Novel acyclic nucleotide analogues GS-343074 and GS-424044 demonstrate antiproliferative and pro-apoptotic activity in canine neoplastic cell lines

J. A. Lawrence, M. K. Huelsmeyer, D. H. Thamm, D. B. Tumas, G. Birkus, I. Kurzman, D. M. Vail

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)246-254
Number of pages9
JournalVeterinary and Comparative Oncology
Volume13
Issue number3
DOIs
StatePublished - Sep 1 2015

Keywords

  • Chemotherapy
  • Comparative oncology
  • Oncology
  • Small animal
  • in vitro models

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