"目录号: HY-13640
Rabacfosadine (GS-9219) 是核苷类似物 PMEG 的新型前药，用作优先靶向淋巴细胞的细胞毒性剂。
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生物活性
Description
Rabacfosadine (GS-9219), a novel prodrug of the nucleotide analogue PMEG, is designed as a cytotoxic agent that preferentially targets lymphoid cells.
In Vitro
In lymphocytes, Rabacfosadine (GS-9219) is converted to its active metabolite, 9-(2-phosphonylmethoxyethyl)guanine (PMEG) diphosphate, via enzymatic hydrolysis, deamination, and phosphorylation. GS-9219 has substantial antiproliferative activity against activated lymphocytes and hematopoietic tumor cell lines. The ability of Rabacfosadine to inhibit the proliferation of activated lymphocytes and of tumor cells of hematopoietic origin is investigated. Rabacfosadine inhibits the proliferation of mitogen-stimulated T and B lymphocytes with EC50values of 135 and 42 nM, respectively, as determined by BrdUrd incorporation. To compare the activity of GS-9219 in dividing and nondividing cells, Rabacfosadine is evaluated in these populations using a metabolism-based sodium XTT assay instead of BrdUrd assays. Results from the XTT assay shows a 127-fold difference between the EC50values of Rabacfosadine in quiescent (EC50=17.2 μM) and proliferating (EC50=135 nM) cells. These results indicate a substantial selectivity of Rabacfosadine toward actively replicating lymphoblasts[1].
In Vivo
Rabacfosadine (RAB) has substantial single-agent activity in dogs with lymphoma, and a different mechanism of action than Doxorubicin (DOX). Open-label, multicenter prospective clinical trial. Dogs receive alternating Rabacfosadine (1.0 mg/kg IV weeks 0, 6, 12) and Doxorubicin (30 mg/m2IV weeks 3, 9, 15). Dogs that achieved complete response (CR) are followed by monthly evaluations. Complete clinicopathological evaluation and assessment of remission and adverse event (AEs) are performed every 21 days. Acute AEs, occurring within 21 days after administration of the first dose of each agent, are compared between Rabacfosadine and Doxorubicin in 46 dogs receiving at least 1 dose of each agent[2].
Clinical Trial
Gilead Sciences
Non-Hodgkin's Lymphoma-Chronic Lymphocytic Leukemia-Multiple Myeloma
July 2007
Phase 1-Phase 2
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