Multidrug Resistance Mechanisms And Anti-drug-resistant Tumor New Drug Research

Recently, cancer has becoming the second leading cause of mortality in China. The yearly death of cancer patients now is 1.54 millions, accounting for 17.64 percent of all deaths. Drug resistance is a major obstacle of cancer chemotherapy and has been closely associated with chemotherapy failure, over 90% of cancer deaths were related to drug resistance. So it has becoming a high topic to understand and overcome drug resistance. There are two sections in this thesis. The first section is about studies on the in vitro and in vivo anti-tumor activity of PH â…¡ -7 and it's possible mechanisms, the second section is about identification and validation of drug resistance-related gene candidates with cDNA microarray, which will provide potential new targets for the diagnosis and therapy of clinical drug resistant tumor.1. Studies on the in vitro and in vivo activity and mechanisms of a new anti-tumor agent PH â…¡-7 characterized by simultaneous effect on multidrug resistant tumor cellsOn the basis of effective treatment of chronic myeloid leukemia of Chinese medicine Danggui Longhui Pill, taken Indirubin, the effective component of the Pill, as a template, our research group designed and synthesized a series of derivatives of oxindole. Among them PH â…¡ -7 is an effective compound. The in vitro activity of PH â…¡-7 was evaluated using a panel of human tumor cell lines and their resistant sublines. The data showed that PH â…¡ -7 inhibited the proliferation of various human tumor cells, the IC₅₀ ranged from 0.34-18.61μmol/L. Especially, PH â…¡ -7 had the same antitumor effect on MDR tumor cells in vitro. The in vivo efficacy of PH â…¡ -7 was evaluated using xenografts of human leukemic K562 cells and its MDR subline K562/A02 by implantation s.c. in BULB/c nude mice. The growth rates of the two kind of tumors were almost equally reduced (P<0.05) by administration of PH â…¡-7 (50mg/kg, i.p.). In order to understand the anti-tumor mechanism of PH II -7, we focused on cell cycle and found PH â…¡-7 arrested cell cycles of a panel of tumor cell lines, including MDR tumor cells, in G1 phase by inhibition of CDK2. Based on these data we...