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Effects of drug efflux proteins and topoisomerase I mutations on the camptothecin analogue gimatecan

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Summary

Clinically relevant resistance to the currently approved camptothecins, irinotecan and topotecan, is poorly understood but may involve increased expression of ATP-dependent drug transporters such as ABCG2 (breast cancer resistant protein, BCRP). Gimatecan (ST1481) is a lipophilic 7-substituted camptothecin derivative that exhibits potent anti-tumor activity in a variety of preclinical cancer models and is under investigation in the clinic. Previous studies reported that gimatecan cytotoxicity was not affected by expression of ABCG2. To confirm and extend this finding, we assessed the cytotoxicity of gimatecan in pairs of isogenic cell lines consisting of transfectants expressing either ABCG2 (including wild-type, R482T, or R482G mutants), ABCB1 (P-glycoprotein), ABCC1 (MRP1), ABCC2 (MRP2), or ABCC4 (MRP4). Expression of wild-type or mutant ABCG2 in human cell lines conferred resistance to topotecan but not to gimatecan. Similarly, intracellular accumulation of gimatecan was unaffected by expression of wild-type ABCG2. Furthermore, expression of P-glycoprotein or MRP2 did not alter gimatecan cytotoxicity. Whereas expression of MRP1 had a minor effect on gimatecan cytotoxicity, expression of ABCC4 was found to significantly reduce the anti-proliferative effects of this drug. Cells containing resistance-conferring mutations in topoisomerase I were also resistant to gimatecan. These results suggest that gimatecan may be more effective than irinotecan or topotecan in cancers that express ABCG2, but not in cancers that express high levels of ABCC4 or contain certain topoisomerase I (TOP1) mutations.

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Acknowledgements

This work was supported by funding from Novartis Pharma AG, Lichtstrasse 35, Basel, Switzerland. The authors would like to thank John Schuetz for providing the Saos-2 MRP4 transfectants.

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Authors and Affiliations

  1. Department of Pharmacology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ, USA

    Murugesan K. Gounder, Ahamed Saleem, Pooja Pungaliya, Diptee Kulkarni & Eric H. Rubin

  2. The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08901, USA

    Ahamed S. Nazar

  3. Novartis Pharmaceuticals, East Hanover, NJ, USA

    Richard Versace

  4. Department of Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ, USA

    Eric H. Rubin

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  1. Murugesan K. Gounder
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  2. Ahamed S. Nazar
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Correspondence to Eric H. Rubin.

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Gounder, M.K., Nazar, A.S., Saleem, A. et al. Effects of drug efflux proteins and topoisomerase I mutations on the camptothecin analogue gimatecan. Invest New Drugs 26, 205–213 (2008). https://doi.org/10.1007/s10637-007-9093-0

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  • DOI: https://doi.org/10.1007/s10637-007-9093-0

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