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In vitro assessment of nucleoside analogs in multiple myeloma

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Abstract

Purpose

To identify nucleoside analogs that may be effective for multiple myeloma (MM), we tested fludarabine, clofarabine, arabinosylguanine, cytarabine, troxacitabine, and gemcitabine in MM cell lines.

Methods

We employed biologic and biochemical assays in MM cell lines to evaluate the clinical potential of these nucleoside analogs.

Results

Among these purine and pyrimidine nucleoside analogs, fludarabine, clofarabine and gemcitabine were the most potent. MM cell lines, resistant to commonly used chemotherapeutic agents for this disease, were more sensitive to gemcitabine with an IC50 in the nanomolar range. The greater cytotoxicity of gemcitabine in MM cells was consistent with greater accumulation of gemcitabine triphosphate, the major cytotoxic metabolite of this drug. MM.1S cells accumulated >100 μM gemcitabine triphosphate but accumulated <20 μM of the other analogs as the respective triphosphates. In addition incubation with gemcitabine resulted in inhibition of DNA synthesis. Incubation with 25, 50 or 100 nM gemcitabine resulted in a dose- and time-dependent increase in the cell population with a subG1 DNA content indicative of apoptosis.

Conclusions

These results suggest that gemcitabine is a potent nucleoside analog in MM cell lines including cell types resistant to other chemotherapeutic agents. The greater activity of gemcitabine compared to other analogs seems to be due to favorable metabolism of this agent.

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Acknowledgements

We would like to thank Dr. William Dalton of the H. Lee Moffitt Cancer Center and Research Institution (Tampa, Fl.) for generously sharing the RPMI 8226 and the melphalan-resistant derivative LR5 MM cell lines.

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Author notes

  1. Chadi Nabhan

    Present address: S.C. Lutheran General Hospital Cancer Care Center, Park Ridge, IL 60056, USA

Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University Medical School, Chicago, IL 60611, USA

    Nancy L. Krett, Chadi Nabhan, Chunguang Ma & Steven T. Rosen

  2. Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA

    Mary Ayres, Billie Nowak, Steffan Nawrocki & Varsha Gandhi

  3. Robert H. Lurie Comprehensive Cancer Center, Room 8340, Olson Pavilion, 303 E. Chicago Avenue, Chicago, IL 60611, USA

    Nancy L. Krett

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  1. Nancy L. Krett
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Corresponding author

Correspondence to Nancy L. Krett.

Additional information

This work was supported in part by grants CA57629 and CA85915 from the National Cancer Institute, Department of Health and Human Services and a Translational Research Award #6506-00 from the Leukemia and Lymphoma Society of America. Steven T. Rosen is the Dr. Ralph and Marion Falk Research Trust Translational Researcher of the Lymphoma Society of America.

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Krett, N.L., Ayres, M., Nabhan, C. et al. In vitro assessment of nucleoside analogs in multiple myeloma. Cancer Chemother Pharmacol 54, 113–121 (2004). https://doi.org/10.1007/s00280-004-0777-2

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  • DOI: https://doi.org/10.1007/s00280-004-0777-2

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