Mechanisms of acquired resistance to 2-(4-aminophenyl)benzothiazole (CJM 126, NSC 34445)

2-(4-aminophenyl)benzothiazole (CJM 126) elicits potent growth inhibition i n human-derived breast carcinoma cell lines, including oestrogen receptor-p ositive (ER+) MCF-7(wt) cells. Analogues substituted in the 3' position wit h I (DF 129), CH3 (DF 203), or CI (DF 229) possess an extended profile of a ntitumour activity with remarkable selective activity in cell lines derived from solid tumours associated with poor prognosis, e.g. breast, ovarian, r enal and colon. Growth inhibition occurs via unknown, possibly novel mechan ism(s) of action. Two cell lines have been derived from sensitive MCF-7(wt) breast cancer cells (IC50 value < 0.001 mu M) following long-term exposure to 10 nM or 10 mu M CJM 126, MCF-7(10) (nM) (126) and MCF-7(10) (mu M) (12 6) respectively, which demonstrate acquired resistance to this agent (IC50 > 30 mu M) and cross-resistance to DF 129, DF 203 and DF 229. Sensitivity t o tamoxifen, benzo[a]pyrene (BP), mitomyin C, doxorubicin and actinomycin D is retained. Resistance may, in part, be conferred by the constitutively i ncreased expression of bcl-2 and p53 proteins detected in MCF-7(10) (nM) (1 26) and MCF-7(10) (mu M) (126) lysates. Significantly decreased depletion o f CJM 126 (30 mu M) from nutrient medium of MCF-7(10) (nM) (126) cells was observed with predominantly cytoplasmic drug localization and negligible DN A strand breaks. N-acetyl transferase (NAT)1 and NAT2 proteins were express ed by all three MCF-7 sub-lines, but significantly higher expression of NAT 2 was accompanied by enhanced acetylation efficacy in MCF-7(10) (nM 126) ce lls. In contrast, CJM 126 (30 mu M) was rapidly depleted from nutrient medi um of MCF-7(10) (mu M) (126) culture and accessed nuclei of these cells exe rting damage to DNA. The major biotransformation product of CJM 126 in MCF- 7(10) (mu M) (126) cells was 2-(4-aminophenyl)-6-hydroxybenzothiazole (6-OH 126). This metabolite possessed no antitumour activity. Accordingly, in th is sub-line, low constitutive expression and activity of cytochrome P450 (C YP) 1A1 was detected. (C) 2000 Cancer Research Campaign.