Effects of minor groove binding drugs on camptothecin-induced DNA lesions in L1210 nuclei.
Topoisomerase I inhibition detected in mammalian cells can be correlated with reduced tumor growth. Camptothecin specifically inhibits topoisomerase I by stabilization of a covalently linked DNA-enzyme complex and associated DNA single-strand breaks. Whether perturbations in nuclear DNA structure can alter camptothecin-induced DNA damage was examined using the non-intercalative DNA minor groove binders distamycin, Hoechst 33258 and DAPI (4',6-diamidino-2-phenylindole). L1210 nuclei were treated with camptothecin alone or in the presence of single minor groove binders. DNA-protein crosslinks and single-strand breaks were determined using potassium-sodium dodecyl sulfate precipitation and alkaline elution respectively. Distamycin produced a dose-dependent decrease in DNA-protein crosslinks and strand breaks. This effect was reduced if nuclei were treated with camptothecin prior to distamycin addition. Distamycin was unable to reverse lesions once induced or to prevent repair of damage upon camptothecin removal. Hoechst 33258 and DAPI also decreased camptothecin-induced DNA damage. The order of inhibitory potency was: distamycin greater than Hoechst greater than DAPI. This order corresponded to the molecular weights as well as to the size of the nucleotide binding sites of the drugs. Identifying agents which alter such DNA lesions should provide better understanding of the chemotherapeutic activity of camptothecin as well as help elucidate new leads for drug combinations of improved therapeutic benefit.
Roswell Park Memorial Institute, Buffalo, NY 14263.
M M
MM
McHugh
R D
RD
Sigmund
T A
TA
Beerman
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D006690:Bisbenzimidazole / Q000494:pharmacology*; D002166:Camptothecin / Q000494:pharmacology*; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000378:metabolism; D004214:Distamycins / Q000494:pharmacology*; D004347:Drug Interactions; D007211:Indoles / Q000494:pharmacology*; D007939:Leukemia L1210; D015394:Molecular Structure; D011758:Pyrroles / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors
D001562:Benzimidazoles; D004273:DNA, Neoplasm; D004214:Distamycins; D007211:Indoles; D011758:Pyrroles; D059004:Topoisomerase I Inhibitors; C007293:DAPI; D006690:Bisbenzimidazole; D002166:Camptothecin