Cytocidal Activity of a Synthetic Isoprenoid N‐Solanesyl‐N N′‐bis(34‐dimethoxy‐benzyl)ethylenediamine and Its Potentiation of Antitumor Drugs against Multidrug‐resistant and Sensitive Cells in vitro

摘要

A synthetic isoprenoid, N‐solanesyl‐N, N′‐bis(3,4‐dimethoxybenzyl)ethylenediamine (SDB‐ethylene‐diamine), inhibited the colony formation of multidrug‐resistant mutant cell lines derived from Chinese hamster V79 (V79/ADM) and human hepatoma PLC/PRF/5 (PLC/COL) cells to a greater extent than that of the parental cells. When combined with other clinically useful antitumor agents, it potentiated the cytotoxic activity of almost all kinds of drugs tested including adriamycin (ADM), actinomycin D, vincristine, cytosine arabinoside, and 5‐fluorouracil (5‐FU), and the potentiation ratios were higher against V79/ADM cells than against V79/S cells. Among the antitumor agents tested, the activities of bleomycin‐group antibiotics were more strongly enhanced by SDB‐ethylenediamine and the potentiation was higher in the parental cells than in V79/ADM cells. SDB‐ethylenediamine enhanced the uptake of ADM and daunorubicin into V79/ADM and its parental cells, but it did not increase the uptake of 5‐FU or peplomycin, indicating that different mechanisms operate for potentiation in the cases of the latter drugs, i.e., not simply an increase of intracellular drug uptake. Two fragments of SDB‐ethylenediamine, solanesol (polyprenoid moiety) and the diamine component (verapamil‐like moiety), showed neither cytotoxic activity nor potentiator activity, even if they were mixed together, indicating that the steric conformation of intact SDB‐ethylenediamine molecule is important for these two activities.