Cyclophosphamide mutagens

McCann J, Simmon Streitwieser D, et al Mutagenicity of chloroacetaldehyde, a possible metabolic product of 1,2-dichloroethane (ethylene dichloride), chloroethanol (ethylene chlorohydrin), and cyclophosphamide. Proc Natl Acad Sci USA 72 3190-3193, 1975... 

Ellenberger J, Mohn GR. 1977. Mutagenic Activity of major mammalian metabolities of cyclophosphamide toward several genes of Escherichia coli. J Toxicol Environ Health 3 637-650. 

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. 

Flales BF. 1983. Relative mutagenicity and teratogenicity of cyclophosphamide and two of its structural analogs. Biochem Pharmacol 32 3791-3795. 

Mirkes PE. 1985. Cyclophosphamide teratogenesis A review. Teratogen, Carcinogen, Mutagen 5 75-88. 

The results of the studies conducted on the 14 chemicals selected by the ILSI project were summarised by Eastin et al. (2001). Most studies confirmed the hypothesis that the dermal Tg.AC model responds to both mutagenic and nonmutagenic carcinogens. However, data from these studies suggested that the mechanism of action could be fundamental in obtaining the expected positive response. For example, topical application of ethinyl oestradiol, clofibrate and diethylstilbestrol gave clear positive results, whereas cyclosporin A was positive only in females and melphalan, phenacetin and cyclophosphamide did not produce any papillomas at SOA. The lack of receptor sites in the skin for these last compounds or selectivity between tissues for proliferative activity of some chemicals, could explain the negative responses. 

Figure 34.5. Metabolic pathway for the bioactivation of cyclophosphamide. (Adapted from Mirkes,P. E. Cyclophosphamide teratogenesis A review. Teratog. Carcinog. Mutagen. 5,75-88, 1985.)...

Zemlickis D, Lishner M, Erlich R, Koren G. Teratogenicity and carcinogenicity in a twin exposed in utero to cyclophosphamide. Teratog Carcinog Mutagen 1993 13(3) 139 3. 

Mjrrh is an oleo gum resin obtained from the stem of Commiphora molmol, a tree that grows in north-east Africa and the Arabian Peninsula. In mice, myrrh showed no mutagenic effects and was a potent cytotoxic drug against solid tumor cells (5). The antitumor potential of C. molmol was comparable to that of cyclophosphamide. Studies in hamsters suggested an antischistosomal activity of myrrh (6). 

In general, drug metabolism serves to inactivate a substrate and increase water solubility of the substrate for excretion, bioactivate a substrate or prodrug (e.g., codeine and cyclophosphamide) to an active or mutagenic principle, or less commonly, extend the elimination half-life of a pharmacologically active or potentially toxic metabohte. Metabolic reactions are often divided into Phase I and Phase II categories, as depicted in Figure 43-1. 

Aidoo, A., Lyn-Cook, L. E., Mittelstaedt, R. A., Heflich, R. H., and Casciano, D. A. (1991). Induction of 6-thioguanine-resistant lymphocytes in Fischer 344 rats following in vivo exposure to M-ethyl-iV-nitrosourea and cyclophosphamide. Environ Mol Mutagen 17, 141-151. 

In the micronucleus test, no mutagenic activity was observed in the bone marrow cells of mice fed diets containing 1330, 5330, or 10,670 ppm annatto daily for 7 days. An increased frequency of micronucleated cells was observed with coadministration of cyclophosphamide in animals fed the highest concentration of annatto, as compared to cyclophosphamide alone (Alves de Lima et al. 2003). 

Some cancer chemotherapeutic drugs are carcinogenic and/or mutagenic. They are widely used in hospital and laboratories, and there is a widespread demand for methods for their safe disposal and for surface decontamination, a field completely neglected. Research was therefore initiated on a number of these compounds doxorubicin, daunorubicin, methotrexate, dichlorom-ethotrexate, cyclophosphamide, ifosfamide, vincristine sulfate, vinblastine sulfate, 6-thioguanine, 6-mer-captopurine, cisplatin, lomustine, chlorozotocin, streptozotocin, carmustine, semustine, PCNU and melphalan. 

D. Chorvatovicova, E. Machova, J. Sandula, G. Kogan, Protective effect of the yeast glucomannan against cyclophosphamide-induced mutagenicity, Mutofion Res., 444,117-122,1999. 

The short-term in vitro mammalian cell chromosome aberration (CA) test measures the frequency of asymmetrical stractural chromosome aberrations after exposure to test chemicals or mutagens. The in vitro chromosomal aberration test may employ crrltures of established cell fines or primary cell cultures. Procedures involve the stimirlation of generally human peripheral blood lymphocytes (HPL) by cyclophosphamide, to divide in whole blood crrltures. Cells in metaphase are analysed for the presence of chromosomal aberrations (Fig. 6.2c) (Clare 2012). 

Kola, L Folb, P. 1. An assessment of the effects of cyclophosphamide and sodium valproate on the viabihty of preimplantation mouse embryos using the fluorescein diacetate test. Teratogen., Carcinogen, Mutagen. 1986,6, 23-31. 

---