Cellular targeting

Camptothecin was discovered as an active anticancer drug isolated from the bark of Camptotheca acuminata. The anticancer activity of camptothecin was discovered in the 1960s by the National Cancer Institute (NCI) as part of a systematic effort to screen for novel anticancer agents derived from natural products. Monroe Wall and Mansuhk Wani identified the chemical structure of camptothecin. They also identified the chemical structure of taxol, again under the auspices of the NCI. Susan Hoiwitz was contracted by the NCI to elucidate the anticancer mechanisms of camptothecin. She found in the early 1970s that camptothecin induced DNA breaks and attested DNA and RNA synthesis. However, it is approximately 12 years later, only after DNA topo-isomerase I (Topi) had been identified in human cells, that Leroy Liu and his coworkers found that Topi was the cellular target of camptothecin [reviewed in [1]. 

Kido Y, Nakae J, Accili D (2001) Clinical review 125 the insulin receptor and its cellular targets. J Clin Endocrinol Metab 86 972-979... 

The ribosome is the cellular target of a large and chemically diverse group of antibiotics. The antibiotic binding sites are clustered at functional centers of the ribosome and the majority are composed exclusively of RNA. The drugs interfere with the positioning and movement of substrates, products and ribosomal components that are essential for protein synthesis. 

Rottman JB, Ganley KP, Williams K, Wu L, Mackay CR, Ringler DJ (1997) Cellular localization of the chemokine receptor CCR5. Correlation to cellular targets of HIV-1 infection. Am J Pathol 151(5) 1341-1351... 

Table 12.1 Cellular-targets for non-antibiotic antibacterial drugs... 

The major cellular target for oxygen radical damage is... 

Nocka, K., Majumder, S., Chabot, B., Ray, P., Cervone, M., Bernstein, A., and Besmer, P. (1989). Expression of the c-kit gene products in known cellular targets of W mutant mice-evidence for an impaired c-kit kinase in mutant mice. Genes Dev. 3 816-826. 

For family C receptors, the importance of and structural basis for interaction with intracellular adaptor or scaffolding proteins have been characterized in great detail, just as the issue of dimer formation is rather clear for these receptors. The main family of adaptor proteins, which ensures the cellular targeting and correct signaling function for the metabotropic glutamate receptors, appear... 

The ability of natural products to inhibition of topoisomerase and precipitate apoptosis mentioned in this chapter are two abilities among several others, of which inhibition of microtubule formation, inhibition of DNA polymerase, protein kinases, protein phosphatase and aromatase, and the use of cytokines, interleukins, and tumor necrosis factor and yet uncovered cellular targets. 

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