Assessment of GS-9219 in a pet dog model of non-Hodgkin's lymphoma

Clin Cancer Res. 2009 May 15;15(10):3503-10. doi: 10.1158/1078-0432.CCR-08-3113. Epub 2009 May 5.


Purpose: To assess, in dogs with naturally occurring non-Hodgkin's lymphoma, pharmacokinetics, safety, and activity of GS-9219, a prodrug of the nucleotide analogue 9-(2-phosphonylmethoxyethyl) guanine (PMEG), which delivers PMEG and its phosphorylated metabolites to lymphoid cells with preferential cytotoxicity in cells with a high proliferation index such as lymphoid malignancies.

Experimental design: To generate proof-of-concept, a phase I/II trial was conducted in pet dogs (n = 38) with naturally occurring non-Hodgkin's lymphoma using different dose schedules of GS-9219. A subset of dogs was further evaluated with 3'-deoxy-3'-(18)F-fluorothymidine positron emission tomography/computed tomography imaging before and after treatment.

Results: The prodrug had a short plasma half-life but yielded high and prolonged intracellular levels of the cytotoxic metabolite PMEG diphosphate in peripheral blood mononuclear cells in the absence of detectable plasma PMEG. Dose-limiting toxicities were generally manageable and reversible and included dermatopathy, neutropenia, and gastrointestinal signs. Antitumor responses were observed in 79% of dogs and occurred in previously untreated dogs and dogs with chemotherapy-refractory non-Hodgkin's lymphoma. The median remission durations observed compare favorably with other monotherapies in dogs with non-Hodgkin's lymphoma. High 3'-deoxy-3'-(18)F-fluorothymidine uptake noted in lymphoid tissues before treatment decreased significantly after treatment (P = 0.016).

Conclusions: GS-9219 was generally well tolerated and showed significant activity against spontaneous non-Hodgkin's lymphoma as modeled in pet dogs and, as such, supports clinical evaluation in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine / analogs & derivatives*
  • Alanine / blood
  • Alanine / pharmacokinetics
  • Alanine / therapeutic use
  • Animals
  • Animals, Domestic
  • Anorexia / chemically induced
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use
  • Area Under Curve
  • Diarrhea / chemically induced
  • Dideoxynucleosides
  • Disease Models, Animal*
  • Dog Diseases / drug therapy*
  • Dog Diseases / metabolism
  • Dog Diseases / pathology
  • Dogs
  • Drug Administration Schedule
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Lymphoma, Non-Hodgkin / metabolism
  • Lymphoma, Non-Hodgkin / pathology
  • Lymphoma, Non-Hodgkin / veterinary*
  • Male
  • Metabolic Clearance Rate
  • Nausea / chemically induced
  • Positron-Emission Tomography / methods
  • Purines / blood
  • Purines / pharmacokinetics
  • Purines / therapeutic use*
  • Tissue Distribution
  • Tomography, X-Ray Computed
  • Treatment Outcome
  • Weight Loss / drug effects


  • Antineoplastic Agents
  • Dideoxynucleosides
  • Purines
  • rabacfosadine
  • Alanine
  • alovudine