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.
Finlay
G J
GJ
Cancer Research Laboratory, University of Auckland Medical School, New Zealand.
Baguley
B C
BC
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