Cleavage behavior of calicheamicin gamma 1 and calicheamicin T.

Abstract

Calicheamicin y"is a potent antitumor antibiotic that cleaves DNA with a high degree of specificity; there is much interest in the recognition process. We have investigated the DNA-cleaving properties of calicheamicin T, a truncated derivative of calicheamicin. We show that calicheamicin T cleaves DNA in a double-stranded fashion, indicating that the first two sugars are sufficient to facilitate binding of the aglycone in the minor groove. However, calicheamicin T cleaves DNA nonselectively. This result suggests that cyclization kinetics do not determine the cleavage speiflcity of the intact drug. Instead, cleavage specificity probably reflects binding specificity. Because of the recognition sites reported in the original cleavage paper, calicheamicin has been assumed to recognize oligopyrimidine DNA sequences containing G-C base pailrs. We show here that calicheamicin also cuts efficiently at APT tracts, sometimes in preference to G-C-rich homopyrimidine tracts. Crystallographic data and experiments with chemical probes indicate that DNA sequences including GC base pairs have significantly different local conformations from DNA sequences containing several (four or more) sequential A-T base pairs. This difference makes it unlikely that calicheamicin simply senses inherent groove conformation and suggests that there is some degree of "induced fit." The ability to recognize both AFT-and G C-rich oligopyrimidine sequences with a high degree of specificity makes calicheamicin an unusual minor-groove binder.

Single Chemical Modifications of the C-1027 Enediyne Core, a Radiomimetic Antitumor Drug, Affect Both Drug Potency and the Role of Ataxia-Telangiectasia Mutated in Cellular Responses to DNA Double-Strand Breaks

“…C-1027 was the most potent followed by deschloro, deshydroxy, and, finally, desmethyl, with cleavage activity varying by up to 55-fold. Furthermore, the DNA cleavage activities compare favorably with the truncated calicheamicin and esperamicin analogues, which were 10-to 1,000-fold weaker than their respective parent compounds (36,37).…”

“…Although the biological activity of truncated versions of the enediynes calicheamicin and esperamicin has previously been characterized (36,37), this is the first study to examine single substitutions on an enediyne chromophore. All of the analogues maintain the ability to cleave cell-free DNA as measured by forms conversion analysis of drug-treated superhelical plasmid DNA (Fig.…”

Monoclonal antibodies in drug targeting

“…Other classes of cytotoxic drugs such as mylansoids (71,72) and enediyne antibiotics (73)(74)(75) have also been conjugated to monoclonal antibodies. These conjugates are being evaluated for specificity and cytotoxicity against a wide range of tumours in different tumour models.…”

Biologically active secondary metabolites from Actinomycetes

“…They act by cleaving DNA in its doublestranded condition. They are highly toxic, but if linked to antibody that selectively delivers drugs to cancer cells, they show only antitumour toxicity [1,71].…”