Cyclophosphamide: review of its mutagenicity for an assessment of potential germ cell risks.
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 tryphimurium 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.(ABSTRACT TRUNCATED AT 400 WORDS)
Anderson
D
D
British Industrial Biological Research Association (BIBRA), Carshalton, Surrey, UK.
Bishop
J B
JB
Garner
R C
RC
Ostrosky-Wegman
P
P
Selby
P B
PB
D000818:Animals; D002869:Chromosome Aberrations; D003520:Cyclophosphamide / Q000633:toxicity*; D018736:DNA Adducts / Q000032:analysis; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D051379:Mice; D009152:Mutagenicity Tests / Q000379:methods / Q000592:standards; D009153:Mutagens / Q000633:toxicity*; D016273:Occupational Exposure / Q000009:adverse effects; D051381:Rats; D015203:Reproducibility of Results; D018570:Risk Assessment; D012854:Sister Chromatid Exchange; D013045:Species Specificity; D013094:Spermatozoa / Q000187:drug effects
D018736:DNA Adducts; D009153:Mutagens; D003520:Cyclophosphamide