FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2045401766> ?p ?o ?g. }

• W2045401766 endingPage "103" @default.
• W2045401766 startingPage "101" @default.
• W2045401766 abstract "Cyclophosphamide (CP) is used to treat a wide range of neoplastic diseases as well as some non-malignant ones such as rheumatoid arthritis. It is also used as an immunosuppressive agent prior to organ transplantation. CP is, however, a known carcinogen in humans and produces secondary tumors. There is little absorption either orally or intravenously and 10% of the drug is excreted unchanged. CP is activated by hepatic mixed function oxidases and metabolites are delivered to neoplastic cells via the bloodstream. Phosphoramide mustard is thought to be the major anti-neoplastic metabolite of CP while acrolein, which is highly toxic and is produced in equimolar amounts, is thought to be responsible for most of the toxic side effects.DNA adducts have been formed after CP treatment in a variety of in vitro systems as well as in rats and mice using 3H-labeled CP. 32P-postlabeling techniques have also been used in mice. However, monitoring of adducts in humans has not yet been carried out. CP has also been shown to induce unscheduled DNA synthesis in a human cell line.CP has produced mutations in base-pair substituting strains of Salmonella typhimurium in the presence of metabolic activation, but it has been shown to be negative in the E. coli chromotest. It has also been shown to be positive in Saccharomyces cerevisiae in D7 strain for many endpoints but negative in D62.M for aneuploidy/malsegregation. It has produced positive responses in Drosophila melanogaster for various endpoints and in Anopheles stephensi.In somatic cells, CP has been shown to produce gene mutations, chromosome aberrations, micronuclei and sister chromatid exchanges in a variety of cultured cells in the presence of metabolic activation as well as sister chromatid exchanges without metabolic activation. It has also produced chromosome damage and micronuclei in rats, mice and Chinese hamsters, and gene mutations in the mouse spot test and in the transgenic lacZ construct of Muta™Mouse.Increases in chromosome damage and gene mutations have been found in the peripheral blood lymphocytes of nurses, pharmacists and female workers occupationally exposured to CP during its production or distribution. Chromosome aberrations, sister chromatid exchanges and gene mutations have been observed in somatic cells of patients treated therapeutically with CP. In general, there is a maximum dose and an optimum time for the detection of genetic effects because the toxicity associated with high doses of CP will affect cell division.In germ cells, CP has been shown to induce genetic damage in mice, rats and hamsters although the vast majority of such studies have used male mice. In males, the germ cell stages determined to be most sensitive to the induction of damage are the post-meiotic stages, which are sampled in the mouse by matings 1–3 weeks after treatment, and particularly the mid- to late-step spermatids sampled by matings 2–3 weeks after treatment. Tests by which CP has been shown to induce germ cell damage through assessment of effects in F1 progeny include those for dominant lethality, heritable translocations, specific locus mutations and malformations. Positive responses have also been reported in tests analyzing for structural chromosome damage in both spermatogonial and meiotic metaphases following exposures of various meiotic and pre-meiotic germ cell stages. CP exposures of meiotic cells have been shown to produce structural aberrations of the synaptonemal complex and to increase the frequency of spermatid micronuclei. Further, CP has been shown to induce structural, as well as some numerical, chromosome damage through analyses of second meiotic metaphases and first cleavage metaphases as well as through karyotypic analysis of F1 embryos. However, CP does not appear to be an effective aneugen. Other germ cell tests through which CP has been shown to produce genotoxic damage include those for sister chromatid exchanges and abnormal sperm head morphology. CP has also been shown to produce primary DNA damage during spermatogenesis as indicated by positive alkaline elution data from a study with rats, and by induction of unscheduled DNA synthesis in the testes of mice, rats and rabbits.Genetic risk estimates for the male have been made for 1 mg/kg of exposure to CP under acute conditions, on the expectation that the additional risk for an individual's offspring could be obtained by multiplying the risk estimates by the total mg/kg to which an individual is exposed. The types of mutational data available following maternal exposures do not justify attempting even an approximation of the estimate of genetic risk for female germ cells. Examples are provided of how the risk estimates could be applied to practical situations based upon male exposures.Three types of risk estimates for human health effects were derived for first generation progeny following paternal exposures. The indirect method of genetic risk estimation was used to estimate the risk from gene mutations and small deficiencies on the basis of data from the mouse morphological specific locus test. Data from the heritable translocation assay were applied to estimate risk from the induction of reciprocal translocations. In addition, an overall estimate of genetic risk was made using a modification of the direct method applied to data on F1 fetal malformations and growth retardation. These latter data are especially important because they show definitively that some mutations induced by CP actually cause serious organismic damage in first generation progeny. However, their use in estimating genetic risk warrants a special caution. Besides the unavoidable complication of making an interspecies extrapolation of phenotypic damage that is inherent in the direct method, the overall estimate of genetic risk has a further uncertainty in that the estimate of induced genetic effects manifest before the age of 25 in humans is based upon induced anomalies in the rat that are observed in late fetal stages.The parallelogram approach was applied to our overall estimate of genetic risk to yield the estimate that, for every mg/kg of paternal exposure, there would be an increase of 600 individuals with serious induced genetic disorders by early adulthood per million liveborn offspring derived from sperm sampled within 5 weeks after treatment (i.e., for all post-meiotic stages). The available data provide no reason to expect any elevation in risk for conceptions more than 90 days after treatment if exposures are to CP alone; the risk between 5 weeks and 90 days after treatment would be relatively slight, and possibly zero. We emphasize that our risk estimates are far from precise. However, they are the best that can presently be given for hereditary damage from CP. The explanations provided for the steps needed to convert mutational information into risk estimates may lead to improvements in estimates of hereditary risk for CP and other chemicals.There is a very extensive data base for CP which extends from the molecular level (except for adducts in humans) through the microbial and insect systems to somatic mammalian cells in various cell lines and primary cells in vitro, somatic cells in vivo, and germ cells in rodents. CP has been used as a positive control substance in many assay systems. In this review, extrapolation has been made from rodents to humans with risk estimates attempted at both individual and population levels." @default.
