WR-1065, a dephosphorylated metabolite of amifostine?(Ethyol), can protect against the immediate and delayed effects of radiation exposure.
WR-1065 can protect against zidovudine (AZT) – induced genetoxicity. The lymphoblastoid cell line MOLT-3 cells were exposed to 0/10μM AZT for 96h. In the first 24h 0/5?μM WR-1065 was added and Cyt B was added in 76h in the cells, the viability of AZT treated MOLT-3 cells did not altered.[1] Moreover, in RKO36 cell lines (derivative RKO human colorectal carcinoma carrying a GFP-pCMV-EGFP2Xho), 4 mM final concentration (EC50) WR-1065 treatment for 30min immediately before irradiation showed protective effects against cell chromosomal damage and death induced by ionizing radiation and delayed genomic instability. But 40??M WR-1065 did not show immediate radio-protective effects in irradiated RKO36 cells.[2] WR-1065 acts as radioprotective agents mainly through suppression of the homologous recombination pathway. In SPD8 Chinese hamster cell line, both 4 mM WR-1065 for 30min and 10 ?M for 24h significantly reduced the homologous recombination induced by 0.2 mM Hydroxyurea for 24h or 100 nM camptothecin for 1h. While WR-1065 did not show its radioprotective effects in irradiated homologous recombination-deficient irs 1SF cells compared with homologous recombination-proficient cells AA8/CXR3(P＜0.05).[3]
With spray drying technique using PLGA (polylactide co-glycolide) as the polymer matrix, WR-1065 were prepared into nanoparticles. 500mg/kg WR-1065/PLGA nanoparticles in which containing 21.7(w/w WR-1065) were administrated orally in mice to determined its radio-protective role. WR-1065PLGA nanoparticles treatment mice showed noteworthy higher 30-day survival, less bone marrow suppression and less intestinal injury compared non-treated control mice, indicated its significant radio-protective effects.[4]
References:
[1]. Ofelia A . Olivero, Michael O. Ong, Han nan M. Braun, Ariadna Marrogi, Kathyiani Divi, James B. Mitchel l, and Miriam C. Poirier. Selective protection of zidovadine-induced DNA-damage by antioxidants WR-1065 and tempol. Environmental and Molecular Mutagenesis (2014)55: 566-572
[2]. Jaroslaw Dziegielewski, Janet E. Baulch, Wilfried Goetz, Mitchell C. Coleman, Douglas R. Spitz, Jeffrey S. Murley, David J. Grdina, and William F. Morgan. WR-1065, the active metabolite of amifostine, mitigates radiation-induced delayed genomic instability. Free Radic Biol Med. (2008)45(12): 1674–1681
[3]. Jaroslaw Dziegielewski, Wilfried Goetz, Jeffrey S. Murley, David J. Grdina, William F. Morgan, and Janet E. Baulch. Amifostine Metabolite WR-1065 Disrupts Homologous Recombination in Mammalian Cells. Radiat Res. (2010) 173(2): 175–183
[4]. Sarala Pamujula,?Vimal Kishore,?Barbara Rider,?Krishna C. Agrawal, and?Tarun K. Mandal. Radioprotection in mice following oral administration of WR-1065/PLGA nanoparticles. (2008) 84(11): 900-908