The control and consequences of bacterial fermentation in the human colon.

The autosomal recessive human disorder ataxia-telangiectasia (A-T) was first described as a separate disease entity 40 years ago. It is a multisystem disease characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, radiosensitivity, predisposition to lymphoid malignancies and immunodeficiency, with defects in both cellular and humoral immunity. The pleiotropic nature of the clinical and cellular phenotype suggests that the gene product involved is important in maintaining stability of the genome but also plays a more general role in signal transduction. The chromosomal instability and radiosensitivity so characteristic of this disease appear to be related to defective activation of cell cycle checkpoints. Greater insight into the nature of the defect in A-T has been provided by the recent identification, by positional cloning, of the responsible gene, ATM. The ATM gene is related to a family of genes involved in cellular responses to DNA damage and/or cell cycle control. These genes encode large proteins containing a phosphatidylinositol 3-kinase domain, some of which have protein kinase activity. The mutations causing A-T completely inactivate or eliminate the ATM protein. This protein has been detected and localized to different subcellular compartments.

The genetic defect in ataxia-telangiectasia

Several aspects of Western diets, alcohol use, and exercise patterns which are related to the risk of colorectal cancer have systemic effects in common. Those which increase the risk of colorectal cancer are positively associated with serum triglycerides and plasma glucose; those which decrease risk are negatively associated with serum triglycerides and plasma glucose. These observations suggest the hypothesis that serum triglycerides and/or plasma glucose may themselves be associated with colorectal cancer risk. Evidence for associations between colorectal neoplasia and triglycerides and glucose comes from two recent studies of adenomatous polyps, presumed precursors for colorectal cancer, and from previous studies of diabetes and cancer. In addition, three randomized trials, one in humans and two in animal models, suggest that diets which would be expected to increase serum triglycerides and plasma glucose increase the levels of cellular indicators of colorectal cancer risk. Biological mechanisms explaining associations between colorectal neoplasia and serum triglycerides and/or plasma glucose might involve luminal or circulatory effects: (a) triglycerides and/or glucose may be associated with fecal bile acids, acids which are positively associated with colorectal cancer risk in epidemiological studies and which promote colorectal cancer in animal models; (b) serum triglycerides and/or plasma glucose might influence circulating hormones, such as insulin, which might themselves be involved in cancer development; (c) serum triglycerides and/or plasma glucose might be indicators of energy available through the circulation for neoplastic cells.(ABSTRACT TRUNCATED AT 250 WORDS)

https://cebp.aacrjournals.org/content/cebp/3/8/687.full.pdf

Epidemiology of colorectal cancer revisited: are serum triglycerides and/or plasma glucose associated with risk?

The risk of hereditary cutaneous malignant melanoma was evaluated in 401 members of 14 families with an autosomal dominant form of melanoma. We documented 127 primary melanomas in 69 famil...

High Risk of Malignant Melanoma in Melanoma-Prone Families with Dysplastic Nevi

Genetic analysis of BRCA1 function in a defined tumor cell line.

The dysplastic nevus syndrome (DNS) is a preneoplastic melanocyte abnormality which occurs in families affected by hereditary cutaneous malignant melanoma (HCMM). Although environmental exposures, especially solar UV-irradiation, have been implicated as risk factors in sporadic melanoma, the role of such exposures in the pathogenesis of HCMM is unknown. We have studied the in vitro radiation responses of six non-tumor skin fibroblast strains from HCMM/DNS patients representing five families. All six HCMM/DNS strains were found to show some degree of enhanced cell killing sensitivity, compared with normal controls, following 254 nm UV-irradiation. The abnormal survival responses appeared to relate to specific characteristics of HCMM/DNS cells since the six strains had essentially normal sensitivity to gamma-radiation. The enhanced photosensitivity was not associated with abnormal patterns in either DNA repair synthesis or UV-induced inhibition and recovery of de novo DNA synthesis. The survival results are consistent with the hypothesis that the genetically determined predisposition to malignant melanoma may directly or indirectly be the consequence of increased susceptibility to UV-induced cellular damage.

