Camptothecins in Cancer Therapy (Cancer Drug Discovery and by Val R. Adams

By Val R. Adams

A severe assessment our present realizing of camptothecins, their shortcomings, and of the chances for bettering their medical functionality. The authors speak about new camptothecin analog improvement, drug supply concerns for optimizing their anticancer task, and their power use in numerous diversified cancers. extra chapters describe what's recognized concerning the biochemistry, the pharmacology, and the chemistry of the camptothecins, together with the mechanism of topoisomerase and the way camptothecins poison this enzyme, using animal types in defining the anticancer capability of camptothecins, and the query of camptothecin resistance.

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Camptothecins in Cancer Therapy (Cancer Drug Discovery and Development)

A severe assessment our present realizing of camptothecins, their shortcomings, and of the chances for bettering their scientific functionality. The authors talk about new camptothecin analog improvement, drug supply concerns for optimizing their anticancer task, and their strength use in numerous diversified cancers.

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Sample text

Each of these structures contained unresolvable portions of the protein in the connector region (Pro635–Phe640). Moreover, the reconstituted enzyme has altered kinetics and is not sensitive to camptothecin in a plasmid relaxation assay (35). Hence, the structures reported here are the first structures of a fully active human TOP-I in covalent complex with DNA in the absence and presence of bound drug. (C) Comparison of the 22mer duplex oligonucleotides of the drug-bound (blue) and nondrug-bound (yellow).

Arg364 makes a hydrogen bond contact with N3 of adenosine at position –1 of the uncleaved strand (–1A). Lys532 makes a hydrogen bond with the oxygen of thymidine at position –1 (–1T). Lys374 and the main chain nitrogens of 362 and 363 make hydrogen bond contacts Chapter 2 / Topoisomerase–DNA–Drug X-Ray Structure 27 with the nonbridging phosphodiester of the uncleaved strand (0P). Consistent with the observed drug-binding mode, mutations at position Arg364 (14) would be expected to destabilize the topotecan binding site and are known to result in camptothecin resistance.

Nucleic Acids Res 23:2973–2979. 13. Staker BL, Hjerrild K, Feese MD, Behnke CA, Burgin AB, Stewart L. 2002 The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc Natl Acad Sci 99:15387–15392. 14. Li XG, Haluska P Jr, Hsiang YH, et al. 1997 Involvement of amino acids 361 to 364 of human topoisomerase I in camptothecin resistance and enzyme catalysis. Biochem Pharmacol 53:1019–1027. 15. Krogh BO, Shuman S 2000. Catalytic mechanism of DNA topoisomerase IB. Mol Cell 5:1035–1041. 16.

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