We identified five structurally related dimethane sulfonates with putative selective cytotoxicity in
renal cancer cell lines. These compounds have a hydrophobic moiety linked to a predicted alkylating group. A COMPARE analysis with the National Cancer Institute Anticancer Drug Screen standard agent database found significant correlations between the IC50 of the test compounds and the IC50 of
alkylating agents (e.g., r = 0.68, P < 0.00001 for
chlorambucil). In this report, we examined whether these compounds had activities similar to those of conventional
alkylating agents. In cytotoxicity studies,
chlorambucil-resistant Walker rat
carcinoma cells were 4- to 11-fold cross-resistant to the test compounds compared with 14-fold resistant to
chlorambucil. To determine effects on cell cycle progression,
renal cell carcinoma (RCC) line 109 was labeled with
bromodeoxyuridine prior to drug treatment. Complete cell cycle arrest occurred in cells treated with an IC90 dose of NSC 268965. p53
protein levels increased as much as 5.7-fold in RCC line 109 and as much as 20.4-fold in
breast cancer line MCF-7 following an 18-hour drug exposure. Finally,
DNA-
protein cross-links were found following a 6-hour pretreatment with all compounds. Thus, the dimethane sulfonate analogues have properties expected of some
alkylating agents but, unlike conventional
alkylating agents, appear to possess activity against RCC.