title: Novel acyclic nucleotide analogues GS-343074 and GS-424044 demonstrate antiproliferative and pro-apoptotic activity in canine neoplastic cell lines.
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.
authors.affiliation: School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Lawrence
authors.affiliation: School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Huelsmeyer
authors.affiliation: Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA.
authors.forename: D H
authors.initials: DH
authors.lastname: Thamm
authors.affiliation: Department of Research and Development, Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Tumas
authors.affiliation: Department of Research and Development, Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Birkus
authors.affiliation: School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA.|Paul P Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: I
authors.initials: I
authors.lastname: Kurzman
authors.affiliation: School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA.|Paul P Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Vail
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004283:Dog Diseases / Q000188:drug therapy* / Q000473:pathology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry / Q000662:veterinary; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D020128:Inhibitory Concentration 50; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000662:veterinary*; D009943:Organophosphorus Compounds / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D009943:Organophosphorus Compounds; C063380:9-((2-phosphonylmethoxy)ethyl)guanine; D006147:Guanine
keywords: chemotherapy; comparative oncology; in vitro models; oncology; small animal