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Prodrug chemotherapeutics bypass p-glycoprotein resistance and kill tumors in vivo with high efficacy and target-dependent selectivity

Oncogene volume 23, pages 3613–3621 (2004)Cite this article

Abstract

Doxorubicin intercalates into DNA, causes double-strand breaks, and leads to apoptotic death. Limitations to the efficacy and therapeutic index of doxorubicin include poor tumor selectivity, high systemic toxicity, and the development of resistance, especially p-glycoprotein (p-gp)-mediated. We chemically coupled doxorubicin to a monoclonal antibody directed to the insulin-like growth factor-1 receptor, a receptor highly overexpressed in most tumors and validated as a tumor target. The prodrug conjugate bounded to tumor cells selectively, and accumulated efficiently and only in receptor-expressing cells. The conjugate was processed to release free doxorubicin inside target cells leading to selective toxicity, had >200-fold improved therapeutic index, and in vivo reduced tumor load with no systemic toxicity. Importantly, the prodrug conjugate is not subject to p-gp efflux and can bypass resistance in vivo. Our studies define a strategy to develop improved and more selective anticancer agents.

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Acknowledgements

We thank the National Institutes of Health (National Institute of Neurological Disease and Stroke Grant R01-NS38569) and the Canadian Institutes of Health Research (CIHR, Grant MT-13265) for their financial support to H Uri Saragovi. V Guillemard received a CIHR doctoral studentship award. We are grateful to Dr M Gagnon and Dr M Alaoui-Jamali (McGill University) for discussions and reagents.

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  1. Department of Pharmacology and Therapeutics, McGill University, 3655 Drummond Ave., #1320, Montréal, H3G 1Y6, QC, Canada

    Veronique Guillemard & H Uri Saragovi

  2. Department of Oncology and the Cancer Center, Lady Davis Institute-Jewish General Hospital, McGill University, 3755 Cote St. Catherine, F-223, Montreal, H3T 1E2, Quebec, Canada

    H Uri Saragovi

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Correspondence to H Uri Saragovi.

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Guillemard, V., Uri Saragovi, H. Prodrug chemotherapeutics bypass p-glycoprotein resistance and kill tumors in vivo with high efficacy and target-dependent selectivity. Oncogene 23, 3613–3621 (2004). https://doi.org/10.1038/sj.onc.1207463

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