Cyclophosphamide teratogenicity

Mirkes PE, Greenaway JC, Rogers JG, et al. 1984. Role of acrolein in cyclophosphamide teratogenicity in rat embryos in vittCL Toxicol Appl Pharmacol 72 281-291. 

Following the development of the test, an in-house validation was conducted to evaluate the performance of FETAX compared to the results in the rat and/or rabbit. Thirteen reference chemicals were tested including eight compounds known to be teratogenic in rats and/or rabbits (caffeine, retinoic acid, hydroxyurea, ethanol, cyclophosphamide, nicotine, acetylsalicylic acid, dexametha-sone) and five non-teratogens (isoniazid, saccharin, paracetamol, penicillin G, sildenafil). The estimation of teratogenicity in rats and rabbits was based on published data (9). 

Fantel AG, Greenaway JC, Juchau MR, Shepard TH (1979) Teratogenic bioactivation of cyclophosphamide in vitro. Life Sci, 25 67-72. 

A good example of a compound that is a teratogen and requires metabolic activation is the anticancer drug cyclophosphamide, which has been studied extensively both in vivo and in vitro. 

Mailing to Sobels (October 1970), EMS. Ethyl methanesulfonate and methyl methane-sulfonate were standard alkylating agents used in routine chemical mutagenesis research. Cyclophosphamide, a known teratogen, was a compound used in cancer chemotherapy. 

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. 

Mirkes PE, Fantel AG, Greenaway JC, et al. 1981. Teratogenicity of cyclophosphamide metabolites phosphoramide mustard, acrolein, and 4-ketochlorophosphamide in rat embryos cultured in vitro Toxicol Appl Pharmacol 58 322-330. 

Schmid BP, Goulding E, Kitchin K, et al. 1981. Assessment of the teratogenic potential of acrolein and cyclophosphamide in a rat embryo culture system. Toxicology 22 235-244. 

Stahlmann R, Bluth U, Neubert 1984. Teratogenic potential of the cyclophosphamide metabolite acrolein. Teratology 29 33A. 

Cyclophosphamide requires metabolic activation to form the teratogenic metabolites, phosphoramide mustard, and acrolein (Figure 34.5). The former metabolite produces single-stranded DNA breaks, DNA-DNA and DNA-protein crosslinking. In contrast, acrolein preferentially binds to proteins, and it concentrates in the... 

The FDA has classified cyclophosphamide as a pregnancy risk factor D drug it is teratogenic in animals, but population studies have not conclusively shown teratogenicity in humans. However, in a study of in utero first-trimester exposure to four doses of cyclophosphamide 20 mg/kg it was concluded that cyclophosphamide is a human teratogen, that there is a distinct embryopathic phenotype, and that there are serious doubts about the safety of cyclophosphamide in pregnancy (68). The congenital malformation rate has been estimated at 10-44% (69). 

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. 

Studies of the teratorgenic potential of cyclophosphamide have demonstrated that cyclophosphamide must be metabolized in order to become teratogenic. 

Because of its potent immunosuppressive properties, cyclophosphamide has been used to prevent organ rejection after transplantation. It has activity in nonneoplastic disorders, including Wegener s granulomatosis, rheumatoid arthritis, and nephrotic syndrome. Caution is advised when the drug is considered for these conditions, both because of its acute toxic effects and because of its potential for inducing sterility, teratogenic effects, and leukemia. 

Bioactivation to a free radical intermediate has been implicated in the teratological mechanism for a number of xenobiotics, including phenytoin and structurally-related AEDs, benzo[a]pyrene, thalidomide, methamphetamine, valproic acid, and cyclophosphamide (Fantel 1996 Wells et al. 2009 Wells and Winn 1996). Unlike in the case of most CYPs, the embryo-fetus has relatively high activities of PHSs and lipoxygenases (LPOs), which via intrinsic or associated hydroperoxidase activity can oxidize xenobiotics to free radical intermediates (Fig. 10) (Wells et al. 2009). These xenobiotic free radical intermediates can in some cases react with double bonds in cellular macromolecules to form covalent adducts, or more often react directly or indirectly with molecular oxygen to initiate the formation of potentially teratogenic reactive oxygen species (ROS). 

The use of cultured rat embryos to evaluate the teratogenic activity of serum cadmium and cyclophosphamide. Teratology, 1979, 19(2) 35A. 

In contrast, Pekar et al. demonstrated that the teratogenic effects of cyclophosphamide are mediated by the induction of a p53-dependent apoptotic response (Pekar et al. 2007). Therefore p53 could also act an inducer of teratogenesis. Torchinsky and Toder (2010)... 

Kirshon B, Wasserstrum N, Willis R, et al. Teratogenic effects of first-trimester cyclophosphamide therapy. Obstet Gynecol 1988 72 462 64. 

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. 

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