The Study Of The Mechanism Of Innate And 5-FU Acquired Resistance Of Human Hepatocellular Carcinoma Bel₇₄₀₂ Cell Line As Well As Reversal Of Multidrug Resistance By Natural Compounds

It is well known that human hepatocellular carcinoma (HCC) is one of the malignant tumors with poor chemosensitivity to anticancer agents. The mechanism of innate resistance of HCC is unknown. To date , 5-fluoropyrimidines such as 5-flourouracil (5-FU), UFT are still the first choice drugs in the treatment of HCC. But its usage is limited because of the rapid development of acquired resistance. As we know, there is no paper dealing with the establishment of acquired resistance of 5-FU in HCC and its active mechanism of resistance in the literature. So, we first studied the innate resistant mechanism of HCC Bel7402 cell line, and then we successfully established a 161 fold resistant cell line named Bel5-FU20000 in vitro by continuous stepwise exposure of Bel7402 cells to 5-FU for 6 months. The biological characteristics and its active mechanism of acquired resistance to 5-FU were further studied, so as to provide theoretical basis for overcoming clinical resistance of HCC and for screening new chemosensitiser. Finally, a series of natural compounds from Chinese herb were screened for their multidrug resistance (MDR) reversal activity in vitro by using above resistant cell lines and other known MDR cell lines. Fortunately, the crude extract (LCC) of the Chinese herb XX and its two components LC and LC1 were found to have highly reversal effect on MDR1. The structure of LC and LC1 are different from any of the classes of the known MDR reversal agents, and no any paper dealt with the reversal activity of those compounds. The results of our study on the innate and 5-FU acquired resistant mechanism of HCC as well as the reversal of MDR by LC compounds from the Chinese herb XX are described as follows.1. The study of innate drug resistance of human hepatocellular carcinoma Bel7402 cell line.The innate resistance of human hepatocellular carcinoma Bel7402 cell line and its reversal by classical MDR reversal agents were studied. MTT assay demonstrated that the Bel7402 cells were innate resistant to Vincristine(VCR) and Doxorubicin (Dox) particularly VCR. Verapamil (Ver), one of the classical MDR reversal agents, effectively reversed the resistance to VCR and Dox,...