In vitro evaluation of dimethane sulfonate analogues with potential alkylating activity and selective renal cell carcinoma cytotoxicity.
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.
Mertins
Susan D
SD
Cancer Therapeutics Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA. smertins@mail.ncifcrf.gov
Myers
Timothy G
TG
Holbeck
Susan L
SL
Medina-Perez
Wilma
W
Wang
Elaine
E
Kohlhagen
Glenda
G
Pommier
Yves
Y
Bates
Susan E
SE
D000477:Alkylating Agents / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity*; D000818:Animals; D001973:Bromodeoxyuridine / Q000032:analysis; D002066:Busulfan / Q000031:analogs & derivatives; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D002330:Carmustine / Q000031:analogs & derivatives; D002453:Cell Cycle / Q000187:drug effects; D004249:DNA Damage; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008698:Mesylates / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity*; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000378:metabolism; D015003:Yeasts / Q000187:drug effects
D000477:Alkylating Agents; D008698:Mesylates; D016159:Tumor Suppressor Protein p53; D002066:Busulfan; D001973:Bromodeoxyuridine; D002330:Carmustine