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


METHODS
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.


CONCLUSIONS
GS-9219 may have utility for the treatment of NHL.
Reiser
Hans
H
Department of Research and Development, Gilead Sciences, Inc., Foster City, California 94404, USA. hans.reiser@gilead.com
Wang
Jianying
J
Chong
Lee
L
Watkins
William J
WJ
Ray
Adrian S
AS
Shibata
Riri
R
Birkus
Gabriel
G
Cihlar
Tomas
T
Wu
Sylvia
S
Li
Bei
B
Liu
Xiaohong
X
Henne
Ilana N
IN
Wolfgang
Grushenka H I
GH
Desai
Manoj
M
Rhodes
Gerald R
GR
Fridland
Arnold
A
Lee
William A
WA
Plunkett
William
W
Vail
David
D
Thamm
Douglas H
DH
Jeraj
Robert
R
Tumas
Daniel B
DB
D000409:Alanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D006147:Guanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D008221:Lymphoid Tissue / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D009943:Organophosphorus Compounds / Q000627:therapeutic use; D011355:Prodrugs / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011687:Purines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D009943:Organophosphorus Compounds; D011355:Prodrugs; D011687:Purines; C531423:rabacfosadine; C063380:9-((2-phosphonylmethoxy)ethyl)guanine; D006147:Guanine; D000409:Alanine