The influence of a mixture of substances occurring in the circulatory system on the effect of different cytostatic drugs on various tumor and normal cell lines
Department of Biochemistry and Medical Chemistry, Faculty of Medicine, University of Pecs, Pecs, Hungary
AIM: Despite the decline of the immune system in AIDS only few kinds of tumor increase in incidence. Moreover, even in these few cases the increase is not caused by the immunosuppression. This shows that the immune system has no absolute role in the prevention of tumors. Therefore, the fact that tumors do not develop in the majority of the population during their lifetime indicates the existence of other defense system(s). According to our hypothesis, the defense is made by certain substances of the circulatory system. Using this hypothesis we were able to select experimentally 16 substances (amino acids, monosacharides, nucleobases, etc.) of the circulatory system (out of the 89 investigated) and demonstrate that the mixture of them had a cytotoxic effect (inducing apoptosis) in vitro and in vivo on different tumor cell lines, but not on normal cells in vitro and on animals. The aim of this study was to investigate whether the mixture of the 16 substances has any influence on the effect of different cytostatic drugs. METHODS: After determining the effective concentration range of the cytostatics, the cells were treated at different concentrations of the given cytostatic drug alone or in combination with the mixture. The viability of cells was assessed by the Trypan blue dye exclusion method or the MTT colorimetric assay. RESULTS: Using various tumor cell lines (A20, HeLa, Jurkat, K562, MCF7, Sp2/0-Ag14) the combination of the mixture and any cytostatics (Cisplatin, Cytarabine, Doxorubicin, Etoposide, Fluorouracil, Methotrexate, Mitomycin, Mitoxantrone, Vinblastine) killed significantly more cancer cells than any of them alone. Contrary to that, in the case of certain cytostatics (Doxorubicin, Fluorouracil, Cisplatin, etc.) the mixture had a significant protective effect on normal cells (LLC-MK2, MDCK). It is also an important result that the tumor cells which survived in some cases despite of increasing the concentration of the cytostatics to a very high value (probably they are resistant cells) could be destroyed when the given cytostatics were applied in combination with the mixture. This effect is supported by the experiments that the mixture of the 16 substances was able to destroy multidrug resistant cells (AT3B-1, MCF7/ADR) even alone. CONCLUSIONS: Our results provide the possibility to improve the efficiency and reduce the side effects of chemotherapy, to destroy the resistant cells and thus, to prevent the recidivism. From the knowledge of substances taking part in the defense system the possibility arose of practical usage as medication, which has been protected by patent in Hungary and in many other countries. On the basis of patents the development of an infusion (Culesol) is in preclinical phase and two products (Culevit^® tablets and Culevit^® cream) containing smaller amounts of the mentioned substances were developed (Immunal Ltd., Budapest, Hungary). Our above conclusions are corroborated by clinical observations used Culevit tablets during chemotherapy (see abstract of L Olasz et. al.).
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in oral session 991 (Synergistic therapies).