The protective role of ammonium trichloro(dioxoethylene-O,O')tellurate in combination with several cytotoxic drugs acting by different mechanisms of action.
We have demonstrated previously that the immunomodulator AS101 can protect mice from acute lethal toxicity mediated by high doses of radiation or chemotherapy. The compound was shown to rescue mice from toxic effects of cyclophosphamide or 5-fluorouracil. The results presented herein demonstrate that pretreatment of mice with AS101 protects them from lethal effects of several chemotherapeutic drugs acting by distinct mechanisms. At sublethal doses, AS101 could prevent hemopoietic damage caused by the drugs. A significantly higher proportion of colony forming cells granulocyte-macrophage as well as a higher level of colony stimulating factor secretion by bone marrow (BM) cells was observed in mice pretreated with AS101 before injection of doxorubicin or cyclohexylchloroethylnitrosourea. Moreover, a significantly higher rate of survival was observed in mice injected with AS101 before treatment with lethal doses of these drugs. AS101 could also rescue BM stromal cells from damages caused by doxorubicin. We show that injection of mice with AS101 or pretreatment of BM cells with AS101 protects BM-colony forming cells granulocyte-macrophage from toxic effects of etoposide. We suggest that the protective effects of AS101 against damages caused by a variety of cytotoxic drugs may be attributed to the ability of the compound to expand the colony forming unit spleen subpopulation of early progenitors, those cells that are resistant to several DNA damaging agents and are the precursor cells essential for reconstitution of the hemopoietic system. It seems that AS101, by minimizing adverse cytotoxicity resulting from a variety of drugs, is a promising candidate for chemoimmunotherapy with cancer patients.
Kalechman
Y
Y
Department of Life Sciences, Bar Ilan University, Ramat Gan, Israel.
Shani
A
A
Sotnik-Barkai
I
I
Albeck
M
M
Sredni
B
B
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003115:Colony-Stimulating Factors / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D005030:Ethylenes / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D008130:Lomustine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D003115:Colony-Stimulating Factors; D005030:Ethylenes; D005047:Etoposide; C054105:ammonium trichloro(dioxoethylene-O,O'-)tellurate; D008130:Lomustine; D004317:Doxorubicin