Acrolein cancer

Basu AK, Marnett LJ. 1984. Molecular requirements for the mutagenicity of malondialdehyde and related acroleins. Cancer Res 44 2848-2854. 

Flales BF. 1982. Comparison of the mutagenicity and teratogenicity of cyclophosphamide and its active metabolites, 4-hydroxycyclophosphamide, phosphoramide mustard, and acrolein. Cancer Res 42 3016-3021. 

Kawabata TT, White KL Jr. 1988. Enhancement of in vivo and in vitro murine immune responses by the cyclophosphamide metabolite acrolein. Cancer Res 48 41-45. 

In a survey of chemical plants (without prior hypothesis) in the German Democratic Republic, nine cancer cases were found in a factory where the main process was dimerization of acetaldehyde and where the main exposures were to acetaldol (3-hydroxybu-tanal), acetaldehyde, butyraldehyde, crotonaldehyde (IARC, 1995) and other higher, condensed aldehydes, as well as to traces of acrolein (lARC, 1985). Of the cancer cases, five were bronchial tumours and two were carcinomas of the oral cavity. All nine patients were smokers. The relative frequencies of these tumours were reported to be higher than those expected in the German Democratic Republic. [The Working Group noted the mixed exposure, the small number of cases and the poorly defined exposed population.]... 

Cyclophosphamide (6.31) is a nitrogen mustard used for cancer treatment (Scheme 6.9). In the body, cyclophosphamide is oxidized to aminal 6.32. Compound 6.32 opens and loses acrolein to form phosphoramide mustard (6.33). Structure 6.33 is a strong bis-electrophile and reacts readily with nucleophiles. In DNA, the nucleophile tends to be N7 of guanine, which is oriented outward into the major groove (Figure 6.6). By reacting twice, 6.33 crosslinks DNA either within the same strand (intrastrand) or across the double helix (interstrand).16... 

Alarcon RA. 1976. Studies on the in vivo formation of acrolein. 3-Hydroxypropylmercapturic acid as an index of cyclophosphamide (NSC-26271) activation. Cancer Treat Rep 60 327-335. 

Alarcon RA, Meinhofer J, Atherton E. 1972. Isophosphamide as a new acrolein- producing antineoplastic isomer of cylophosphamide. Cancer Res 32 2519-2523. 

Chung FL, Young R, Hecht SS. 1984. Formation of cyclic 1,N2- propanodeoxyguanosine adducts in DNA upon reaction with acrolein or crotonaldehyde. Cancer Res 44 990-995. 

Cox R, Gooha S, Irving C. 1987. Acrolein, a metabolite of cyclophosphamide, alters DNA methylase activity in a non-competitive fashion by reacting with -SH groups of the enzyme [Abstract], Proc Ann Meet Am Assoc Cancer Res 28 86. 

Crook TR, Souhami RL, McLean AE. 1986. Cytotoxicity, DNA cross-linking, and single strand breaks induced by activated cyclophosphamide and acrolein in human leukemia cells. Cancer Res 46 5029- 5034. 

Grafstrom RC, Dypbukt JM, Willey JC, et al. 1988. Pathobiological effects of acrolein in cultured human bronchial epithelial cells. Cancer Res 48 1717-1721. 

Low JE, Borch RF, Sladek NE. 1982. Conversion of 4-hydroperoxycyclophosphamide to phosphoramide mustard and acrolein mediated by bifunctional catalysts. Cancer Res 42 830-837. 

Marinello AJ, Bansal SK, Paul B, et al. 1984. Metabolism and binding of cylophosphamide and its metabolite acrolein to rat hepatic microsomal cytochrome P-450. Cancer Res 44 4615-4621. 

Smith RA, Sysel IA, Tibbels TS, et al. 1988. Implications for the formation of abasic sites following modification of polydeoxycytidylic acid by acrolein in vitro. Cancer Lett 40 103-109. 

Steiner PE, Steele R, Koch FC. 1943. The possible carcinogenicity of overcooked meats, heated cholesterol, acrolein, and heated sesame oil. Cancer Res 3 100-107. 

Wrabetz E, Peter G, Hohorst HJ. 1980. Does acrolein contribute to the cytotoxicity of cyclophosphamide J Cancer Res clin Oncol 98 119-126. 

Acrolein also forms when hying food and may be one of the agents responsible for the rising frequency of colon cancer in western countries. 

Acrolein, in IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans. Some Monomers, Plastics and Synthetic Elastomers and Acivlein, Vol. 19, International Agency for Research on Cancer, Lyon, France, 1979, pp. 479-494. 

Hemorrhagic cystitis and bladder cancer are well-known complications of cyclophosphamide. The damage to the urinary bladder epithelium is caused by acrolein, a metabolite of cyclophosphamide that is excreted in the urine. In bone marrow transplant recipients, prior administration of busulfan, which itself causes hemorrhagic cystitis, can increase this risk (23). Mesna (2-mercaptoethane sodium sulfonate) is used to prevent this adverse effect. It is excreted by the kidney, and it binds and detoxifies acrolein in the urine mesna also prevents the breakdown of acrolein precursors. Intravesical prostaglandin E2 has been suggested as an alternative treatment (23). 

Anti-cancer drugs such as cyclophosphamide (15), aniline mustard, and nitrosoureas are transformed to reactive metabolites which are the toxic species required for their anti-cancer activity. Experiments with selectively deuterated analogs of these drugs has distinguished which pathway, among several alternative pathways of metabolism, is responsible for antitumor activity. For example, a deuterium isotope effect was observed for the formation of 4-ketocyclophosphamide (16), formed by the oxidation of the carbon alpha to the phosphoramide nitrogen, but there was no Isotope effect on the anti-tumor activity. However, there was a marked effect on the subsequent -elimination reaction and consequent decrease in anti-tumor activity by deuterium substitution at C-5. Thus, the formation of acrolein and phosphoramide mustard is rate determining for the anti-tumor activity of cyclophosphamide. 

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