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 stepwise selection of cancer cells resistant to a single antineoplastic agent may lead to resistance to multiple agents (multidrug resistance). One of the well known mechanisms leading to multidrug resistance is the over-expression of the mdr 1 gene product, the 170 kDa membrane P-glycoprotein which is an ATP-driven efflux pump of xenobiotics. We studied the effects of dextran-conjugated doxorubicin in combination with colchicine, vinblastine and free doxorubicin respectively on the killing of human KB 3-1 carcinoma cells and its 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 analyzed by the medium-effect principle and the calculated Combination Indices at different cell survival levels. When added alone conjugated doxorubicin was not as effective as doxorubicin in cell killing. When conjugated doxorubicin was combined with free doxorubicin or colchicine at high (over 75%) killing rates, a significant degree of synergism was observed in the killing of multidrug resistant KB-V1 cells. This synergism was not observed in non-resistant KB-3-1 cells nor when conjugated doxorubicin was combined with vinblastine.