Alkylating agents, in cancer

Besides being used as an alkylating agent in cancer chemotherapy, cyclophosphamide is a unique drug when used as an immunosuppressant. First, it is the most powerful of all such drugs. Second, it kills proliferating cells, and evidently alkylates a certain region of... 

Kobayashi H, Man S, Graham CH, Kapitain SJ, Teicher BA, Kerbel R.S (1993) Acquired multicellular-mediated resistance to alkylating agents in cancer. Proc Natl Acad Sci. USA 90 3294-3298... 

Tew KD, Colvin OM, Chabner BA (2001) Alkylating agents. In Cancer Chemotherapy and Biotherapy. Principles and Practice (Chabner BA, Longo DL, eds), pp 373 14. Philadelphia Lipin-cott Williams and Wilkins. 

Describe the mechanism of action of alkylating agents in cancer chemotherapy. 

Penman, B.W., Hoppe, rv, H., and Thilly, W.G. (1979). Concentration-dependent mutation by alkylating agents in human lymphoblasts and Sal-monella typhimurium N-methyl-N-nitrosourethane and 0 -propiolactone," J. Natl. Cancer Inst. 63,903. 

Francia G, Green SK, Bocci G, et al. Down-regulation of DNA mismatch repair proteins in human and murine tumor spheroids implications for multicellular resistance to alkylating agents. Mol Cancer Ther. 2005 4 1484-1494. 

Mitomycin C, an antibiotic produced by fermentation of streptomyces, has been used extensively in Japan for the treatment of stomach cancer which is prevalent in that country. It probably acts after conversion into an alkylating agent in vivo, and it also contains quinone and urethane moieties which may contribute to its anti-tumour effect. A related series of compounds, the pyrol-lizidine alkaloids, occur in a variety of plants and are known to cause acute liver cytotoxicity when accidentally ingested93). Like mitomycin C, these agents are almost certainly metabolised in vivo by liver microsomes to alkylating agents which cause the liver toxicity. Some of these alkaloids have antitumour properties, presumably because the active metabolite formed in the liver is stable enough to reach the tumour. 

D.E.V. Wilman and T.A. Connors, Molecular stucture and antitumour activity of alkylating agents, in Molecular Aspects of Anti-Cancer Drug Action, S. Neidle and M.J. Waring (eds.), MacMillan Press, London, 1983, p. 233. 

Sarkaria JN, Kitange GJ, James D, Plummer R, Calvert H, Weller M, Wick W (2008) Mechanisms of chemoresistance to alkylating agents in malignant glioma. Clin Cancer Res 14 2900-2908... 

Altretamine, formerly known as hexamethylmelamine, is similar in structure to alkylating agents but is known to have anticancer activity in cancer cells resistant to alkylating agents. Altretamine is well absorbed after oral administration and undergoes rapid and extensive demethylation in the liver. Peak plasma concentrations were observed 0.5 to 3 hours after administration. The terminal half-life is 4.7 to 10.2 hours. 

Mitomycin C is an alkylating agent that forms cross-links with DNA to inhibit DNA and RNA synthesis. The pharmacokinetics of mitomycin C are best described by a two-compartment model, with an a half-life of 8 minutes and a terminal half-life of 48 minutes.31 Liver metabolism is the primary route of elimination. Mitomycin C has shown clinical activity in the treatment of anal, bladder, cervix, gallbladder, esophageal, and stomach cancer. Side effects consist of myelosuppression and mucositis, and it is a vesicant. 

HD is a vesicant (blister agent) and alkylating agent producing cytotoxic action on the hematopoietic (blood-forming) tissues which are especially sensitive. The rate of detoxification of HD in the body is very slow, and repeated exposures produce a cumulative effect. It causes blisters, irritates the eyes, and it is toxic when inhaled. HD has been determined to be a human carcinogen by the International Agency for Research on Cancer. 

Alkylating agents are also mutagenic substances that have been used in cancer chemotherapy. Alkylating agents such as nitrogen or... 

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