The expression of
nitric oxide synthase (NOS) was studied by
NAD(P)H diaphorase histochemical localization method in (i) individual cells of the normal colonic mucosa (n = 13) which served as control, (ii)
colonic polyps (n = 14), (iii) colonic
carcinoma (n = 20) and (iv) peritumoral mucosa (2 and 5 or 10 cm away from the
tumor). Four of the
tumor specimens had normal epithelium adjacent to the
cancer, which thus served as an internal control. The expression of NOS activity in
colon cancer was significantly reduced as compared to the control group of individuals (P < 0.004); undetectable in 25%, diminished in 45%, normal in 30%. On comparing the expression in normal mucosa and
polyps there was a significant reduction of the expression in
polyps (P < 0.027); undetectable in 14%, reduced in 35%, normal in 51%. When compared to the peritumoral mucosa at 2 and 10 cm the
tumor showed a significant reduction in expression of NOS activity (P < 0.001 and P < 0.0001 respectively). There was no significant difference seen in the expression at 2 and 10 cm (P = 0.329). The peritumoral mucosa at a distance of 2 cm away from the
tumor when compared to the control mucosa showed no significant difference (P = 1.000), although there is a tendency to a high normal expression of NOS activity in the mucosa at a distance of 2 cm. Similarly, there was no significant difference between the control mucosa and the peritumoral mucosa obtained at a distance of 10 cm (P = 0.383). The expression of NOS activity in all tissues examined was abolished by preincubation of tissue with the selective NOS inhibitor
L-NMMA but not with
D-NMMA. Our data showed extensive and significant reduction as identified by the
NAD(P)H diaphorase method in the expression of NOS activity, thereby reflecting the activity of
nitric oxide in
colon cancer and
colonic polyps. The generalized suppression of this activity, which precedes the onset of overt
neoplasia, may be an important event in colon
carcinogenesis. This aberrant expression could also be compatible with the selective advantage to either
tumor promotion and metastatic progression or to tumoricidal activity.