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

Clin Cancer Res. 2008 May 1;14(9):2824-32. doi: 10.1158/1078-0432.CCR-07-2061.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


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