Rabacfosadine (GS-9219), a novel proagent 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 EC 50 values 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 EC 50 values of Rabacfosadine in quiescent (EC 50 =17.2 μM) and proliferating (EC 50 =135 nM) cells. These results indicate a substantial selectivity of Rabacfosadine toward actively replicating lymphoblasts. MCE has not independently confirmed the accuracy of these methods. They are for reference only.
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/m 2 IV 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. MCE has not independently confirmed the accuracy of these methods. They are for reference only.
Animal administration
Dogs Dogs are given alternating doses of Rabacfosadine and Doxorubicin every 3 weeks. Rabacfosadine is administered at a dosage of 1.0 mg/kg as a 30-minute IV infusion on weeks 0, 6, and 12. Doxorubicin is administered at a dosage of 30 mg/m 2 (1.0 mg/kg for dogs weighing <15 kg) as an approximately 20-minute IV infusion on weeks 3, 9, and 15. Concurrent cytotoxic chemotherapy of any kind and concurrent corticosteroids are not allowed. A CBC is performed 1 week after the first Rabacfosadine and Doxorubicin treatments (weeks 1 and 4). All dogs have a physical examination with lymph node measurements, owner history, CBC, serum biochemistry profile (SBC), and urinalysis performed at each chemotherapy visit. Thoracic radiographs are recommended at week 15 and approximately every 2 months thereafter in responding dogs. Dose delays, reductions, or both, and supportive treatment for AEs are carried out at the discretion of the attending clinician. Dogs that experienced a complete response (CR) are followed with monthly physical examinations after week 15 until relapse, when they are considered off study. Dogs that experienced partial response (PR) or stable disease (SD) at week 15 are considered off study and censored from analysis at that time. At the time of study withdrawal, dogs are eligible for additional treatment at the discretion of the attending clinician. aladdin has not independently confirmed the accuracy of these methods. They are for reference only.
Form:Solid