Abnormal sensitivity to UV-radiation in cultured skin ibroblasts from patients with hereditary cutaneous malignant melanoma and dysplastic nevus syndrome

Current evidence suggests that the complex nature of mammalian chromatin can result in the concealment of DNA damage from repair enzymes and their co-factors. Recently it has been proposed that the acetylation of histone proteins in chromatin may provide a surveillance system whereby damaged regions of DNA become exposed due to changes in chromatin accessibility. This hypothesis has been tested by: (i) using n-butyrate to induce hyperacetylation in human adenocarcinoma (HT29) cells; (ii) monitoring the enzymatic accessibility of chromatin in permeabilised cells; (iii) measuring u.v. repair-associated nicking of DNA in intact cells and (iv) determining the effects of n-butyrate on cellular sensitivity to DNA damaging agents. The results indicate that the accessibility of chromatin to Micrococcus luteus u.v. endonuclease is enhanced by greater than 2-fold in n-butyrate-treated cells and that there is a corresponding increase in u.v. repair incision rates in intact cells exposed to the drug. Non-toxic levels of n-butyrate induce a block to G1 phase transit and there is a significant growth delay on removal of the drug. Resistance of HT29 cells to u.v.-radiation and adriamycin is enhanced in n-butyrate-treated cells whereas X-ray sensitivity is increased. Although changes in the responses of cells to DNA damaging agents mustmore » be considered in relation to the effects of n-butyrate on growth rate and cell-cycle distribution, the results are not inconsistent with the proposal that increased enzymatic-accessibility/repair is biologically favourable for the resistance of cells to u.v.-radiation damage. Overall the results support the suggested operation of a histone acetylation-based chromatin surveillance system in human cells.« less

n-Butyrate alters chromatin accessibility to DNA repair enzymes

The cellular basis for the enhanced sensitivity to ionising radiation and some DNA damaging chemicals in ataxia-telangiectasia (AT) cells is not clearly understood. Abnormalities in cell-cycle traverse, chromosome stability and DNA synthesis patterns have suggested that a chromatin associated defect may be the primary lesion in AT. This study involves an attempt to define such an anomaly by the use of a vital DNA specific bis-benzimidazole dye (Hoechst 33342) and deoxyribonuclease II as probes for chromatin organisation in intact and permeabilised human cells respectively. Despite similar DNA binding characteristics (determined by flow cytometry) of Ho33342 in normal and AT transformed fibroblasts, the AT cells show: (i) enhanced cell killing and increased accumulation of cells in G2 phase of the cell-cycle [both biological responses being relatively resistant in AT cells to modification by an inhibitor of poly (ADP ribosyl)ation], (ii) no resistance of de novo DNA synthesis to Ho33342-induced inhibition, (iii) elevated levels of slow-rejoining ligand-induced DNA strand-breaks, and (iv) enhanced expression of chromatin regions accessible to an exogenously supplied endonuclease. The results are interpreted on the basis that a chromatin anomaly of enhanced nuclease susceptibility, involving a minor fraction of the genome, may be a controlling factor in the expression of the various in vivo and in vitro characteristics of AT cells.

Relationship between a chromatin anomaly in ataxia-telangiectasia cells and enhanced sensitivity to DNA damage

The dysplastic nevus syndrome (DNS) is a preneoplastic melanocyte abnormality which occurs in families affected by hereditary cutaneous malignant melanoma (HCMM). A putative role of host-environmental interactions in the etiology of hereditary melanoma has been strengthened by the recent finding that fibroblasts derived from HCMM/DNS patients demonstrated enhanced sensitivity to u.v.-irradiation in vitro. We report here an extension of these studies in which we have examined the in vitro responses to a model environmental carcinogen, 4-nitroquinoline 1-oxide (4NQO), of six non-tumor skin fibroblast strains from HCMM/DNS patients representing five families. Three of the six HCMM/DNS strains showed enhanced cell killing with sensitivities greater than that of a xeroderma pigmentosum (XP) variant strain but less than those of ataxia telangiectasia and XP Group D cell strains. The inhibition and recovery of de novo DNA synthesis, together with the expression of repair synthesis, following 4NQO exposure appeared to be normal in HCMM/DNS strains, irrespective of their subsequent clonogenic potential. Our data point to a metabolic anomaly which may contribute to the carcinogenic risk of the melanoma prone preneoplastic state presented by some DNS patients.

Abnormal responses to the carcinogen 4-nitroquinoline 1-oxide of cultured fibroblasts from patients with dysplastic nevus syndrome and hereditary cutaneous malignant melanoma.

Paul J. Smith

Papers

Abnormal sensitivity to UV-radiation in cultured skin ibroblasts from patients with hereditary cutaneous malignant melanoma and dysplastic nevus syndrome

n-Butyrate alters chromatin accessibility to DNA repair enzymes

Relationship between a chromatin anomaly in ataxia-telangiectasia cells and enhanced sensitivity to DNA damage

Abnormal responses to the carcinogen 4-nitroquinoline 1-oxide of cultured fibroblasts from patients with dysplastic nevus syndrome and hereditary cutaneous malignant melanoma.