Enhanced tolerance to high cytostatic doses by means of oligoelements Mn, Se, and Zn plus Lachesis muta venom: In vivo and in vitro studies

We evaluated, in vivo and in vitro, the increased tolerance to treatment with high doses of chemotherapeutic drugs produced by the administration of oligoelements (Zn, Se, Mn) plus Lachesis muta venom (O-LM). Cyclophosphamide, methotrexate, and 5-fluoruracil (CMF) were administrated to male rats treated daily with O-LM. The doses of CMF tested covered from 1- to 20-fold the dose used in human patients. Human neoplastic and normal cell lines were challenged in vitro with increasing doses of 5-fluoruracil (5-FU) in the presence and absence of O-LM. Results indicated a significantly higher global survival in O-LM-treated rats versus Control rats. LD50 in O-LM rats was 18.5-fold the basic CMF dose versus 14.1 in controls. Eighty percent of Control rats showed severe bone marrow aplasia, sepsis, and secondary leukemia, while only 20% of O-LM-treated rats showed these effects and no leukemia cases were observed. O-LM treatment produced a significant inhibition of cell proliferation of malignant cells, while in normal cells O-LM increased colony formation. In transformed cells, the cytostatic effect of 5-FU was significantly enhanced by O-LM pre-treatment, in contrast with the protective effect exerted on normal cells. Toxicological studies clearly demonstrated that O-LM did not produce any toxic or undesirable effect when administered to normal animals. Whole body weight, water and food consumption, and laboratory parameters remained unchanged after O-LM administration, even with a dose 10-fold higher than that employed in the experimental work. Results obtained afford the possibility of applying this protective treatment to human patients undergoing high-dose chemotherapy. J. Trace Elem. Exp. Med. 16:39–53, 2003. © 2003 Wiley-Liss, Inc.