azaguanine and Abnormalities--Drug-Induced

Hamster embryos in utero on the 11th or 12th day of gestation were treated simultaneously with aminopyrine (Ap) and sodium nitrite (NaNO2) by oral administration of the compounds to the mothers by stomach tube. For measurement of induction of 8 AG-resistant mutations, the embryonic cells from treated and control mothers were cultured in MEM plus 10% FBS for 72 h and then selected in medium containing 10 or 20 microgram/ml of 8 AG. The number of 8 AG-resistant colonies was markedly increased after co-administration of Ap and NaNO2, and slight induction of mutations was also observed in cells from mothers given NaNO2 alone. This treatment also caused morphological or malignant transformation of cultured cells. About 5- to 6-fold increase in the number of transformed colonies was observed in cells from mothers given Ap plus NaNO2. Cells from the transformed colonies produced tumors when implanted into the cheek pouches of young golden hamsters. These tumors were diagnosed as pleomorphic fibrosarcomas. Similar results were obtained with cells from embryos treated transplacentally with NDMA as positive controls. A single transplacental oral application of Ap at 200 mg/kg or of NaNO2 had only slight biological actions to the cultured embryonic cells. NDMA was produced in the stomach of animals treated simultaneously with Ap and NaNO2. A small amount of NDMA was also detected in the stomach after a single dose of NaNO2.

Topics: Abnormalities, Drug-Induced; Aminopyrine; Animals; Azaguanine; Cells, Cultured; Cricetinae; Dimethylnitrosamine; Female; In Vitro Techniques; Maternal-Fetal Exchange; Mutation; Neoplasms; Nitrites; Pregnancy; Sodium Nitrite

Hamster embryos were treated with various doses of NaNO2 in utero, by its oral administration to the mothers, and then the embryonic cells were examined for micronucleus formation, chromosomal aberrations, morphological or malignant transformation and drug-resistant mutations. For induction of resistant mutations, the cells were cultured in normal medium for 72 h, and then selected in media containing 8-azaguanine (10 or 20 microgram/ml) or 1 mM ouabain. This treatment with NaNO2 caused marked dose-dependent induction of 8-azaguanine- and ouabain-resistant mutations. Cultured embryonic fibroblasts in the resting state also showed a marked dose-dependent increase in micronucleus formation but not an increase in chromosomal aberrations. This treatment also caused morphological and neoplastic transformation of the cells. Transplacental oral treatment with DMN, as a positive control, caused changes of similar extent in biological effects of embryonic fibroblasts, and in addition it caused chromosomal aberrations in metaphase plates. On the contrary, transplacental oral application of NaNO2 did not induce any biological change in cultured embryonic fibroblasts.

Topics: Abnormalities, Drug-Induced; Animals; Azaguanine; Carcinogens; Cell Transformation, Neoplastic; Chromosome Aberrations; Cricetinae; Drug Evaluation, Preclinical; Drug Resistance; Embryo, Mammalian; Female; Maternal-Fetal Exchange; Mesocricetus; Mutagens; Nitrites; Ouabain; Pregnancy; Sodium Nitrite; Teratogens