THE PROTECTIVE ROLE OF THE IMMUNOMODULATOR AS101 AGAINST CHEMOTHERAPY-INDUCED ALOPECIA STUDIES ON HUMAN AND ANIMAL-MODELS

The immunomodulator AS101 has been demonstrated to exhibit radioprotec tive and chemoprotective effects in mice. Following phase-I studies, p reliminary results from phase-II clinical trials on non-small-cell-lun g-cancer patients showed a reduction in the severity of alopecia in pa tients treated with AS101 in combination with chemotherapy. To further substantiate these findings, the present study was extended to includ e 58 patients treated either with the optimal dose of 3 mg/m(2) AS101 combined with carboplatin and VP-16, or with chemotherapy alone. As co mpared with patients treated with chemotherapy alone, there was a sign ificant decrease in the level of alopecia in patients receiving the co mbined therapy. The newly developed rat model was used to elucidate th e protective mechanism involved in this effect. We show that significa nt prevention of chemotherapy-induced alopecia is obtained in rats tre ated with Ara-C combined with AS101, administered i.p. or s.c. or appl ied topically to the dorsal skin. We show that this protection by AS10 1 is mediated by macrophage-derived factors induced by AS101. Protecti on by AS101 can be ascribed, at least in part, to IL-1, since treatmen t of rats with IL-IRA largely abrogated the protective effect of AS101 . Moreover, we demonstrate that in humans there is an inverse correlat ion between the grade of alopecia and the increase in IL-1 alpha. In a ddition, protection by AS101 could be related to PGE2 secretion, since injection of indomethacin before treatment with AS101 and Ara-C partl y abrogated the protective effect of AS101. To assess the ability of A S101 to protect against chemotherapy-induced alopecia, phase-II clinic al trials have been initiated with cancer patients suffering from vari ous malignancies. (C) 1996 Wiley-Liss, Inc.