methylnitronitrosoguanidine and Gardner-Syndrome

Fibroblast cell strains were obtained from skin biopsies taken from patients with adenomatosis of the colon and rectum (ACR), and their relatives. A total of 50 different fibroblast strains were tested for their frequencies of sister chromatid exchange (SCE) in vitro. These strains included nine from patients with the Gardner syndrome, 21 from patients with non-Gardner ACR, and 20 cell strains from healthy relatives who were not at an increased risk for ACR. In 23 strains, the SCE frequencies after in vitro exposure to N-methyl-N'-nitro-N-nitroso-guanidine (MNNG) were also determined. Both with and without MNNG induction, SCE values in the Gardner strains were found to be significantly higher than in the control strains (p less than 0.02 and p less than 0.03, respectively). Non-Gardner ACR strains differed only slightly from controls, thus making the difference between the control group and the pooled Gardner + non-Gardner ACR group not significant. In all groups, there was a significant increase in SCE after MNNG exposure, and those strains which had low SCE values spontaneously, also tended to have relatively moderate SCE values after MNNG induction. There was no significant difference between the ratios of SCE values with and without MNNG exposure in the different groups.

Topics: Adolescent; Adult; Aged; Cells, Cultured; Child; Female; Fibroblasts; Gardner Syndrome; Humans; Intestinal Polyps; Male; Methylnitronitrosoguanidine; Middle Aged; Sister Chromatid Exchange; Skin

Fibroblast cell strains were established from skin biopsies taken from patients with adenomatosis of the colon and rectum (ACR) and their relatives. A total of 57 different strains (33 from patients and 24 from healthy members of ACR families not at an increased risk for colon polyposis) were tested for their frequencies of spontaneous structural chromosome aberrations, i.e., chromatid and isochromatid gaps, breaks, and interchanges. In 47 strains (27 from patients, 20 from controls), the frequencies of structural chromosome aberrations were also determined after exposing the cells to N-methyl-N'-nitro-N-nitroso-guanidine (MNNG). Both spontaneously and after mutagen treatment, the group of patient strains exhibited, on average, approximately twice the number of chromosome aberrations found in the control group. This increase was highly significant (p less than 0.001), even though there was a considerable overlap between patient and control strains. Treatment with MNNG led to a marked increase in chromosome aberrations in both patients and controls. The small differences in aberration frequencies seen between Gardner and other patient strains were clearly insignificant.

Topics: Adolescent; Adult; Aged; Cells, Cultured; Child; Chromosome Aberrations; Colonic Neoplasms; DNA Repair; Female; Fibroblasts; Gardner Syndrome; Humans; Intestinal Polyps; Male; Methylnitronitrosoguanidine; Middle Aged; Mutagens; Rectal Neoplasms; Skin

Lymphocytes from passive smokers, and patients with FA, Alz, or FPC were studied for SCEs in cultures treated with MMC, 4NQO, or MNNG. Fanconi anemia lymphocytes were also studied for cell cycle Tab. 3. Mean SCE frequencies in FPC or normal cells. (Table; see text) kinetics, and CAs after completion of 1, 2, or 3 or more divisions in MMC-treated cultures. The results can be summarized as follows: (1) lymphocytes from passive smokers showed a slightly higher induction of SCEs than nonsmokers when exposed to MMC. (2) FA cells had about 1.4 times higher frequencies of SCEs than normal cells in both MMC-treated and untreated cultures while they showed several times higher frequencies of CAs in both cultures. Analyses of cell cycle kinetics by the sister chromatid differential staining method revealed that MMC treatments of FA and normal cells led to a clearly dose-related delay in cell turnover times, the duration of delay being much longer in FA than in normal cells. (3) Alz cells showed about 1.5 times higher induction of SCEs in MMC-treated cultures whereas they had only 10% as much SCEs as controls when exposed to 4NQO. Familial polyposis coli cells showed no significant difference in the induction of SCEs in untreated cultures and cultures treated with MMC, 4NQO, and MNNG.

Topics: 4-Nitroquinoline-1-oxide; Adolescent; Adult; Alzheimer Disease; Anemia, Aplastic; Cell Cycle; Cells, Cultured; Child; Colonic Polyps; Fanconi Anemia; Female; Gardner Syndrome; Humans; Lymphocytes; Male; Methylnitronitrosoguanidine; Middle Aged; Mitomycin; Mitomycins; Sister Chromatid Exchange; Tobacco Smoke Pollution

We report here that skin fibroblasts from individuals with hereditary adenomatosis of the colon and rectum (ACR), an autosomal dominant trait, were not abnormally sensitive to x-rays, UV-light or MNNG. ACR cells were also competent in restoring x-rays and UV-light induced damage of SV40 T-antigen expression following infection of these cells by the irradiated virus. We concluded, therefore, that sensitivity to x-rays, UV-light and MNNG can not be used to identify gene-carriers dominantly predisposed to colon cancer.

Topics: Disease Susceptibility; DNA Repair; Fibroblasts; Gardner Syndrome; Humans; Intestinal Polyps; Methylnitronitrosoguanidine; Skin; Ultraviolet Rays; X-Rays

Adenomatosis of the colon and rectum (ACR) is an inherited form of cancer. Assuming that phenotypic expressions that appear in cell strains reflect its biological abnormalities, the study of cultured skin fibroblasts derived from individuals with an inherited form of cancer such as ACR provides a unique study for analysis of the oncogenic process. Growth disorders and increased susceptibility to tumor promoters and to transformation by an oncogenic RNA tumor virus have been demonstrated in these skin fibroblasts. We found that human skin fibroblasts (PF) derived from ACR individuals were sensitive to a chemical carcinogen. Cells treated only with various levels of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) underwent morphological alteration. The morphologically altered cells formed large cell aggregates when suspended in liquid growth medium above an agar base and grew to high saturation densities but did not form colonies in soft agar. Transformed cells were resistant to rechallenge of MNNG (1 microgram/ml) and showed prolonged life span compared to those untreated cells. However, no tumors were produced when cells were inoculated subcutaneously into nude mice. Data suggest that neoplastic transformation of these skin cells by chemical carcinogens is a multi-phase process.

Topics: Cell Transformation, Neoplastic; Cells, Cultured; Fibroblasts; Gardner Syndrome; Humans; Methylnitronitrosoguanidine; Skin; Tetradecanoylphorbol Acetate