Efficacy of dinaline and its methyl and acetyl derivatives against colorectal cancer in vivo and in vitro.

Dinaline [4-amino-N-(2'-aminophenyl)-benzamide, Din], p-N-methyldinaline (Me-Din) and p-N-acetyldinaline (Ac-Din) were evaluated for their antineoplastic efficacy in acetoxymethylmethylnitrosamine-induced colorectal carcinomas in Sprague-Dawley rats and in two human colon cancer cell lines. Din was very effective at all dosages (10, 7.7 and 5.9 mg/kg) as indicated by the ratio of median tumour volume of treated and control groups (T/C%) values of 0.4, 16 and 10.6, respectively, but also caused a corresponding mortality of 87, 47 and 13%, respectively, as opposed to 15% in the control group. Me-Din also showed significant tumour growth inhibition at all dosages (13.8, 10.6, 8.2 and 6.2 mg/kg), as evidenced by T/C% values of 2, 5.7, 8.4 and 25, respectively. The corresponding mortality was 47, 20, 27 and 30%, respectively. Ac-Din showed the lowest mortality with 20, 13 and 20% at dosages of 9.1, 7.0 and 5.3 mg/kg, respectively, whereas application of 11.9 mg/kg resulted in 100% mortality. T/C values of 18.3, 11.1 and 21.6%, respectively, demonstrated again high anticancer efficacy. Compared to the combination therapy with 5-FU and leucovorin (25 mg/kg each), p-N-acetyldinaline (7.0 mg/kg) was 4-fold more effective as indicated by T/C% values of 81.4 versus 21.9 at similar toxicity. In vitro, all three compounds were similarly active with IC50 concentrations between 1 and 2.2 micrograms/ml after 48 h of exposure and 0.6 to 1.6 micrograms/ml after 72 h of incubation. The MTT dye conversion assay correlated well with cell counts obtained by cell counting except for low dosages after short incubation periods when it stimulated cell proliferation. These results suggest that dinaline and its derivatives have clinical potential.