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,N1-bis[2-(dimethylamino)ethyl]-9,10-anthracene-bis(methylamine)) and R26 (N,N1-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 similar in vitro potency as mitoxantrone, but showed no cross-resistance against mitoxantrone-resistant WiDr colon or doxorubicin-resistant 8226 myeloma cell lines. In contrast to the cell line data, only of the 22 fresh human tumors showed significant in vitro sensitivity (i.e. less than 50% survival of tumor colony forming units) to either R6 or R26 tested at high concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
Alberts
D S
DS
Department of Medicine, College of Medicine, University of Arizona, Tucson 85724.
Dorr
R T
RT
Wunz
T P
TP
Remers
W A
WA
Einspahr
J
J
Liu
R
R
Salmon
S E
SE
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000873:Anthracenes; D000970:Antineoplastic Agents