PARTIAL SYNERGISM BETWEEN DEXTRAN-CONJUGATED DOXORUBICIN AND CANCER DRUGS ON THE KILLING OF MULTIDRUG-RESISTANT KB-V1 CELLS

One of the major problems in cancer chemotherapy is the development of tumor resistance to drug treatment. In in vitro experiments, the step wise selection of cancer cells resistant to a single antineoplastic ag ent may lead to resistance to multiple agents (multidrug resistance). One of the well known mechanisms leading to multidrug resistance is th e over-expression of the mdr1 gene product, the 170 kDa membrane P-gly coprotein which is an ATP-driven efflux-pump of xenobiotics. We studie d the effects of dextran-conjugated doxorubicin in combination with co lchicine, vinblastine and free doxorubicin respectively on the killing of human KB 3-1 carcinoma cells and ifs multidrug resistant subclone KB-V-1 cells. Cell survival was quantified by the tetrazolium salt MTT assay. Cytotoxicity studies were designed so that data could be analy zed by the medium-effect principle and the calculated Combination Indi ces at different cell survival levels. When added alone conjugated dox orubicin was not as effective as doxorubicin in cell killing. When con jugated doxorubicin was combined with free doxorubicin or colchicine a t high (over 75%) killing rates, a significant degree of synergism was observed in the killing of multidrug resistant KB-V1 cells. This syne rgism was not observed in non-resistant KB-3-1 cells nor when conjugat ed doxorubicin was combined with vinblastine.