistance to a new cytotoxic arylchloroethyl urea in various drug-resistant tumor cells

  • Original Articles
  • Aryl Chloroethyl Ureas, Drug Resistance, Cytotoxicity, Cancer
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Abstract

1-Aryl 3-(2-chloroethyl) ureas (CEUs), a new class of potent antineoplastic agents, were recently developed in our laboratory. These compounds were designed from the aromatic moiety of chlorambucil and the unnitrosated pharmacophore of carmustine. In the present study we investigated the effect of the potent CEU derivative 4-tert-butyl-[3-(2-chloroethyl)ureido] benzene (tBCEU) on tumor cell lines selected for resistance to a wide range of anticancer drugs. The resistance mechanisms found in these cells included increased expression of P-glycoprotein, increased intracellular concentration of glutathione and/or glutathione-S-transferase activity, alteration of topoisomerase II, and increased DNA repair. Whereas the resistant cell lines were found to be highly resistant to a panel of clinically known anticancer drugs, tBCEU was found to be equally cytotoxic to both resistant and parental cells. The nitrobenzylpyridine assay indicated that tBCEU is a weaker alkylating agent than chlorambucil. This lack of cross-resistance in various resistant tumor cells suggests that tBCEU could be potentially useful in the treatment of cancers resistant to conventional anticancer drugs.

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Abbreviations

ADR:

Adriamycin

BCNU:

carmustine

CDDP:

cisplatin

CEUs:

arylchloroethyl ureas

CLB:

chlorambucil

MLN:

melphalan

NBP:

4-(4-nitrobenzyl)pyridine

ND:

not determined

tBCEU:

4-tert-butyl-[3-(2-chloroethyl) ureido] benzene

VBL:

vinblastine

WT:

wild type

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Authors and Affiliations

  1. Centre de recherche, Hôpital Saint-François d'Assise, 10 rue de l'Espinay, G1L 3L5, Québec, Canada

    René C.-Gaudreault, Philippe Béchard, Jacques Lacroix & Patrick Poyet

  2. Lady Davis Institute for Medical Research, The Jewish General Hospital, H3T 1E2, Montreal, Canada

    Moulay A. Alaoui-Jamali & Gerald Batist

Authors
  1. René C.-Gaudreault
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  2. Moulay A. Alaoui-Jamali
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  3. Gerald Batist
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  4. Philippe Béchard
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  5. Jacques Lacroix
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  6. Patrick Poyet
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C.-Gaudreault, R., Alaoui-Jamali, M.A., Batist, G. et al. Lack of cross-resistance to a new cytotoxic arylchloroethyl urea in various drug-resistant tumor cells. Cancer Chemother. Pharmacol. 33, 489–492 (1994). https://doi.org/10.1007/BF00686506

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  • DOI: https://doi.org/10.1007/BF00686506

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