THE ROLE OF P53, P21(WAF1) (C1P1), AND BCL-2 IN RADIORESISTANT COLORECTAL-CARCINOMA/

Genetic alterations in the p53 tumor suppressor gene are common in hum an colorectal cancers, occurring in approximately 70% of tumors. In vi tro studies have shown that wild-type p53 is involved in controlling c ell cycle checkpoint functions and apoptosis involved in the cytotoxic response induced by ionizing radiation and several anticancer chemoth erapeutic agents. Wild-type p53 protein can transcriptionally activate the WAF gene, which encodes a cyclin-dependent kinase inhibitory prot ein, p21(WAF1/CIPI) protein, and transcriptionally repress the bcl-2 g ene, which encodes an inhibitor of apoptosis. To learn more about the in vivo relationship between p53 protein and the expression of p21(WAF 1/CIPI), and bcl-2 proteins in human colorectal cancers treated with r adiation therapy, we examined the expression of these proteins by immu nohistochemistry in pre-irradiated biopsy specimens and surgical speci mens with residual tumor of 27 patients with colorectal carcinoma. Cel l proliferation was measured using Ki-67 expression in the tumor cells . The p53 protein was not detected in normal colorectal mucosa, but it was expressed in 21 of 27 (78%) of pre-irradiated tumor samples and i n 19 of 27 (70%) of post-irradiated tumors. Expression of the bcl-2 pr otein in normal colorectal mucosa was confined to the basal epithelial cells of the crypts. Diffuse bcl-2 staining was detected in tumor cel ls in 13 of 27 (48%) of pre-irradiated samples and in 14 of 27 (52%) o f post-irradiated samples. p21(WAF1/CIPI) expression was detected in 1 4 of 27 (52%) of pre-irradiated samples but only in 7 of 27 (26%) of p ost-irradiated samples. No inverse relationship between expression of p53 protein and abnormal bcl-2 expression was apparent. p21(WAF1/CIPI) ,, expressed in most nonproliferating Ki-67-negative epithelial cells at the apical tips of the crypts in normal colorectal mucosa, but not in proliferating Ki-67-positive cells of adjacent adenomatous mucosa. An inverse relationship between Ki-67 and p21(WAF1/CIPI) expression wa s observed in normal colorectal mucosa and adjacent adenomatous mucosa . After radiation therapy, p53 protein accumulation did not change amo ng residual tumors in 18 cases (three of which were initially negative and remained negative); in four cases there was a significant increas e, and five cases had a substantial decrease of p53 expression. Aberra nt bcl-2 expression is not correlated with expression of p53 and does not increase significantly In post-irradiated tumor cells. p21(WAF1/CI PI) expression is markedly reduced in tumor cells that survive radiati on therapy. Copyright (C) 1997 by W.B. Saunders Company.