DNA sequence–selective adenine alkylation, mechanism of adduct repair, and in vivo antitumor activity of the novel achiral seco-amino-cyclopropylbenz[e]indolone analogue of duocarmycin AS-I-145
AS-I-145 is a novel achiral seco -amino-cyclopropylbenz[ e ]indolone ( seco -amino-CBI) analogue of duocarmycin that has evolved from an alternative strategy of designing CC-1065/duocarmycin agents lacking the characteristic chiral center of the natural agents. The sequence specificity of this compo...
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Veröffentlicht in: | Molecular cancer therapeutics 2007-10, Vol.6 (10), p.2708-2718 |
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Zusammenfassung: | AS-I-145 is a novel achiral seco -amino-cyclopropylbenz[ e ]indolone ( seco -amino-CBI) analogue of duocarmycin that has evolved from an alternative strategy of designing CC-1065/duocarmycin agents
lacking the characteristic chiral center of the natural agents. The sequence specificity of this compound was assessed by
a Taq polymerase stop assay, identifying the sites of covalent modification on plasmid DNA. The adenine-N3 adducts were confirmed
at AT-rich sequences using a thermally induced strand cleavage assay. These studies reveal that this compound retains the
inherent sequence selectivity of the related natural compounds. The AS-I-145 sensitivity of yeast mutants deficient in excision
and post-replication repair (PRR) pathways was assessed. The sensitivity profile suggests that the sequence-specific adenine-N3
adducts are substrates for nucleotide excision repair (NER) but not base excision repair (BER). Single-strand ligation PCR
was employed to follow the induction and repair of the lesions at nucleotide resolution in yeast cells. Sequence specificity
was preserved in intact cells, and adduct elimination occurred in a transcription-coupled manner and was dependent on a functional
NER pathway and Rad18. The involvement of NER as the predominant excision pathway was confirmed in mammalian DNA repair mutant
cells. AS-I-145 showed good in vivo antitumor activity in the National Cancer Institute standard hollow fiber assay and was active against the human breast MDA-MD-435
xenograft when administered i.v. or p.o. Its novel structure and in vivo activity renders AS-I-145 a new paradigm in the design of novel achiral analogues of CC-1065 and the duocarmycins. [Mol Cancer
Ther 2007;6(10):2708–18] |
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ISSN: | 1535-7163 1538-8514 |
DOI: | 10.1158/1535-7163.MCT-07-0294 |