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Title: Abnormal sensitivity of skin fibroblasts from familial polyposis patients to DNA alkylating agents

Fibroblast cell strains derived from different patients all afflicted with genetic predisposing to the development of intestinal polyposis and cancer were tested for their sensitivity to the lethal effects of the DNA alkylating agents methylmethanesulfonate (MMS), ethyl methanesulfonate, N-methyl-N'-nitro-N-nitrosoguanidine, and 4-nitroquinoline 1-oxide. The genetic syndromes studied were: (a) adenomatosis of the colon and rectum only, an autosomal dominant trait; (b) Turcot's syndrome, a rare autosomal recessive polyposis syndrome also characterized by central nervous system tumors; and (c) Gardner's syndrome, an autosomal dominant syndrome which, in addition to intestinal polyposis, is also clinically characterized by osteomas and soft tissue tumors. Fibroblasts from a patient with Turcot's syndrome were hypersensitive to MMS, having a D0 value of 0.24 mM (p less than 0.01) versus the normal average D0 of 0.36 mM and a D10 value of 0.95 mM (p less than 0.01) compared with the normal average value of 1.3 mM. Fibroblasts from the Gardner's syndrome proband were moderately sensitive to MMS, ethyl methanesulfonate, and N-methyl-N'-nitro-N-nitrosoguanidine due to significant differences of D10 values of 0.60 mM (p less than 0.01), 15 mM (p less than 0.01), and 4.8 microM (p less than 0.025), respectively, versus the normal average values of 1.3 mM,more » 28 mM, and 9.4 microM. Fibroblasts from the clinically affected Gardner's syndrome daughter of the proband were significantly more sensitive to MMS treatment, D0 of 0.22 mM (p less than 0.01) versus the normal average D0 of 0.36 mM and a D10 of 0.97 mM (p less than 0.01) versus the normal average. This differential sensitivity to the several DNA alkylating agents suggests that different mechanisms of hypersensitivity to these chemicals may be associated with fibroblasts from the various forms of familial polyposis.« less
Authors:
;
Publication Date:
OSTI Identifier:
5364768
Resource Type:
Journal Article
Resource Relation:
Journal Name: Cancer Res.; (United States); Journal Volume: 42:4
Research Org:
Harvard University School of Public Health, Boston, Massachusetts
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; DNA; ALKYLATING AGENTS; BIOLOGICAL EFFECTS; CENTRAL NERVOUS SYSTEM; FIBROBLASTS; GENETIC VARIABILITY; INTESTINES; METHYL METHANESULFONATE; NEOPLASMS; NITROSO COMPOUNDS; SENSITIVITY; SKIN; SURVIVAL CURVES; TUMOR CELLS; ANIMAL CELLS; BIOLOGICAL VARIABILITY; BODY; CONNECTIVE TISSUE CELLS; DIGESTIVE SYSTEM; DISEASES; ESTERS; GASTROINTESTINAL TRACT; MUTAGENS; NERVOUS SYSTEM; NUCLEIC ACIDS; ORGANIC COMPOUNDS; ORGANIC NITROGEN COMPOUNDS; ORGANIC SULFUR COMPOUNDS; ORGANS; SOMATIC CELLS; SULFONIC ACID ESTERS 550901* -- Pathology-- Tracer Techniques