Cyclophosphamide teratogenesis: A review

Abstract

Cyclophosphamide (CP) is one of the best studied teratogens; it produces primarily central nervous system and skeletal anomalies in rats, mice, rabbits, monkeys, and humans. Furthermore, CP is one of the most extensively studied antineoplastic agents. Recent work using in vitro rodent embryo culture has demonstrated that CP must be bioactivated to be teratogenic. This finding extends earlier work showing that CP must be activated to achieve its antineoplastic and mutagenic effects. Activation of CP to its teratogenic, mutagenic, and antineoplastic form is mediated by microsomal cytochrome P-450 monooxygenases, which convert CP to 4-hydroxycyclophosphamide (4OHCP). In the absence of detoxification, 4OHCP spontaneously breaks down to phosphoramide mustard (PM) and acrolein (AC). PM is the CP metabolite believed to be responsible for the antineoplastic and mutagenic effects of CP, whereas AC is thought to cause the side effects associated with CP chemotherapy. Recent work has shown that the teratogenic effects of CP are mediated by both PM and AC. Although it is far from proven, available evidence supports the hypothesis that DNA is the primary target in terms of the teratogenic, mutagenic, and antineoplastic effects of CP. Although the nature of the DNA lesions produced by CP, which are responsible for its teratogenic, mutagenic, and antineoplastic effects, is not completely understood, cross-linking of DNA seems to play a critical role in the antineoplastic properties of CP. Preliminary information obtained from embryos exposed to CP metabolites suggests that, although DNA cross-linking might play a role in CP teratogenesis, metabolite-induced DNA strand breakage and/or induction of mutations might also play a role. Although insights into the molecular mechanisms underlying CP teratogenesis are just beginning to accumulate, the availability of in vitro embryo culture combined with the modern armamentarium of molecular biology will allow teratologists to probe further the molecular aspects of teratogenesis.

Teratogen-induced cell death in postimplantation mouse embryos: differential tissue sensitivity and hallmarks of apoptosis

“…Assessment of apoptosis in day 9.0 mouse embryos Vital staining Previous work has shown that cyclophosphamide (Mirkes, 1985a;Mirkes et al, 1991) and hyperthermia (Mirkes, 1985b) induce cell death within the body but not the heart of early postimplantation rat embryos. In this report we extend these findings to early postimplantation mouse embryos exposed to these two teratogens, and in addition, to sodium arsenite.…”

“…Like PCD, teratogen-induced cell death is selective, i,e., different cells and tissues within the developing embryo exhibit different sensitivities to the induction of cell death by teratogens. As an example, we and others have shown that neuroectoderm of the early postimplantation rodent embryo is exquisitely sensitive to the cell-death inducing potential of different teratogens, including cyclophosphamide (Mirkes, 1985a;Mirkes et al, 1991), hyperthermia (Mirkes, 1985b), N-acetoxy-2-acetylaminofluorene (Thayer and Mirkes, 1995), cadmium (unpublished data) and deoxyadenosine (Gao et al, 1994). In contrast, the cells of the heart are extremely resistant to the cell death-inducing potential of these teratogens.…”

Can lactoferrin modulate the immunostimulant activity of levamisole in rats immunosuppressed by cyclophosphamide?

“…Several compounds have been reported to have immunostimulation properties. Cyclophosphamide (CYP) is an alkylating agent widely used as cancer chemotherapy and autoimmune disease therapy [2]. CYP is a well-known and powerful immunosuppressive agent with dosespecific effects.…”

Fertility, pregnancy planning, and pharmacotherapy during the pregnancy, postpartum and breastfeeding period in patients with rheumatoid arthritis and other inflammatory arthropathies

“…W badaniach na zwierzętach wykazano wpływ cyklofosfamidu (CYC) na rozwój charakterystycznego zespołu zaburzeń rozwojowych mózgowia, kończyn oraz twarzy [27]. Cyklofosfamid miał nieprzewidywalny wpływ na rozwój płodu ludzkiego, gdyż podawany w I trymestrze ciąży nie zawsze powodował malformacje [28][29][30][31][32].…”