Potentiation by phenylbisbenzimidazoles of cytotoxicity of anticancer drugs directed against topoisomerase II.
Analogues of the phenylbisbenzimidazole dye pibenzimol bind tightly to the minor groove of DNA. A clonogenic assay has been used to investigate the effects of these compounds on the cytotoxicity of the topoisomerase II directed anti-cancer drugs amsacrine, CI-921 (an amsacrine analogue), acridine carboxamide, etoposide and doxorubicin. Although pibenzimol itself was inactive, several of its analogues reduced the toxicity of etoposide, amsacrine and CI-921 towards a Lewis lung mouse tumour line at concentrations between 1 and 20 mumol/l. Doxorubicin cytotoxicity was unaffected, suggesting that this drug has a distinct mechanism of action. At concentrations below 1 mumol/l, some of these dyes potentiated the cytotoxicity of etoposide and CI-921 towards Lewis lung cells. Potentiation of CI-921 activity was also found with the human tumour lines HT29 (colon), SW620 (colon) and FME (melanoma). Novel treatments may arise from the potentiation of topoisomerase II directed cytotoxicity.
Cancer Research Laboratory, University of Auckland Medical School, New Zealand.
G J
GJ
Finlay
B C
BC
Baguley
D000166:Acridines / Q000627:therapeutic use; D000677:Amsacrine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000494:pharmacology*; D006690:Bisbenzimidazole / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy; D004317:Doxorubicin / Q000627:therapeutic use; D004357:Drug Synergism; D005047:Etoposide / Q000627:therapeutic use; D005456:Fluorescent Dyes / Q000627:therapeutic use; D007939:Leukemia L1210 / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000166:Acridines; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D005456:Fluorescent Dyes; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; D005047:Etoposide; D004317:Doxorubicin; D006690:Bisbenzimidazole; C017807:bisbenzimide ethoxide trihydrochloride; C042315:asulacrine