In vitro cytotoxicity against fresh human tumors and P388 leukemia predicts the differential in vivo activity of a series of anthracene anticancer drugs

To date, random anticancer drug screening has proven to be relatively inefficient and non-specific with respect to selecting active compounds for most tumor types (except for leukemia/lymphoma). Although large numbers of compounds from diverse sources were evaluated for many years in the P388 mouse leukemia model, only a few clinically useful drugs have been identified by this in vivo screening method. Thus, there is intense interest in the development of more effective in vitro screening models for new anticancer drugs. In the present paper we have compared the discriminating power for fresh human tumors from patients, human tumor cell lines developed from 11 patients and murine P388 leukemia in tumor colony forming assays as indicators of cytotoxicity for a series of anthracene antitumor agents. Two of a series of 21 novel bisantrene analogs, R6 (N, N-bis[2-(dimethylamino)ethyl]-9,10-anthracenebis(methylamine)) and R26 (N, N-bis(1-ethyl-3-piperidinyl)-9,10-anthracene-bis(methylamine)) produced significant cytotoxicity against the 11 human tumor cell lines and were therefore selected for additional in vitro and in vivo studies. R26 was specifically selected for further testing since it had Ion or doxorubicin-resistant 8226 myeiomd ten lines, in contrast to the cell line data, only one of the 22 fresh human tumors showed significant in vitro sensitivity (i.e.