절제가능한 대장암환자에서 thymidylate synthase, Cox-2, VEGF, p53의 의의

Abstract

목적: 전이성 대장암에서 몇몇 신약들이 개발되어 무병생존율과 전체생존율이 증가하고 있다. 이들 약제 중 5-Fluorouracil (5-FU)는 아직까지 가장 유용한 약제 중 하나이며 이를 포함한 항암요법을 시행할 환자를 선택하는 것은 중요한 문제이다. 타이미딜레이트 합성효소 (Thymidylate synthase, TS) 는 DNA 합성과 복구에 필요한 데옥시우리딜레이트에서 데옥시타이미딜레이트로 이화적 메칠화에 중요한 역할을 한다. 대장암에서 TS의 예후적 가치에 대해 의견의 일치를 보지 못하고 있다. 한편, TS, 사이클로옥시게네이즈 2 (Cyclooxygense-2, Cox-2), 혈관내피성장인자(Vascular endothelial growth factor, VEGF), p53의 발현 정도가 5-FU를 포함한 항암요법에 대한 반응 및 예후와 연관이 있을 것으로 알려져 있다. 본 연구는 TS, Cox-2, VEGF, p53에 대한 Dukes병기 B, C의 대장암 환자에서 임상적 의의에 대하여 조사하였다. 방법: TS, Cox-2, VEGF, p53의 발현은 Dukes병기 B, C의 절제된 대장암 91건에 대하 면역조직화학적 염색방법을 이용하여 결정하였다. TS, Cox-2, VEGF, p53 사이의 연관에 대하여 평가하였으며 이 각각의 단백의 표현과 생존 기간을 포함한 임상병리학적인 인자들과의 관계를 조사하였다. 결과: TS, Cox-2, VEGF, p53의 표현율은 각각 35.2%, 56.0%, 51.6%, 48.4%였다. TS의 발현이 VEGF, p53과 연관이 있었다(각각, p<0.05, p<0.01). TS가 저발현된 환자들은 TS가 고발현된 환자들 보다 생존 기간이 길었다(p=0.025). 게다가, TS와 VEGF 또는 TS와 p53의 공통발현은 생존율과 유의한 관계를 보였다(각각, p=0.043, p=0.0047). 그러나 연령, Dukes병기, 종양위치, 조직학적유형, 임파절전이, 재발과 TS의 표현율에 따른 차이는 없었다. 결론: 이러한 결과들은 TS의 과발현이 대장암의 나쁜 예후 인자로 고려될 수 있음을 제시한다. 핵심단어: thymidylate synthase, Cox-2, VEGF, p53, 대장암; Purpose: In the treatment of advanced metastatic colorectal cancer, several new agents, such as irinotecan and oxaliplatin, have been developed, which have improved both disease free and overall survivals. Among these agents, 5-fluorouracil (5-FU) still remains one of the most active agents, and the selection of patients who can benefit from 5- FU-based chemotherapy is still important. Thymidylate synthase (TS) plays a key role in the catalytic methylation of deoxyuridylate to deoxythymidylate, which is required for DNA synthesis and repair. TS level has been studied for its role in prognostic value for the colon cancer and the controversies of its value also have existed. And cyclooxygenase (Cox)-2, vascular endothelial growth factor (VEGF), and p53 have been known to be associated with clinical response to 5-FU based chemotherapy as well as the prognosis. This study was conducted to investigate the clinical significances of TS, Cox-2, VEGF, and p53 in patients with Dukes’ B and C adenocarcinoma of the colon. Methods: Expression of TS, Cox-2, VEGF, and p53 were determined by immunohistochemical staining from 91 cases of resected colorectal cancer specimens (Dukes’ B and C). The relationships among TS, Cox-2, VEGF, and p53 expression and the correlation between expressions of these proteins with various clinicopathological factors, including overall survival were evaluated. Results: The expression rates of TS, Cox-2, VEGF and p53 were 35.2%, 56.0%, 51.6% and 48.4%, respectively. The expression of TS was correlated to the expression of VEGF and p53 (P<0.05 and P<0.01, respectively). The patients with TS low-expression tumors had a longer survival than those with TS high-expression (P=0.025). In addition, the coexpression of TS and VEGF or p53 was significantly correlated to overall survival (P=0.043 and P=0.0047, respectively). However, there was no significant difference in other clinicopathological parameters such as age, sex, Dukes’ stage, tumor site, histologic type, lymph node involvement or recurrence between the TS positive and negative groups. Conclusions: These results suggested that overexpression of TS might be used as a poor prognostic factor for adenocarcinoma of the colon. Key words: thymidylate synthase, cyclooxygenase-2, vascular endothelial growth factor, p53, colon cancer