Amifostine increases cure rate of cisplatin on ascites hepatoma 22 via selectively protecting renal thioredoxin reductase

It has been demonstrated via in vitro experiments that the anti-cancer drug cisplatin (CDDP) can inactivate thioredoxin reductase (TrxR), a molecular target for cancer therapy. The present study in mice revealed that CDDP at pharmacological doses inhibited TrxR activity in both ascitic hepatoma 22 (H22) cells and kidney, leading to suppression of H22 cells proliferation along with nephrotoxicity. Amifostine, a clinical used cytoprotective agent, protected against CDDP-induced TrxR inactivation in kidney but not in H22 cells. Such an excellent selective modulation of amifostine on TrxR led us to exploit the potential of amifostine in increasing cure rate of CDDP on cancer. In mice, CDDP at the doses of 5 and 7.5 mg/kg once weekly for 4 weeks could not completely control H22 ascites development and the cure rate was no more than 12.5%; CDDP 9 mg/kg by the same schedule prominently suppressed the ascites development, but finally resulted in 87.5% mortality caused by CDDP toxicity. Thus, these dose-dependent therapeutic results well recapitulated the clinical dilemma of chemotherapy on cancer. However, co-treatment of CDDP (9 mg/kg) and amifostine largely reduced CDDP toxicity, and obtained a cure rate as high as 87.5%. Overall, the present study demonstrates both pharmacological and toxicological effects of CDDP involve TrxR inactivation, and the large enhancement on CDDP cure rate in H22 ascites model by using amifostine is, at least in part, ascribed to its selective modulation on TrxR.