Abnormal Sensitivity of Skin Fibroblasts from Familial Polyposis Patients to DNA Alkylating Agents¹

Fibroblast cell strains derived from different patients all afflicted with genetic diseases predisposing to the development of intestinal polyposis and cancer were tested for their sensitivity to the lethal effects of the DNA alkylating agents methyl methanesulfonate (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. Survival (relative cloneforming ability) of the various polyposis fibroblast strains was compared to the average survival of three normal human fibroblast strains by t test analysis of the respective values for the inverse of the slope of the survival curve (D₀) and the concentration resulting in 10% survival (D₁₀) with p < 0.05 considered significant.

Fibroblasts from the patient with adenomatosis of the colon and rectum (strain GM2355) were moderately but significantly sensitive to 4-nitroquinoline 1-oxide with D₀ and D₁₀ values of 0.069 µm (p < 0.05) and 0.15 µm (p = 0.01), respectively, compared with the normal values of 0.10 µm and 0.26 µm. In addition, strain GM2355 was significantly more sensitive to ethyl methanesulfonate based on D₁₀ comparison only, 24 mm versus the normal average D₁₀ of 28 mm (p < 0.05). Fibroblasts from the patient with Turcot's syndrome were hypersensitive to MMS, having a D₀ value of 0.24 mm (p < 0.01) versus the normal average D₀ of 0.36 mm and a D₁₀ value of 0.95 mm (p < 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 < 0.01), 15 mm (p < 0.01), and 4.8 µm (p < 0.025), respectively, versus the normal average values of 1.3 mm, 28 mm, and 9.4 µm. 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 < 0.01) versus the normal average D₀ of 0.36 mm and a D₁₀ of 0.97 mm (p < 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.