Multidrug-resistant Chinese Hamster Ovary Cells Low-Molecular-Weight Anticancer Agents on Comparison of the Cytotoxic Effects of the High- and Updated Version

Neocarzinostatin (NCS), styrene-maleic acid copolymer-conjugated neocarzinostatin (SMANCS), and ricin exhibited cytotoxicity against two different types of Chinese hamster ovary cells, parental AUXB1 cells and the multidrug-resistant (MI )K) subline CHRC5 cells at the nanomolar range. These doses were much lower than those of the other anticancer drugs tested (micromolar range), even after a short incubation. MDK CHRC5 cells were 20 to 900 times more resistant to Adriamycin, aclacinomycin, vinblastine, and mitomycin C than were AUXB1 cells. However, the resistance of CHRC5 cells to NCS, SMANCS, or ricin was relatively low: the 50% colony inhibitory concentration was only 5 to 10 times higher than that for parental AUXB1 cells. CHRC5 cells were not resistant to 5-fluorouracil and c/i-diamminedichloroplatinum(II), but the effective doses of these agents to them were III1 -10" times higher, and longer incubation times were required to produce the same cytotoxicity as NCS and SMANCS. Furthermore, cell-bound NCS, SMANCS, and ricin were not released from AUXB1 or CHRC5 cells during a 120-min incubation, although Adriamycin was excreted very rapidly from CHRC5 cells after binding and internalization. These results strongly suggest that NCS, SMANCS, and ricin, which are internalized into cells by endocytosis, were not excreted from the cells by active efflux and exhibited a pronounced anticancer effect against MDR cells.