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 Ilana 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
Department of Research and Development, Gilead Sciences, Inc., Foster City, California 94404, USA.
Clin Cancer Res. 2008 May 1;14(9):2824-32. doi: 10.1158/1078-0432.CCR-07-2061.
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.
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.
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.
GS-9219 may have utility for the treatment of NHL.
GS - 9219是核苷酸类似物9 -（2 - 膦酰甲氧基乙基）鸟嘌呤（PMEG）的新型前药，被设计为一种优先靶向淋巴细胞的细胞毒性药物。我们的目标是表征GS - 9219的抗增殖活性、药代动力学、药效学和安全性。
通过增殖试验筛选和药代动力学筛选选择了GS - 9219。在淋巴细胞中表征了GS - 9219的激活途径，并针对一系列造血和非造血细胞类型评估了其细胞毒性活性。为了测试GS - 9219中存在的前药部分在体内是否比PMEG具有优势，在静脉内给予正常比格犬后，评估了等摩尔剂量的GS - 9219和PMEG的药代动力学、药效学（淋巴结生发中心耗竭）和毒性。最后，在五只患有自发性晚期非霍奇金淋巴瘤（NHL）的宠物犬中，评估了单次静脉内给予GS - 9219作为单一疗法的抗肿瘤疗效的概念验证。
在淋巴细胞中，GS - 9219通过酶促水解、脱氨和磷酸化转化为其活性代谢物PMEG二磷酸。GS - 9219对活化淋巴细胞和造血肿瘤细胞系具有显著的抗增殖活性。相比之下，静息淋巴细胞和实体瘤细胞系对GS - 9219不太敏感。GS - 9219而非PMEG在可耐受剂量下使正常比格犬淋巴组织中的生发中心耗竭。此外，单次给药后，GS - 9219在五只患有自发性NHL的犬中显示出显著的体内疗效，不良事件为无或低级别。
GS - 9219可能对NHL的治疗有用。
