GS-9219--a novel acyclic nucleotide analogue with potent antineoplastic activity in dogs with spontaneous non-Hodgkin's lymphoma.

Abstract

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.

• Authors: Hans Reiser, Jianying Wang, Lee Chong, William J Watkins, Adrian S Ray, Riri Shibata, Gabriel Birkus, Tomas Cihlar, Sylvia Wu, Bei Li, Xiaohong Liu, Ilana N Henne, Grushenka H I Wolfgang, Manoj Desai, Gerald R Rhodes, Arnold Fridland, William A Lee, William Plunkett, David Vail, Douglas H Thamm, Robert Jeraj, Daniel B Tumas
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 9 Pg. 2824-32 (May 01 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18451250 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Organophosphorus Compounds
• Prodrugs
• Purines
• rabacfosadine
• 9-((2-phosphonylmethoxy)ethyl)guanine
• Guanine
• Alanine

Topics

• Alanine (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics, therapeutic use)
• Animals
• Antineoplastic Agents (adverse effects, pharmacokinetics, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dogs
• Guanine (analogs & derivatives, therapeutic use)
• Lymphoid Tissue (cytology, drug effects, metabolism)
• Lymphoma, Non-Hodgkin (drug therapy)
• Organophosphorus Compounds (therapeutic use)
• Prodrugs (adverse effects, chemistry, pharmacokinetics, therapeutic use)
• Purines (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Tissue Distribution