THE ANTITUMORAL EFFECT OF THE IMMUNOMODULATOR AS101 AND PACLITAXEL (TAXOL) IN A MURINE MODEL OF LUNG ADENOCARCINOMA

The immunomodulator ammonium trichloro(dioxyethylene-0-0')tellurate (A S101) has been shown to possess antitumoral properties in several muri ne models, In the present study, we demonstrate a synergistic in vivo antitumor effect of AS101 and Taxol against early stage Madison 109 lu ng adenocarcinoma, Treatment with optimal doses of Taxol (25 and 17 mg /kg) and AS101 (0.5 mg/kg) resulted in 66.6 and 43.3% cures, We propos e that the antitumor effect is the result of both a direct and indirec t effect of the drugs on tumor cells, AS101 and Taxol directly inhibit ed clonogenicity of M109 cells in a synergistic dose-dependent manner. Exposure of M109 cells to clinically achievable concentrations of Tax ol and AS101 produced a synergistic internucleosomal DNA fragmentation associated with programmed cell death. We suggest that AS101 renders tumor cells more susceptible to chemotherapy in general and to Taxol i n particular, partly by increasing the wild-type p53 protein expressio n that is required for efficient execution of the death program, Moreo ver, we demonstrate a synergistic effect of AS101 and Taxol in increas ing the tumoricidal activity of macrophages. This activity is produced by nitric oxide secretion, The synergistic antitumoral effects of AS1 01 and Taxol were partly ablated both in vitro and in vivo by inhibiti on of nitric oxide synthase, These findings indicate that AS101 in com bination with Taxol may be a promising antitumor drug, and illustrate the mechanism of action of both drugs when acting synergistically, Pha se II clinical trials have been initiated using AS101 in combination w ith Taxol.