2-(4-AMINOPHENYL)BENZOTHIAZOLES - NOVEL AGENTS WITH SELECTIVE PROFILES OF IN-VITRO ANTITUMOR-ACTIVITY

2-(4-Aminophenyl)benzothiazole (CJM 126) elicits biphasic growth-inhib itory effects against a panel of oestrogen receptor-positive (ER+) and oestrogen receptor-negative (ER-) human mammary carcinoma cell lines in vitro, yielding IC50 values in the nan range. Substitutions adjacen t to the amino group in the 2-phenyl ring with a halogen atom or methy l group enhance potency in sensitive breast lines (pM IC50 values). Tr ansient biphasic dose responses were induced but rapidly eradicated af ter specific drug exposure periods. Two human prostate carcinoma cell lines were refractory to the growth-inhibitory properties of 2-(4-amin ophenyl)benzothiazoles; IC50 values > 30 mu M were obtained. Potency a nd selectivity were confirmed when compounds were examined in the Nati onal Cancer Institute's Developmental Therapeutics screen; the spectru m of activity included specific ovarian, renal, colon al; well as brea st carcinoma cell lines. Moreover, comparing 6-day and 48-h incubation s, the exposure time-dependent nature of the biphasic: response was co rroborated. Differential perturbation of cell cycle distribution follo wed treatment of MCF-7 and MDA 468 cells with substituted 2-(4-aminoph enyl)benzothiazoles. In MDA 468 populations only, accumulation of even ts in G(2)/M phase was observed. Two MCF-7 cell lines were established with acquired resistance to CJM 126 (IC50 values > 20 mu M), which ex hibit cross-resistance to substituted benzothiazoles, but equal sensit ivity to tamoxifen and doxorubicin. Compared with standard anti-tumour agents evaluated in the National Cancer Institute in vitro cell panel , benzothiazoles revealed unique profiles of growth inhibition, sugges ting a models) of action shared with no known clinically active class of chemotherapeutic agents.