Novel acyclic nucleotide analogues GS‐343074 and GS‐424044 demonstrate antiproliferative and pro‐apoptotic activity in canine neoplastic cell lines |
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| Authors: | M K Huelsmeyer D H Thamm D B Tumas G Birkus I Kurzman D M Vail |
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| Institution: | 1. School of Veterinary Medicine, University of Wisconsin‐Madison, Madison, WI, USA;2. Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA;3. Department of Research and Development, Gilead Sciences Inc, Foster City, CA, USA;4. Paul P Carbone Comprehensive Cancer Center, University of Wisconsin‐Madison, Madison, WI, USA |
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| Abstract: | GS‐9219, a novel prodrug of the nucleotide analogue 9‐(2‐phosphonylmethoxyethyl) guanine (PMEG) has significant activity as monotherapy in dogs with non‐Hodgkin's lymphoma. Phase I trials have been initiated in humans based on the encouraging activity observed in canine lymphoma. Two new analogues of GS‐9219 (GS‐343074 and GS‐424044) were recently produced for evaluation as potential novel antineoplastic agents against solid tumours. As a preclinical step, effect of GS‐343074 and GS‐424044 were evaluated against ten canine cancer cell lines for antiproliferative effect. Both analogues displayed antiproliferative activity against multiple canine cancer cell lines, although GS‐343074 was more potent and of broader spectrum compared to GS‐424044. Flow cytometric analysis of cells that experienced growth inhibition support apoptotic death as a mechanism of action for both analogues. On the basis of in vitro results described here, GS‐343074 and GS‐424044 show promise as novel anticancer agents in canine cancer. |
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| Keywords: | chemotherapy comparative oncology in vitro models oncology small animal |
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