The protective role of the immunomodulator AS101 against chemotherapy-induced alopecia studies on human and animal models

Abstract

The immunomodulator AS I0 I has been demonstrated to exhibit radioprotective and chemoprotective effects in mice. Following phase-I studies, preliminary resulk from phase-ll clinical trials on non-small-cell-lung-cancer patients showed a reduction in the severity of alopecia in patients treated with A S l O l in combination with chemotherapy. To further substantiate these findings, the present study was extended to include 58 patienk treated either with the optimal dose of 3 mg/rn2 AS I0 I combined with carboplatin and VP-16, or with chemotherapy alone. As compared with patienk 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 AS 10 I, administered i.p. or S. C. or applied topically to the dorsal skin. We show that this protection by AS I0 I is mediated by macrophage-derived factors induced by AS I0 I. Protection by AS I0 I can be ascribed, at least in part, to IL-I, since treatment of rats with IL-IRA largely abrogated the protective effect of AS I0 I. Moreover, we demonstrate that in humans there is an inverse correlation between the grade of alopecia and the increase in IL-la. In addition, protection by A S l O l could be related to PGE2 secretion, since injection of indomethacin before treatment with AS I0 I and Ara-C partly abrogated the protective effect of AS 10 I. To assess the ability of AS 10 I to protect against chemotherapy-induced alopecia, phase-ll clinical trials have been initiated with cancer patienk suffering from various malignancies.o 1996 Wiley-Liss, Inc.The psychological impact of chemotherapy-induced alopecia represents one of the more devastating side effects of cancer chemotherapy and, in some instances, leads patients to refuse potentially curative chemotherapy (Hood, 1986). Although this complication has been known for many decades, little progress has been made in its prevention or treatment (Wood, 1985), in part because of lack of a suitable, reproducible experimental model. A new model has now been developed in which chemotherapy induces total alopecia in 8-dayold rats (Hussein et al., 1990). This model enables the investigation of agents that might protect against chemotherapyinduced alopecia, and the elucidation of their mechanism of action.The immunomodulator ASlOl [ammonium trichloro (dioxyethylene-0,O') tellurate] has been shown by us to exhibit radioprotective properties when injected into mice prior to sub-lethal and lethal doses of irradiation (Kalechman et al., 1990). In addition, AS101 was found to protect mice from hemopoietic damage caused by sub-lethal doses of various chemotherapeutic drugs, and to increase the rate of survival of mice treated with lethal doses of these agents. These include cyclophosphamide (Kalechman et al., 1991a), 5-FU (Kalechman et al., 1991b)...

A Novel Organotellurium Compound (RT-01) as a New Antileishmanial Agent

“…The antimonial compounds, the first choice treatment to all forms of leishmaniasis has the disadvantage of both toxicity (pancreatitis, cardiotoxicity, hematological disorders, and skeletal muscle toxicity) and clinical resistance where they have been used for a long time [3,4]. Although a toxicity profiles of are not yet established, it can be expected that RT-01 may present similar non-or low toxicity as other organotellurane compounds due to lack of apparent toxicity of RT-01 in mice as reported in this study, excellent safety profile on clinical trials for cancer of other organotelluranes and the common tellurium-thiol chemistry of these compounds [8,13,14,21].…”

“…Organotellurane compounds present protease inhibition activity, which is specific for cysteine proteases, like papain and cathepsin B [7,8]. Various tellurane compounds have been described as presenting tumoricidal, antiviral, anti-protozoan parasite Babesia rodhaini activities, and immunomodulatory properties [7][8][9][10][11][12][13][14]21]. In addition to their effects, tellurium containing-compounds are characterized by low toxicity [8,13,14].…”

“…Several tellurides show antioxidative and immunomodulating proprieties and antitumor activities [5][6][7][8][9][10][11][12]. Clinical trials with a tellurane compound are presently underway [13,14]. The synthetic organotellurane compound RT-01 ( Fig.…”

Six cases of permanent alopecia after various conditioning regimens commonly used in hematopoietic stem cell transplantation

“…There are no approved preventative treatments for CIA in humans although several experimental and pharmacological approaches are under evaluation. Treatments to prevent or minimize alopecia include physical means such as scalp tourniquets (no longer used due to patient discomfort) 20 and scalp hypothermia, 11,21 and pharmacologic means that include topical vitamin D 3 analogue, 22 AS101, 23 Minoxidil [24][25][26] or Cs 27,28 and other experimental drugs. 19 Most of these treatments have either limited or very selective activity or have not been tested in humans yet.…”

Redox Modulation of Adjacent Thiols in VLA-4 by AS101 Converts Myeloid Leukemia Cells from a Drug-Resistant to Drug-Sensitive State

“…AS101, an organotellurium(IV) compound previously (13,14) used in Phase II clinical trials in patients with cancer, is a potent immunomodulator with a variety of potential therapeutic applications (15)(16)(17). The compound has been shown to have beneficial effects in diverse preclinical and clinical studies (13,14,18).…”