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 radioprotective and chemoprotective effects in mice. Following phase-I studies, preliminary results from phase-II clinical trials on non-small-cell-lung-cancer patients showed a reduction in the severity of alopecia in patients treated with AS101 in combination with chemotherapy. To further substantiate these findings, the present study was extended to include 58 patients treated either with the optimal dose of 3 mg/m2 AS101 combined with carboplatin and VP-16, or with chemotherapy alone. As compared with patients treated with chemotherapy alone, there was a significant decrease in the level of alopecia in patients receiving the combined therapy. The newly developed rat model was used to elucidate the protective mechanism involved in this effect. We show that significant prevention of chemotherapy-induced alopecia is obtained in rats treated with Ara-C combined with AS101, administered i.p. or s.c. or applied topically to the dorsal skin. We show that this protection by AS101 is mediated by macrophage-derived factors induced by AS101. Protection by AS101 can be ascribed, at least in part, to IL-1, since treatment of rats with IL-1 RA largely abrogated the protective effect of AS101. Moreover, we demonstrate that in humans there is an inverse correlation between the grade of alopecia and the increase in IL-1 alpha. In addition, protection by AS101 could be related to PGE2 secretion, since injection of indomethacin before treatment with AS101 and Ara-C partly abrogated the protective effect of AS101. To assess the ability of AS101 to protect against chemotherapy-induced alopecia, phase-II clinical trials have been initiated with cancer patients suffering from various malignancies.
C.A.I.R. Institute, Marilyn Finkler Cancer Research Center, Bar Ilan University, Ramat Gan, Israel.
B
B
Sredni
R H
RH
Xu
M
M
Albeck
U
U
Gafter
R
R
Gal
A
A
Shani
T
T
Tichler
J
J
Shapira
I
I
Bruderman
R
R
Catane
B
B
Kaufman
J K
JK
Whisnant
K L
KL
Mettinger
Y
Y
Kalechman
D000505:Alopecia / Q000139:chemically induced*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D003561:Cytarabine / Q000494:pharmacology; D016207:Cytokines / Q000502:physiology; D015232:Dinoprostone / Q000502:physiology; D005030:Ethylenes / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000502:physiology; D008175:Lung Neoplasms / Q000188:drug therapy*; D008264:Macrophages / Q000502:physiology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012795:Sialoglycoproteins / Q000494:pharmacology
D016207:Cytokines; D005030:Ethylenes; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012795:Sialoglycoproteins; D003561:Cytarabine; C054105:ammonium trichloro(dioxoethylene-O,O'-)tellurate; D015232:Dinoprostone; D007213:Indomethacin