The local three-dimensional structure of DNA is important in interactions with proteins involved in repair, transcription, recombination, and chromatin condensation. Recently, it has been proposed that antibiotics can induce formation of DNA structures that can recruit these proteins with cytotoxic results. The best-studied example of this phenomenon is the antitumor medicine cisplation, a tetra coordinate platinum complex [cis-Pt (NH2) 2Cl2]. Cisplatin is used alone or in combination with other antitumor agents to treat a variety of tumors including testicular, ovarian, bone, and lung cancers. This platinum complex forms inter- and intrastrand cross-links in double-stranded DNA with the latter adduct comprising 90% of DNA lesions. These bonds arise from displacement of chloride ligands on platinum by N-7 atoms of two neighboring guanines. Structural studies on intrastrand cross-linked DNA adducts show that the double helix is strongly bent toward the major groove.

Bent structure of the DNA-cisplatin adduct are specifically recognized by several DNA-binding proteins that include nucleotide excision repair (NER) proteins and high-mobility-group proteins such as HMG-1. It has been proposed that the cytotoxicity of cisplatin adducts is a complicated process mediated by specific interactions with these proteins. Cellular process such as transcription and apoptosis (programmed cell death) are affected by formation of cisplatin-DNA adducts. The lesions themselves and the adduct-protein complexes are likely to interfere with transcription. NER proteins are recruited to repair the lesion, but excision repair is prone to introduction of DNA strand breaks.

Accumulation of these breaks will ultimately induce apoptosis as the DNA becomes too damaged to function. Similar mechanisms have also been proposed to account for cytotoxicity of other DNA-binding medicine such as ditercalinium. This bifunctional molecule forms noncovalent adducts with DNA that are also highly bent. Cytotoxicity is thought to arise from induction of abortive repair pathways that lead to DNA strand breaks.

Interactions of the cisplatin-DNA adduct with HMG proteins may also contribute to its cytotoxicity. Binding of HMG proteins may incorrectly signal that the damaged region of DNA is transcriptionally active and prevent condensation into folded chromatin structures. These complexes might also perpetuate the lesion by shielding the DNA-cisplatin adducts from repair.

http://www.healthknow.info/antitumor_antibiotics.asp

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