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

Hans Reiser, Jianying Wang, Lee Chong, William J. Watkins, Adrian S. Ray, Riri Shibata, Gabriel Birkus, Tomas Cihlar, Sylvia Wu, Bei Li, Xiaohong Liu, Llana N. Henne, Grushenka H.I. Wolfgang, Manoj Desai, Gerald R. Rhodes, Arnold Fridland, William A. Lee, William Plunkett, David Vail, Douglas H. Thamm & 2 others Robert Jeraj, Daniel B. Tumas

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Abstract

Purpose: GS-9219, a novel prodrug of the nucleotide analogue 9-(2-phosphonylmethoxyethyI) 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.

LanguageEnglish (US)
Pages2824-2832
Number of pages9
JournalClinical Cancer Research
Volume14
Issue number9
DOIs
StatePublished - May 1 2008

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Antineoplastic Agents
Non-Hodgkin's Lymphoma
Nucleotides
Dogs
Guanine
Lymphocytes
Germinal Center
Pharmacokinetics
Prodrugs
GS-9219
Deamination
Diphosphates
Pets
Cytotoxins
Lymphoid Tissue
Tumor Cell Line
Hydrolysis
Research Design
Lymph Nodes
Phosphorylation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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GS-9219-A novel acyclic nucleotide analogue with potent antineoplastic activity in dogs with spontaneous non - Hodgkin's lymphoma. / Reiser, Hans; Wang, Jianying; Chong, Lee; Watkins, William J.; Ray, Adrian S.; Shibata, Riri; Birkus, Gabriel; Cihlar, Tomas; Wu, Sylvia; Li, Bei; Liu, Xiaohong; Henne, Llana N.; Wolfgang, Grushenka H.I.; Desai, Manoj; Rhodes, Gerald R.; Fridland, Arnold; Lee, William A.; Plunkett, William; Vail, David; Thamm, Douglas H.; Jeraj, Robert; Tumas, Daniel B.

In: Clinical Cancer Research, Vol. 14, No. 9, 01.05.2008, p. 2824-2832.

Research output: Contribution to journalArticle

Reiser, H, Wang, J, Chong, L, Watkins, WJ, Ray, AS, Shibata, R, Birkus, G, Cihlar, T, Wu, S, Li, B, Liu, X, Henne, LN, Wolfgang, GHI, Desai, M, Rhodes, GR, Fridland, A, Lee, WA, Plunkett, W, Vail, D, Thamm, DH, Jeraj, R & Tumas, DB 2008, 'GS-9219-A novel acyclic nucleotide analogue with potent antineoplastic activity in dogs with spontaneous non - Hodgkin's lymphoma' Clinical Cancer Research, vol. 14, no. 9, pp. 2824-2832. https://doi.org/10.1158/1078-0432.CCR-07-2061
Reiser, Hans ; Wang, Jianying ; Chong, Lee ; Watkins, William J. ; Ray, Adrian S. ; Shibata, Riri ; Birkus, Gabriel ; Cihlar, Tomas ; Wu, Sylvia ; Li, Bei ; Liu, Xiaohong ; Henne, Llana N. ; Wolfgang, Grushenka H.I. ; Desai, Manoj ; Rhodes, Gerald R. ; Fridland, Arnold ; Lee, William A. ; Plunkett, William ; Vail, David ; Thamm, Douglas H. ; Jeraj, Robert ; Tumas, Daniel B. / GS-9219-A novel acyclic nucleotide analogue with potent antineoplastic activity in dogs with spontaneous non - Hodgkin's lymphoma. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 9. pp. 2824-2832.
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abstract = "Purpose: GS-9219, a novel prodrug of the nucleotide analogue 9-(2-phosphonylmethoxyethyI) 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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T1 - GS-9219-A novel acyclic nucleotide analogue with potent antineoplastic activity in dogs with spontaneous non - Hodgkin's lymphoma

AU - Reiser, Hans

AU - Wang, Jianying

AU - Chong, Lee

AU - Watkins, William J.

AU - Ray, Adrian S.

AU - Shibata, Riri

AU - Birkus, Gabriel

AU - Cihlar, Tomas

AU - Wu, Sylvia

AU - Li, Bei

AU - Liu, Xiaohong

AU - Henne, Llana N.

AU - Wolfgang, Grushenka H.I.

AU - Desai, Manoj

AU - Rhodes, Gerald R.

AU - Fridland, Arnold

AU - Lee, William A.

AU - Plunkett, William

AU - Vail, David

AU - Thamm, Douglas H.

AU - Jeraj, Robert

AU - Tumas, Daniel B.

PY - 2008/5/1

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N2 - Purpose: GS-9219, a novel prodrug of the nucleotide analogue 9-(2-phosphonylmethoxyethyI) 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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