Fluorinated 2-(4-amino-3-methylphenyl)benzothiazoles possess potent antiproliferative activity against certain
cancer cells, similar to the unfluorinated
2-(4-amino-3-methylphenyl)benzothiazole (
DF 203,
NSC 674495). In "sensitive"
cancer cells,
DF 203 is metabolized by, can induce expression of, and binds covalently to
CYP1A1. Metabolism appears to be essential for its antiproliferative activity through
DNA adduct formation. However, a biphasic dose-response relationship compromises its straightforward development as a chemotherapeutic agent. We investigated whether fluorinated
benzothiazoles inhibit
cancer cell growth without the biphasic dose-response, and whether the fluorinated
benzothiazoles are also metabolized into reactive species, with binding to macromolecules in sensitive
cancer cells. One fluorinated
benzothiazole, 2-(4-amino-methylphenyl)-5-fluorobenzothiazole (5F 203, NSC 703786) did exhibit potent, antiproliferative activity without a biphasic dose-response. The fluorinated
benzothiazoles were also metabolized only in cells, which subsequently showed evidence of cell death. We used microsomes from genetically engineered human B-lymphoblastoid cells expressing
cytochromes P450 (
CYP1A1,
CYP1A2, or CYP1B1) to clarify the basis for fluorinated
benzothiazole metabolism. 5F 203 induced
CYP1A1 and CYP1B1
mRNA expression in sensitive breast and
renal cancer cells, whereas 5F 203 induced
CYP1A1 mRNA but not CYP1B1
mRNA expression in sensitive
ovarian cancer cells. 5F 203 did not induce
CYP1A1 or CYP1B1
mRNA expression in any "resistant"
cancer cells. The fluorinated
benzothiazoles induced
CYP1A1 protein expression exclusively in sensitive cells. [14C]5F 203 bound substantially to subcellular fractions in sensitive cells but only minimally in resistant cells. These data are concordant with the antiproliferative activity of fluorinated
benzothiazoles deriving from their ability to become metabolized and bind to macromolecules within sensitive cells.