Mechanism of the antitumor effect of the immunodmodulator AS101 and prevention by AS101 of bone-marrow toxicity when administered with taxol

Extensive research has been conducted on the anitmltotic, antitumor drug, Taxol, found to be effective in treating refractory ovarian cancer and to have considerable clinical potential in treating breast, lung and other cancers. The immunomodulator AS101 has recently been shown to act in synergy with various chemotherapeutic drugs to produce an antitumor effect in murine models and to prevent adverse effects of cytotoxic drugs in mice and cancer patients. The present study was designed to evaluate the ability of AS101 to spare BM toxicity in normal or B16 melanoma tumor-bearing mice treated with a combination of Taxol and AS101, and to partly elucidate the mechanism of their synergistic antitumor effect. We demonstrate that treatment with AS101 24 hours before the first of three injections of Taxol (25mg/kg/injection every other day) significantly increased the number of circulating white blood cells and platelets. Neutrophil and lymphocyte numbers were significantly increased in AS101-treated mice receiving chemotherapy. AS101 also increased the number of GM progenitors in the BM and prevented the decrease in IL-6 and GM-CSF. We show that in vitro treatment of B16 melanoma or human SK-28 melanoma cells with AS101 or Taxol inhibited tumor growth in a dose-dependent manner. Combined treatment (Taxol+AS101) induced a synergistic inhibition which was accompanied by an increase in protein expression of the cyclin-dependent kinase inhibitor p21 WAF1 and activation of MAP kinase. Previous depletion of c-raf-1 inhibited both p21 WAF1 induction and activation of MAP kinase. These findings suggest that the synergistic inhibition of Taxol and AS101, accompanied by p21 WAF1 induction and activation of MAP kinase, is dependent on c-raf-1 expression.