埼玉医科大学雑誌 第31巻 第4号別頁 (2004年10月) T51-T57頁 ◇論文(図表を含む全文)は,PDFファイルとなっています.

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Thesis
肺癌における組織内Thymidylate synthase(TS)およびDihydropyrimidine dehydrogenase(DPD)活性と予後に関する検討

赤石 亨
埼玉医科大学呼吸器外科
(指導:金子 公一助教授 )


医学博士 甲第920号 平成16年3月19日 (埼玉医科大学)


Tissue Activities of Thymidylate Synthase (TS) and Dihydroprimidine Dehydrogenase (DPD) and Their Prognostic Relevance in Primary Lung Cancer

 Tissue expressions of thymidylate synthase (TS), a target enzyme for 5-flurouacil (5-FU)-based anticancer agents, and dihydroprimidine dehydrogenase (DPD), a degradation enzyme for 5-Fu-based anticancer agents, have been suggested to be potentially associated with not only antitumor efficacy in anticancer drugs but also tumor characteristics and prognosis. Tissue activities of TS and DPD were measured, and their relationships with tumor characteristics such as histological type, degree of cell differentiation, etc., and prognosis were examined. Further, the relationship between the levels of TS and DPD expressions and those of TS and DPD activities was investigated by immunohistological staining utilizing anti-TS antibody, anti-DPD antibody, cyclin A and ki-67. In a total of 55 patients with surgically resected primary lung cancer, enzymatic activities in cancerous tissues of their resected lung tumors as well as normal lung tissues were measured. TS activity in the tumor lung tissue and normal lung tissue was 0.031 pmol/mg protein (hereafter the unit omitted) and 0.022, respectively, and DPD activity in the tumor lung tissue and normal lung tissue was 302.6 031 pmol/min/mg protein (hereafter the unit omitted)and 90.1, respectively, exhibiting a trend toward an elevated level of both activities in the tumor lung tissues. TS activity showed no difference between the two types(squamous cell carcinoma and adrenocarcinoma) but DPD activity was high in the cases of adrenocarcinoma. TS activity was high at earlier disease stages I and II, while DPD activity was lower at stages I and II, compared to stages III and IV. TS and DPD activities in recurrent cases were 0.027 and 271.1, respectively, where in non-recurrent cases they were 0.037 and 290.1, respectively, thus showing a slightly elevated level of TS activity in the non-recurrent cases. On immunohistological staining of cancerous tissues, in both TS and DPD staining, the level of their activities tended to be high in cases stained positively, and a correlation was observed between enzymatic activity and expression of enzyme. In cases shown positive for TS staining, many cases were positive for cyclin A as well as Ki-67 and a similar pattern was observed in cases shown positive for DPD staining. However, in the DPD staining, marked tissue inhomogeneity was observed and, even in cases stained positively, there were some such cases as the negative part being mixed in a portion of the tissue, which even led us to consider this as the cause of fluctuations in the level of activity. The levels of TS and DPD activities in the lung cancer tissue were seen in part correlated with tumor characteristics and prognosis and, further, their usefulness was also suggested as markers for not only prognostic evaluation but also pre- and post-operative adjuvant chemotherapies.
Keywords: Thymidylate synthase, Dihydroprimidine dehydrogenase, 5-flurouacil, lung cancer, cyclinA, Ki-67
(C) 2004 The Medical Society of Saitama Medical School
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