Recently, we reported a new class of
DNA-targeted hybrid
platinum-
acridine agents. The parent
intercalator,
ACRAMTU, a
9-aminoacridine derivative, intercalates into the minor groove of
DNA, causing the corresponding prototypical conjugate, PT-
ACRAMTU (type I/n=2), to form
DNA adducts dissimilar to traditional
platinum drugs. Both these agents show cytotoxic activity in leukemic and
ovarian cancer cells. Following the use of clonogenic survival assays, we report on the cytotoxic effects of
ACRAMTU, PT-
ACRAMTU, and three PT-
ACRAMTU derivatives, on additional cell lines including colon (RKO), lung (H460), and
cisplatin-sensitive (A2780) and
cisplatin-resistant (A2780/CP) ovarian cells. While a dose-dependent effect was observed with both
ACRAMTU and PT-
ACRAMTU, an enhanced cytotoxic effect was seen with PT-
ACRAMTU in all cell lines. PT-
ACRAMTU appeared to have a similar IC50 value to
cisplatin except in H460
lung cancer cells in which PT-
ACRAMTU had a twofold lower IC50 value. PT-
ACRAMTU appeared to act in a time-dependent manner. In H460 cells the IC50 value of PT-
ACRAMTU was 235-fold higher following a 1-h incubation than following a 24-h incubation (0.27 microM), while following an 8-h incubation the IC50 value was 0.41 microM. Three derivatives of PT-
ACRAMTU were also tested. A tetraalkylated derivative, type II/n=2, generated the highest IC50 values in all cell lines, while the trialkylated derivative, type III/n=2, generated IC50 values similar to its isomer, PT-
ACRAMTU. PT-
ACRAMTU with an added CH2 group in the
thiourea linker (type I/n=3) showed IC50 values similar to the type I/n=2 prototype in H460 lung cells. An apoptotic response to PT-
ACRAMTU appeared to be generated in H460 cells as evidenced by
DNA laddering. These results suggest that type I/n=2 and type I/n=3 may be promising agents for the treatment of
lung cancer and should be pursued in animal models.