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 (AS101) has been shown to possess antitumoral properties in several murine models. In the present study, we demonstrate a synergistic in vivo antitumor effect of AS101 and Taxol against early stage Madison 109 lung 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 propose that the antitumor effect is the result of both a direct and indirect effect of the drugs on tumor cells. AS101 and Taxol directly inhibited clonogenicity of M109 cells in a synergistic dose-dependent manner. Exposure of M109 cells to clinically achievable concentrations of Taxol 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 in particular, partly by increasing the wild-type p53 protein expression that is required for efficient execution of the death program. Moreover, we demonstrate a synergistic effect of AS101 and Taxol in increasing the tumoricidal activity of macrophages. This activity is produced by nitric oxide secretion. The synergistic antitumoral effects of AS101 and Taxol were partly ablated both in vitro and in vivo by inhibition of nitric oxide synthase. These findings indicate that AS101 in combination with Taxol may be a promising antitumor drug, and illustrate the mechanism of action of both drugs when acting synergistically. Phase II clinical trials have been initiated using AS101 in combination with Taxol.
Kalechman
Y
Y
C.A.I.R. Institute, Marilyn Finkler Cancer Research Center, Bar llan University, Ramat Gan, Israel.
Shani
A
A
Dovrat
S
S
Whisnant
J K
JK
Mettinger
K
K
Albeck
M
M
Sredni
B
B
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005030:Ethylenes / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D005030:Ethylenes; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide; C054105:ammonium trichloro(dioxoethylene-O,O'-)tellurate; D017239:Paclitaxel