Anticancer drug camptothecin

Our group is currently working on the formulation of another potent anticancer drug, camptothecin, that is clinically inactive due to its very low water solubility and poor stability under physiological pH, which causes the drug to be converted from its active lactone form to its inactive carboxylate form. Two different amphiphilic... 

Hsiang YH, Liu LF. Identification of mammalian DNA topoi-somerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res 1988 48 1722—1726. 

Keywords Alkaloids topotecan anticancer drugs camptothecin irinotecan topoisomerase I ... 

Efficient intracellular delivery of the anticancer drug camptothecin (CPT) by hollow silica/titania nanoparticles has been reported [114]. Monodispersed hollow nanoparticles (about 50 nm) were prepared by titania coating of Stober silica particles followed by silica dissolution and redeposition in an ammonia solution (Figure 11.13). Surface modification of these particles with an antibody herceptm, a... 

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]. 

The protected E-ring moiety of (S)-camptothecin has been prepared in enantio-merically enriched form by the enzymatic resolution of a triester with PLE in a pH 7 phosphate buffer-acetonitrile (5 1) solution (Figure 6.7). The alkaloid camptothecin is an inhibitor of the enzyme topoisomerase and some of its derivatives are anticancer drugs [52]. 

Another area in which natural products have had a major impact on longevity and quality of life is in the chemotherapy of cancer. In fact, most major anticancer drugs are derived from plants or microorganisms (see Chapter 62). Examples include bleomycin, doxorubicin, daunorubicin, vincristine, vinblastine, mitomycin, streptozocin, and most recently, additions of paclitaxel (Taxol ), ironotecan (a camptothecin derivative), and etoposide and tenoposide (podophyllo-toxin derivatives). 

Paclitaxel, camptothecin, vincristine, vinblastine, and other compounds currently under development as potential anticancer drugs (i.e., the bryostatins isolated from marine dinoflagellates) were discovered through a broad-based screening program to identify, using a whole-cell inhibition assay, natural products that are active against a battery of representative cancer cell lines. 

During the course of clinical development, it is often important to identify the structures of metabolites. This information provides an opportunity to better understand interpatient variability in pharmacokinetics and toxicity. Clinical studies performed by Lokiec and coworkers, 1996 on a semisynthetic derivative of 20(S)-camptothecin, CPT-11, demonstrate the use of LC/MS to investigate the in vivo metabolic pathways. CPT-11 is a potent inhibitor of topoisomerase II, which is an enzyme involved in DNA duplication, and exhibits significant activity against various types of tumors in clinical studies. The understanding and control of the main biotransformation pathways are particularly important for anticancer drugs because therapeutic doses are often close to the maximum tolerated dose. 

Kaufmann SH. Induction of endonucleolytic DNA cleavage in human acute myelogenous leukemia cells by etoposide, camptothecin, and other cytotoxic anticancer drugs A cautionary note. Cancer Res 1989 49 5870-5878. 

A variety of plant substances with planar, polycyclic, aromatic structures can intercalate with DNA, examples being the quinoline alkaloid camptothecin and the furanocoumarin phenolic psoralen (Table 12.1). A variety of plant-derived anthraquinones and naphthoquinones bind to DNA and it is notable that the structurally related anthraquinones mitox-antrone and adriamycin are clinically employed as anticancer drugs (Table 12.1). DNA-binding compounds that interfere with DNA repair, DNA replication and gene expression are cytotoxic and have potential as anticancer agents (see Chapter 9). 

HPMA conjugates of other anticancer drugs such as paclitaxel, camptothecin, and platinates were synthesized and evaluated in both animals and humans. Controlled drug release at the tumor sites was a major challenge for these systems. 

The anticancer drugs delivered by liposomes include many small molecule drugs such as DOX, daunoru-bicin, platinates, taxanes, camptothecin, etc. The most successful development is DOX-encapsulated pegylated liposomes, with a trade name of Doxil in the U.S. market or Cylax in the European market. Doxil has shown significant clinical advantages over free DOX and conventional DOX liposomes.f Enhanced tumor accumulation of Doxil has been demonstrated in numerous preclinical studies over a variety of tumor models. Similar effects were also observed in clinical uses. 

A few years after the introduction of Taxol in 1996, further phytogenic anticancer drugs were launched to treat advanced cancers. Topotecan, marketed by Smith Kline Beecham under the trade name of Hycamtin, was approved by the FDA to treat ovarian cancers that have resisted other chemotherapy drugs. Furthermore, irinotecan was introduced by Pharmacia Upjohn under the trade name of Camptosar for the treatment of metastatic cancer of the colon or rectum. Both compounds are derivatives of camptothecin which was isolated from the Chinese tree Camptotheca acuminata, well known in Chinese Traditional Medicine for anticancer treatment [65]. Isolation of the bioactive principle camptothecin and its structure elucidation had already been performed in 1966... 

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