THYMIDYLATE SYNTHASE QUANTITATION IN HUMAN COLON CANCER

大肠肿瘤会影响大约二十人之一 在美国1992年，美国约有6万名患者。 会死于扩散性大肠癌5-氟尿嘧啶（5-FU）， 最有效和广泛使用的抗结肠直肠癌的全身性药物， 形成了几乎所有针对这种疾病的系统治疗的基础。最好的 5-FU作用的已知机制是其阻断 通过抑制酶将胸苷掺入DNA 胸苷酸合成酶（TS）。 通过蛋白质测定对肿瘤内TS进行定量表明， 肿瘤内的这种量之间的一致的反比关系， 酶和肿瘤对5-FU反应的可能性。最近，适应 PCR技术的发展提供了一种超灵敏的方法， 定量测量TS的基因表达， 10毫克的人类肿瘤组织。由此获得的初步数据 技术证实了上述的反向关系。通过 将联合国系统的数据管理和统计资源 西南肿瘤组，该项目将采用PCR技术， 确定TS在播散性大肠肿瘤中的基因表达， 以及那些为了治愈而切除的肿瘤。前瞻性 TS在播散性大肠癌中表达的测量将是 用于确认TS表达水平预测应答 和/或对5-FU的抗性。注意到临床耐药（进展）后 对于那些最初表现出临床反应的患者， 再次进行活检以评估TS表达的变化。是 预期通过PCR技术测定的TS表达将 定义患者对5-FU的先天性和获得性耐药的“标志物” 大肠癌肿瘤内TS表达可用于 确定是否有扩散性大肠癌患者应该 接受5-FU或实验性药物作为一线治疗。通过 正常粘膜、原发性肿瘤和淋巴内TS表达的测量 结节（有和无肿瘤），遗传变异的范围， 来自同一患者的组织将被确定并与 这些肿瘤的自然史。通过比较TS的定量 登记患者的复发率和生存率 西南肿瘤组大肠癌术后试验，其作用 作为独立的预后变量。

Tumors of the large bowel will affect approximately one in twenty persons in the United States. In 1992, approximately 60,000 patients in the U.S. will die of disseminated large bowel cancer. 5-Fluorouracil (5-FU), the most active and widely used systemic agent against colorectal cancer, forms the basis of almost all systemic therapy for this disease. The best understood mechanism of 5-FU action is its ability to block the incorporation of thymidine into DNA by inhibition of the enzyme thymidylate synthase (TS). Quantitations of intratumoral TS by protein assays have suggested a consistent inverse relationship between the intratumoral amount of this enzyme and the likelihood of tumor response to 5-FU. Recently, adaptation of PCR technology has provided an ultra-sensitive method for quantitatively measuring the genetic expression of TS using as little as 10 mg of human tumor tissue. Preliminary data obtained with this technology confirms the inverse relationship mentioned above. By incorporating the data management and statistical resources of the Southwest Oncology Group, this project will employ PCR technology to ascertain the genetic expression of TS in disseminated large bowel tumors, as well as in those tumors which have been resected for cure. Prospective measurements of TS expression in disseminated large bowel cancer will be utilized to confirm that the level of TS expression predicts response and/or resistance to 5-FU. Upon noting clinical resistance (progression) for those patients initially exhibiting a clinical response, tumors will be biopsied again to assess for a change in TS expression. It is anticipated that TS expression, as determined by PCR technology, will define a "marker" of innate and acquired resistance to 5-FU in patients with large bowel cancer. Intratumoral TS expression could then be used to determine whether a patient with disseminated large bowel cancer should receive 5-FU or an experimental agent as first line treatment. Through measurement of TS expression within normal mucosa, primary tumor and lymph nodes (with and without tumor), the range of genetic variability among tissues from the same patient will be ascertained and correlated with the natural history of these tumors. By comparing the quantitation of TS expression with recurrence and survival for patients registered on Southwest Oncology Group postoperative large bowel cancer trials, its role as an independent prognostic variable will be determined.