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

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By Val R. Adams

A serious assessment our present realizing of camptothecins, their shortcomings, and of the chances for bettering their scientific functionality. The authors speak about new camptothecin analog improvement, drug supply concerns for optimizing their anticancer job, and their power use in a number of diverse 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 versions in defining the anticancer strength of camptothecins, and the query of camptothecin resistance.

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1996 Camptothecin resistance related to druginduced down-regulation of topoisomerase I and to steps occurring after the formation of protein-linked DNA breaks. Ann N Y Acad Sci 803:74–92. 139. Liu LF, Desai SD, Li TK, Mao Y, Sun M, Sim SP. 2000 Mechanism of action of camptothecin. Ann N Y Acad Sci 922:1–10. 140. Desai SD, Mao Y, Sun M, Li TK, Wu J, Liu LF. 2000 Ubiquitin, SUMO-1 and UCRP in camptothecin sensitivity and resistance. Ann N Y Acad Sci 922:306–308. 141. Desai SD, Li TK, Rodriguez-Bauman A, Rubin E, Liu LF.

52 Hecht 5. 1. Nonhomologous Recombination Nonhomologous, or illegitimate, recombination refers to processes by which chromosomal rearrangements occur in DNA regions having little or no sequence homology. Although this phenomenon is quite common and is thought to be linked to cancer and genetic diseases (49), the underlying molecular mechanisms are not clear. However, it certainly is clear that any such rearrangement must involve the formation and ultimate joining of DNA ends. Enzymes such as topoisomerases that catalyze DNA cleavage and ligation reactions must, therefore, be regarded as candidates for mediating such transformations.

PDB accession numbers are 1K4T for the ternary topo70DNA-Topotecan complex, and 1K4S for the binary topo70-DNA complex (patents pending). REFERENCES 1. Champoux JJ. DNA 2001 Topoisomerases: structure, function, and mechanism. Ann Rev Biochem 70:369–413. 2. Stivers JT, Shuman S, Mildvan AS. 1994 Vaccinia DNA topoisomerase I: singleturnover and steady-state kinetic analysis of the DNA strand cleavage and ligation reactions. Biochemistry 33:327–329. 3. Pourquier P, Pommier Y. 2001 Topoisomerase I-mediated DNA damage.

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