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.

Assessment of GS-9219 in a Pet Dog Model of Non-Hodgkin's Lymphoma

“…Evaluation of GS-9219 in normal beagle dogs previously showed, at doses that were generally well tolerated, selective depletion of replicative lymphoid tissues while sparing other tissues. Preliminary antineoplastic activity in dogs with naturally occurring non-Hodgkin's lymphoma has also been shown (6).…”

“…However, the utility of PMEG as an anticancer agent is limited by its poor cellular permeability and nonspecific toxicity, especially for the kidney and gastrointestinal tract (3)(4)(5). GS-9219, a novel double prodrug of PMEG, was designed as a cytotoxic agent that preferentially targets lymphoid cells (6). In lymphocytes, GS-9219 is hydrolyzed intracellularly to 9-(2-phosphonylmethoxyethyl)-N 6 -cyclopropyl-2,6-diaminopurine (cPrPMEDAP) and subsequently deaminated to PMEG.…”

“…In lymphocytes, GS-9219 is hydrolyzed intracellularly to 9-(2-phosphonylmethoxyethyl)-N 6 -cyclopropyl-2,6-diaminopurine (cPrPMEDAP) and subsequently deaminated to PMEG. PMEG is then converted to its active phosphorylated form, PMEG diphosphate (6). The fact that rodents, unlike humans or dogs, have high plasma levels of carboxyesterase, which rapidly metabolizes GS-9219, precluded their use in preclinical models (7).…”

The clinical potential of the acyclic (and cyclic) nucleoside phosphonates. The magic of the phosphonate bond

“…These antitumor effects were not further explored, however. Instead, two phosphonoamidate prodrugs of cPrPMEDAP, namely GS-9191 and [63]. In both cases, the active cytotoxic agent is PMEG (first described by De Clercq et al [3]) which, like all other ANPs, has to be converted to its diphosphate, PMEGpp, before being able to interact, as chain terminator, in the DNA polymerase reaction.…”

Point mutations in human guanylate kinase account for acquired resistance to anticancer nucleotide analogue PMEG

“…1) represent the ANP with enhanced cytotoxic properties and possible use as novel antitumor compounds [3,4]. PMEG, in a form of a double prodrug GS-9219, has been previously shown to be active against NonHodgkin's lymphoma in dogs [5], while PMEDAP significantly prolonged survival of SD-rats with spontaneous lymphoma [6]. The advantage of ANP over conventional nucleotides lies in the chemical and metabolic stability of phosphonic bond.…”