• W2045401766 created "2016-06-24" @default.
• W2045401766 creator A5058277007 @default.
• W2045401766 creator A5065909596 @default.
• W2045401766 date "1977-09-01" @default.
• W2045401766 modified "2023-10-17" @default.
• W2045401766 title "In vitro testing of an indirect mutagen (cyclophosphamide) with human leukocyte cultures: Activation with liver microsomes and use of a dialysis bag" @default.
• W2045401766 cites W1982709192 @default.
• W2045401766 cites W1999003683 @default.
• W2045401766 cites W1999767122 @default.
• W2045401766 cites W2000692241 @default.
• W2045401766 cites W2005144358 @default.
• W2045401766 cites W2007115073 @default.
• W2045401766 cites W2008790155 @default.
• W2045401766 cites W2011917537 @default.
• W2045401766 cites W2084536312 @default.
• W2045401766 cites W2095076086 @default.
• W2045401766 cites W317921614 @default.
• W2045401766 doi "https://doi.org/10.1016/0027-5107(77)90250-0" @default.
• W2045401766 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/339073" @default.
• W2045401766 hasPublicationYear "1977" @default.
• W2045401766 type Work @default.
• W2045401766 sameAs 2045401766 @default.
• W2045401766 citedByCount "34" @default.
• W2045401766 crossrefType "journal-article" @default.
• W2045401766 hasAuthorship W2045401766A5058277007 @default.
• W2045401766 hasAuthorship W2045401766A5065909596 @default.
• W2045401766 hasConcept C114246631 @default.
• W2045401766 hasConcept C126322002 @default.
• W2045401766 hasConcept C185592680 @default.
• W2045401766 hasConcept C202751555 @default.
• W2045401766 hasConcept C2776639595 @default.
• W2045401766 hasConcept C2776694085 @default.
• W2045401766 hasConcept C2776755627 @default.
• W2045401766 hasConcept C2779978075 @default.
• W2045401766 hasConcept C55493867 @default.
• W2045401766 hasConcept C71924100 @default.
• W2045401766 hasConcept C87644729 @default.
• W2045401766 hasConcept C98274493 @default.
• W2045401766 hasConceptScore W2045401766C114246631 @default.
• W2045401766 hasConceptScore W2045401766C126322002 @default.
• W2045401766 hasConceptScore W2045401766C185592680 @default.
• W2045401766 hasConceptScore W2045401766C202751555 @default.
• W2045401766 hasConceptScore W2045401766C2776639595 @default.
• W2045401766 hasConceptScore W2045401766C2776694085 @default.
• W2045401766 hasConceptScore W2045401766C2776755627 @default.
• W2045401766 hasConceptScore W2045401766C2779978075 @default.
• W2045401766 hasConceptScore W2045401766C55493867 @default.
• W2045401766 hasConceptScore W2045401766C71924100 @default.
• W2045401766 hasConceptScore W2045401766C87644729 @default.
• W2045401766 hasConceptScore W2045401766C98274493 @default.
• W2045401766 hasIssue "1" @default.
• W2045401766 hasLocation W20454017661 @default.
• W2045401766 hasLocation W20454017662 @default.
• W2045401766 hasOpenAccess W2045401766 @default.
• W2045401766 hasPrimaryLocation W20454017661 @default.
• W2045401766 hasRelatedWork W1990092119 @default.
• W2045401766 hasRelatedWork W2007115073 @default.
• W2045401766 hasRelatedWork W2024756813 @default.
• W2045401766 hasRelatedWork W2033495781 @default.
• W2045401766 hasRelatedWork W2085150364 @default.
• W2045401766 hasRelatedWork W2414084612 @default.
• W2045401766 hasRelatedWork W2433523684 @default.
• W2045401766 hasRelatedWork W2748952813 @default.
• W2045401766 hasRelatedWork W2899084033 @default.
• W2045401766 hasRelatedWork W4254426385 @default.
• W2045401766 hasVolume "56" @default.
• W2045401766 isParatext "false" @default.
• W2045401766 isRetracted "false" @default.
• W2045401766 magId "2045401766" @default.
• W2045401766 workType "article" @default.