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Comparison of the Cytotoxic Effects of the High- and Low-Molecular-Weight Anticancer Agents on Multidrug-resistant Chinese Hamster Ovary Cells in Vitro¹

Department of Microbiology, Kumamoto University Medical School, Kumamoto 860, Japan

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 (MDR) subline CH^RC5 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. MDR CH^RC5 cells were 20 to 900 times more resistant to Adriamycin, aclacinomycin, vinblastine, and mitomycin C than were AUXB1 cells. However, the resistance of CH^RC5 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. CH^RC5 cells were not resistant to 5-fluorouracil and cis-diamminedichloroplatinum(II), but the effective doses of these agents to them were 10³ 10⁶ 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 CH^RC5 cells during a 120-min incubation, although Adriamycin was excreted very rapidly from CH^RC5 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.

¹ This work was supported by a Cancer Research Grant from Japanese Monbusho.

² To whom correspondence should be addressed.

Received 4/24/89. Revised 11/22/89. Accepted 12/ 4/89.

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