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GS-9219—A Novel Acyclic Nucleotide Analogue with Potent Antineoplastic Activity in Dogs with Spontaneous Non–Hodgkin's Lymphoma

Authors' Affiliations: ¹ Department of Research and Development, Gilead Sciences, Inc., Foster City, California; ² Department of Experimental Therapeutics, M. D. Anderson Cancer Center, Houston, Texas; ³ Center for Clinical Trials and Research, School of Veterinary Medicine and ⁴ Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, Wisconsin; and ⁵ College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado

Requests for reprints: Hans Reiser, Department of Research and Development, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404. Phone: 650-522-6327; E-mail: hans.reiser{at}gilead.com.

Purpose: GS-9219, a novel prodrug of the nucleotide analogue 9-(2-phosphonylmethoxyethyl)guanine (PMEG), was designed as a cytotoxic agent that preferentially targets lymphoid cells. Our objective was to characterize the antiproliferative activity, pharmacokinetics, pharmacodynamics, and safety of GS-9219.

Experimental Design: GS-9219 was selected through screening in proliferation assays and through pharmacokinetic screening. The activation pathway of GS-9219 was characterized in lymphocytes, and its cytotoxic activity was evaluated against a panel of hematopoietic and nonhematopoietic cell types. To test whether the prodrug moieties present in GS-9219 confer an advantage over PMEG in vivo, the pharmacokinetics, pharmacodynamics (lymph node germinal center depletion), and toxicity of equimolar doses of GS-9219 and PMEG were evaluated after i.v. administration to normal beagle dogs. Finally, proof of concept of the antitumor efficacy of GS-9219 was evaluated in five pet dogs with spontaneous, advanced-stage non–Hodgkin's lymphoma (NHL) following a single i.v. administration of GS-9219 as monotherapy.

Results: In lymphocytes, GS-9219 is converted to its active metabolite, PMEG diphosphate, via enzymatic hydrolysis, deamination, and phosphorylation. GS-9219 has substantial antiproliferative activity against activated lymphocytes and hematopoietic tumor cell lines. In contrast, resting lymphocytes and solid tumor lines were less sensitive to GS-9219. GS-9219, but not PMEG, depleted the germinal centers in lymphoid tissues of normal beagle dogs at doses that were tolerated. In addition, GS-9219 displayed significant in vivo efficacy in five dogs with spontaneous NHL after a single administration, with either no or low-grade adverse events.

Conclusion: GS-9219 may have utility for the treatment of NHL.

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