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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GS-9191 is a novel double prodrug of the nucleotide analog 9-(2-phosphonylmethoxyethyl)guanine (PMEG) designed as a topical agent to permeate skin and be metabolized to the active nucleoside triphosphate analog in the epithelial layer. The prodrug was shown to be metabolized intracellularly to 9-(2-phosphonylmethoxyethyl)-N 6 -cyclopropyl-2,6,diaminopurine (cPrPMEDAP) and subsequently deaminated to PMEG. The active form, PMEG diphosphate, was shown to be a potent inhibitor of DNA polymerase ␣ and ß while showing weaker activity against mitochondrial DNA polymerase ␥ (50% enzyme inhibition observed at 2.5, 1.6, and 59.4 M, respectively). GS-9191 was markedly more potent than PMEG or cPrPMEDAP in a series of human papillomavirus ( Human papillomaviruses (HPV) cause proliferative lesions in the skin and squamous mucosa, predominantly in the form of hyperplasias, papillomas, and condylomas. Currently recommended treatments for HPV-mediated diseases include patient-applied treatments (podofilox gel or imiquimod cream), provider-applied treatments (cryotherapy, podophyllin resin, and trichloroacetic acid), or surgical removal of the lesion (infrared coagulation, laser surgery, and a loop electrical excision procedure) (5). The primary pharmacological therapy for external anogenital warts is topically applied imiquimod cream (Aldara), a nucleoside-like compound that acts as an immune response modifier. This therapy has limited efficacy in males relative to females (33% versus 72%, respectively), a high incidence of recurrence, local tolerability issues, and a relatively long duration of treatment (up to 16 weeks) (26). Podofilox gel (Condylox package insert; Watson Pharmaceuticals, Inc., Corona, CA), which is also applied externally, is an antiproliferative agent (antimitotic agent) with similar efficacy as imiquimod (12,27,28). Cidofovir, a nucleotide analog with antiproliferative and antiviral activity (1), has been tested as a potential treatment for anogenital warts and has shown positive effects (25; also J. Douglas, T. Corey, S Tyring, J. Kreisel, B. Bowden, D. Crosby, T. Berger, M. Conant, B. McGuire, H. S. Jaffe, presented at the 4th Conference on Retroviruses and Opportunistic Infections, Washington DC, 22 to 26 January, 1997). While the existing antiproliferative agents have proven therapeutic utility, there is a need for new agents that are better tolerated and have an improved response rate and/or a shorter duration of treatment.The acyclic nucleotide, 9-(2-phosphonylmethoxyethyl)guanine (PMEG) forms an active phosphorylated metabolite, PMEG diphosphate (PMEG-DP), in cells, which inhibits the growth of various transformed cell lines due to potent inhibition of the nuclear DNA polymerases ␣, ␦ and ε, resulting in inhibition of DNA synthesis and/or DNA repair (15,16,21). In animal models, PMEG has antiproliferative effects; however, the utility of PMEG as an antiproliferative agent is limited by its poor cellular permeability and toxicity (18,23). An N 6 -substituted prodrug of PMEG, 9-(2-phosphonylmethoxyeth...

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