Calicheamicin γ ₁ ^I and DNA: Molecular Recognition Process Responsible for Site-Specificity

Abstract

Calicheamicin gamma 1I is a recently discovered diyne-ene-containing antitumor antibiotic that cleaves DNA in a double-stranded fashion, a rarity among drugs, at specific sequences. It is proposed that the cutting specificity is due to a combination of the complementarity of the diyne-ene portion of the aglycone with DNA secondary structures and stabilization by association of the thiobenzoate-carbohydrate tail with the minor groove.

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.…”

Specific inhibition of formation of transcription complexes by a calicheamicin oligosaccharide: a paradigm for the development of transcriptional antagonists.

“…Double-strand DNA cleavage occurs through bioreduction of the trisulfide and subsequent 1,4-benzenoid diradical formation, which results in hydrogen abstraction from adjacent nucleotide bases (10-13). Affinity cleavage experiments (7,8) MATERIALS AND METHODS Preparation of Nuclear Extracts and DNA-Bhin Assays. Nuclear extracts were prepared as previously described (19) from TAg Jurkat cells (20) stimulated for 2 hr with 2 pM ionomycin plus phorbol 12-tetradecanoate 13-acetate (PTA) at 20 ng/ml, HeLa cells stimulated for 2 hr with PTA at 20 ng/ml, or MDCK cells.…”

“…(B) Hypothetical model of CLM-MG (thick lines) bound to an AGGA site of B-form DNA. The model was initially based upon affinity cleavage experiments with CLM (7,8) and is supported by more recent experiments involving atom transfer between a labeled oligonucleotide and CLM (9).…”

“…Double-strand DNA cleavage occurs through bioreduction of the trisulfide and subsequent 1,4-benzenoid diradical formation, which results in hydrogen abstraction from adjacent nucleotide bases (10)(11)(12)(13). Affinity cleavage experiments (7,8) demonstrate that CLM preferentially cleaves DNA at cytosine-containing homopyrimidine tracts, preferentially TCCT. Comparisons of the DNA cleavage specificity of CLM derivatives indicate that the aryltetrasaccharide domain is largely responsible for sequence-specific DNA binding (8,(14)(15)(16)(17)(18) MATERIALS AND METHODS Preparation of Nuclear Extracts and DNA-Bhin Assays.…”

“…Affinity cleavage experiments (7,8) demonstrate that CLM preferentially cleaves DNA at cytosine-containing homopyrimidine tracts, preferentially TCCT. Comparisons of the DNA cleavage specificity of CLM derivatives indicate that the aryltetrasaccharide domain is largely responsible for sequence-specific DNA binding (8,(14)(15)(16)(17)(18) MATERIALS AND METHODS Preparation of Nuclear Extracts and DNA-Bhin Assays. Nuclear extracts were prepared as previously described (19) from TAg Jurkat cells (20) (24), Oct-i (25) and Oct-i-associated protein (OAP) (26), NFKB (27), HNF-1 (28), and Spl (29) was measured by electrophoretic mobility-shift assay.…”