2-(4-aminophenyl)benzothiazole (
CJM 126) elicits potent growth inhibition in human-derived
breast carcinoma cell lines, including oestrogen receptor-positive (ER+) MCF-7wt cells. Analogues substituted in the 3' position with I (DF 129), CH3 (
DF 203), or Cl (DF 229) possess an extended profile of antitumour activity with remarkable selective activity in cell lines derived from solid tumours associated with poor prognosis, e.g. breast, ovarian, renal and colon. Growth inhibition occurs via unknown, possibly novel mechanism(s) of action. Two cell lines have been derived from sensitive MCF-7wt
breast cancer cells (IC50 value < 0.001 microM) following long-term exposure to 10 nM or 10 microM
CJM 126, MCF-7(10 nM 126) and MCF-7(10 microM 126) respectively, which demonstrate acquired resistance to this agent (IC50 > 30 microM) and cross-resistance to DF 129,
DF 203 and DF 229. Sensitivity to
tamoxifen,
benzo[a]pyrene (BP), mitomyin C,
doxorubicin and
actinomycin D is retained. Resistance may, in part, be conferred by the constitutively increased expression of bcl-2 and p53
proteins detected in MCF-7(10 nM 126) and MCF-7(10 microM 126 lysates. Significantly decreased depletion of
CJM 126 (30 microM) from nutrient medium of MCF-7(10 microM 126) cells was observed with predominantly cytoplasmic
drug localization and negligible
DNA strand breaks. N-acetyl
transferase (
NAT)1 and NAT2
proteins were expressed by all three MCF-7 sub-lines, but significantly higher expression of NAT2 was accompanied by enhanced acetylation efficacy in MCF-7(10 nM 126) cells. In contrast,
CJM 126 (30 microM) was rapidly depleted from nutrient medium of MCF-7(10 microM 126) culture and accessed nuclei of these cells exerting damage to
DNA. The major biotransformation product of
CJM 126 in MCF-7(10 microM 126) cells was 2-(4-aminophenyl)-6-hydroxybenzothiazole (6-
OH 126). This metabolite possessed no antitumour activity. Accordingly, in this sub-line, low constitutive expression and activity of
cytochrome P450 (
CYP) 1A1 was detected.