Die teratogene Wirkung von Cyclophosphamid während der embryonalen Entwicklungsphase bei der Ratte

T, von Kreybig

doi:10.1007/bf02308522

Cited by 36 publications

(5 citation statements)

References 12 publications

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“…In summary, the results of these studies, with the exception of those of Ashby et a1 [51], indicate that CP administered prior to or on day 10 of gestation is either without effect or is embryolethal whereas exposure at appropriate doses of CP during days 10-16 of gestation results in a variety of malformations in near-term rat fetuses. The reason for the discrepancy between the results of Ashby et a1 [51] and those of von Kreybig [48], Chaube et a1 [49], and Singh [50] is unknown but might be related to strain differences. A common finding in all of these reports, however, is that nervous system and mesenchymal tissues are particularly sensitive to the teratogenic effects of CP.…”

Section: Cp Teratogenesis In Vlvo Ratmentioning

confidence: 99%

Cyclophosphamide teratogenesis: A review

Mirkes

1985

Teratog Carcinog Mutagen

180

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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.

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Section: Cp Teratogenesis In Vlvo Ratmentioning

confidence: 99%

Cyclophosphamide teratogenesis: A review

Mirkes

1985

Teratog Carcinog Mutagen

180

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“…Cyclophosphamide is a potent teratogen in a variety of vertebrates, including the human (Gerlinger et al, 1963;Greenberg and Tanaka, 1964;Shoji and Ohzu, 1965;Von Kreybig, 1965;Chaube et al, 1967;Gibson and Becker, 1968;Toledo, et al, 1971;Singh, 1971;Fritz and Hess, 1971;Spielmann et al, 1977;Ujhazy et al, 1979;McClure et al, 1979;Gilani and Chatzinoff, 1983;Jayaseelan et al, 1984;Shah et al, 1989a). When injected into pregnant animals, CP produces a wide variety of malformations in the fetus including those of limb, palate, tail, brain, and mandible.…”

Section: Introductionmentioning

confidence: 99%

Differentiation of cyclophosphamide‐treated hamster secondary palate: Ultrastructural and biochemical observations

Shah

1990

Am. J. Anat.

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A study was undertaken to analyze the ultrastructural aspects and the enzyme acid phosphatase cytochemistry and biochemistry of the pathogenesis of cyclophosphamide (CP)-induced cleft palate in hamster fetuses. The initial CP-induced alterations were the appearance of lysosomes in the mesenchymal cells of the vertically developing palatal primordia within 8 hr of drug administration. The mesenchymal lysosomal activity, which increased during the next 16 hr, was abnormal and interpreted as a sub-lethal response to CP treatment. Subsequently, the lysosomal activity in the mesenchyme diminished gradually and, 48 hr after CP treatment, was absent. At this time, lysosomes were seen in the epithelial cells of the vertical palate. Fifty-six hours after CP treatment, unlike controls where palatal shelves were already fused, lysosomal activity subsided in the epithelial cells. Changes, however, continued to be seen at the epithelial-mesenchymal interface. These changes were characterized by discontinuity in the basal lamina, and by epithelial-mesenchymal contacts. They persisted for 8 hr but were absent thereafter. Sixty-four hours after CP administration, the vertical shelves became horizontal and remained so until term. Following analysis of data, both from the literature and from the present study, it was suggested that CP first affected mesenchymal cell proliferation, and then its cytodifferentiation, during the critical phase of early vertical development; consequently the reorientation of the shelves to a horizontal plane was delayed, inducing cleft palate.

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“…These differences in malformations may also be due to other factors, since the lethal and teratogcnic effects induced by cyclophosphamide in rat foetuses by different workers have also shown variations. Although Kreybig (1965) did not find any effect of the cyclophosphamide when injected into pregnant rats on the 11th day of gestation, Chaube et al (1967) found that the same drug given on the 11th day of gestation produced brain and facial malformations in the litters. However, in experiments conducted by Singh (1970), cyclophosphamide caused resorption of all the embryos when injected in the mother rat on the 11th day of gestation.…”

Section: A E M B R Y O Showing Parrot Beak Deformity Absence O F Eymentioning

confidence: 97%

“…It has proved to be teratogenic to various laboratory animals, e.g. rat (Wilson 1964, Kreybig 1965, Kreybig & Schmidt 1967, Chaube et al 1967, Singh 1970, rabbit (Gerlinger 1964), and mice (Shoji & Ohzu 1965, Gibson & Becker 1968. Chick embryos were the first to be subjected to the teratological effects of cyclophosphamide (Gerlinger et al 1963) when this drug was injected into Ihe albumen of the chick eggs prior to their incubation.…”

mentioning

confidence: 99%