Cancer antineoplastic agents

Cancer. Cancer is a cellular malignancy characterized by loss of normal controls resulting in unregulated growth, lack of differentiation, and the abihty to invade local tissues and metastasize. Most cancers are potentially curable, if detected at an early enough stage. The ideal antineoplastic agent would destroy cancer cells without adverse effects or toxicities to normal cells. No such dmg exists. 

The antineoplastic agent mitindomide (160) in fact represents the well-known product from irradiation of maleimide in benzene [30]. The activity of this old compound was uncovered by one of the large antitumor screens maintained by the National Cancer Institute, The structure is sufficiently complex and the starting materials sufficiently available to lead one to suspect that the product is still produced photochemically. The product can be rationalized by assuming successive 1,4 and 1,2 additions to benzene. Intermediate 159a involves the 1,4 followed by 1,2 addition intermediate 159b presupposes the steps occur in the reverse order. 

Cancer or neoplastic disease is a genomic disorder of the body s own cells which start to proliferate and metastasize in an uncontrolled fashion that is ultimately detrimental to the individual. Antineoplastic agents are used in conjunction with surgery and radiotherapy to restrain that growth with curative or palliative intention. The domain of antineoplastic chemotherapy is cancer that is disseminated and therefore not amenable to local treatment modalities such as surgery and radiotherapy. 

Antineoplastic agents that cannot be grouped under subheadings 1-9 include miltefosine which is an alkylphosphocholine that is used to treat skin metastasis of breast cancer, and crispantase which breaks down asparagine to aspartic acid and ammonia. It is active against tumor cells that lack the enzyme asparaginase, such as acute lymphoblastic leukemia cells. Side effects include irritation of the skin in the case of miltefosine and anaphylactic reactions in the case of crispantase. Another recent development is the proteasome inhibitor bortezomib which is used to treat multiple myeloma. 

Cancer treatment is a multimodality treatment, i.e., surgery is combined with radiotherapy and antineoplastic chemotherapy. The latter treatment mode is used mainly for cancers which have disseminated. Different forms of cancer differ in their sensitivity to chemotherapy with antineoplastic agents. The most responsive include lymphomas, leukemias, choriocarcinoma and testicular carcinoma, while solid tumors such as colorectal, pancreatic and squamous cell bronchial carcinomas generally show a poor response. The clinical use of antineoplastic agents is characterized by the following principles. 

Cancer, Molecular Mechanism of Therapy Antineoplastic Agents Alkylating Agents Antimetabolites... 

The epidermal growth factor receptor 2 (HER-2) is a protein found on the surface of cells. Heterodimerization of HER-2 activates the enzyme tyrosine kinase, triggering reactions that cause the cells to grow and multiply. HER-2 is found at abnormally high levels on the surface of many types of cancer cells, which may divide excessively. Antibodies targeting HER-2 (e.g., trastuzumab) are used as antineoplastic agents. 

Markman, M. (1986). Intraperitoneal antineoplastic agents for tumors principally confined to the peritoneal cavity. Cancer Treatm. Rev., 1, 219-242. 

Antineoplastic agents—Handbooks, manuals, etc. 2. Cancer—Chemo therapy—Handbooks, manuals, etc. I. Dreisbach, Luke P. II. Title. III. Series. 

Wagner, B. A., Buettner, G. R., and Burns, C. P., 1992, Membraneperoxidative damage enhancement by the ether Upid class of antineoplastic agents. Cancer Res. 52 6045-6051. 

Gao L, Cueto MA, Asselbergs F, Ataoja P (2002) Cloning and functional characterization of HDACll A novel member of the human histone deacetylase family. J Biol Chem 277 25748-25755 Garcia-Manero G, Issa JP (2005) Histone deacetylase inhibitors A review of their clinical stams as antineoplastic agents. Cancer Invest 23 635-642... 

Finally these compounds may also present in the future some interest in the area of novel anti-tumor drugs, or in photochemotherapy [12], Up to now the mechanism of action of the Pt complexes as antineoplastic agents has been extensively examined [13]. In spite of their successful applications, there is a need in compounds that are less toxic than the Pt derivatives. Therefore novel photo-active metallic compounds could offer future possibilities for cancer treatment. The fact that a drug would become active exclusively under illumination might represent an advantage. 

Pettit GR, Lippert JW. (2000) Antineoplastic agents 429. Syntheses of the combretastatin A-1 and combretastatin B-1 prodrugs. Anti-Cancer Drug Des 15 203-216. 

Intensive intermittent schedules of drug treatment should allow time for recovery from the acute toxic effects of antineoplastic agents, primarily bone marrow toxicity. The use of non-myelosuppressive agents can be considered during the recovery period, especially for treatment of fast-growing cancers. 

Neurotoxicity is rarely dose hmiting in cancer chemotherapy. The only antineoplastic agent that has a dose-limiting neurotoxicity is... 

Figure 7.1 Drug targets at the level of cellular structure. The mammalian cell presents a variety of druggable targets. The most important ones are located at the level of the cell membrane. Within the cell, cytoplasmic organelles, such as mitochondria, are beginning to be exploited as potential drug targets. The nucleus, at the center of the cell, is an important target for the development of antineoplastic agents for the treatment of cancer.

Nucleic-acid-related molecules (nucleotides, nucleosides, purines, pyrimidines) may also be used as dmgs themselves (and not only as dmg receptors). Once again, as discussed in chapters 7 and 9, this is most relevant in the areas of cancer and infectious disease, with purine/pyrimidine analogs being exploited as antimetabolites. 5-Fluorouracil is a well-described antineoplastic agent. Analogously, 5-fluorocytosine is used as an antifungal... 

Platinum complexes (e.g., di-platinum, 8.100) are used as antineoplastic agents in the treatment of cancer. Their use is described in chapter 7. 

Ellagic acid is an astringent, hemostatic, antioxidant, antimutagenic, and possibly an antineoplastic agent from strawberries, raspberries, grapes, walnuts, and pecans. Its human dietary role in cancer prevention is uncertain and in planta function is unknown. 

Considerable evidence supports the contention that excessive oxidative stress, i.e., the generation of higher-than-normal amounts of ROS, interferes with the cytotoxic effects of antineoplastic agents on cancer cells. Important to this concept is how oxidative stress influences the progression of a cell through the cell cycle and at which phases of the cell-cycle antineoplastic agents are cytotoxic (see Figure 8.1). 

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