Predicting 5‐fluorouracil chemosensitivity of liver metastases from colorectal cancer using primary tumor specimens: Three‐gene expression model predicts clinical response

Abstract

We identified genes related to 5-fluorouracil (5-FU) sensitivity in colorectal cancer and utilized these genes for predicting the 5-FU sensitivity of liver metastases. Eighty-one candidate genes involved in 5-FU resistance in gastric and colon cancer cell lines were previously identified using a cDNA microarray. In this study, the mRNA expression levels of these 81 selected genes and the genes of 5-FUrelated enzymes, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and orotate phosphoribosyltransferase (OPRT), were measured using real-time quantitative RT-PCR assays of surgically resected materials from primary colorectal tumors in 22 patients. Clinical responses were estimated by evaluating the effects of 5-FU-based hepatic artery injection (HAI) chemotherapy for synchronous liver metastases. Four genes (TNFRSF1B, SLC35F5, NAG-1 and OPRT) had significantly different expression profiles in 5-FU-nonresponding and responding tumors (p < 0.05). A ''Response Index'' system using three genes (TNFRSF1B, SLC35F5 and OPRT) was then developed using a discriminate analysis; the results were well correlated with the individual chemosensitivities. Among the 11 cases with positive scores in our response index, 9 achieved a reduction in their liver metastases after 5-FU-based chemotherapy, whereas only 1 of the 11 cases with negative scores responded well to chemotherapy. Our ''Response Index'' system, consisting of TNFRSF1B, SLC35F5 and OPRT, has great potential for predicting the efficacy of 5-FU-based chemotherapy against liver metastases from colorectal cancer. ' 2006 Wiley-Liss, Inc.Key words: 5-fluorouracil; chemosensitivity; colorectal cancer; liver metastasis; prediction Colorectal cancer is one of the most common malignancies and the second cause of death from cancer in the United States. 1 Recent improvements in early diagnosis and surgical therapy have facilitated the detection of early colorectal cancer and have contributed to a constantly decreasing death rate 1 ; however, some patients remain undiagnosed until their tumor has reached an advanced stage. The prognosis of patients with colorectal cancer depends on the stage of the disease. Patients with Dukes A disease have a good prognosis, but those with Dukes D disease, especially those with hepatic metastases, have a very poor prognosis.2 Furthermore, despite the complete curative resection of the primary tumor, many patients develop local or distant recurrences, and distant recurrences and metastatic tumors remain a major cause of death for patients with colorectal cancer.2 Therefore, the most efficacious strategy for improving surgical outcome in patients with colorectal cancer is to control distant recurrences and metastases effectively using neoadjuvant and adjuvant chemotherapy.5-Fluorouracil (5-FU) is the most frequently used chemotherapeutic agent for neoadjuvant and adjuvant chemotherapy against metastatic colorectal cancer. However, despite combined chemotherapy with 5-FU and other agents (Cisplatin, Leucovorin or Oxaliplatin...

Evaluations of biomarkers associated with 5-FU sensitivity for non-small-cell lung cancer patients postoperatively treated with UFT

“…Previous clinical studies also revealed the positive expression and activity of OPRT to be associated with the responsiveness to 5-FU in a variety of human cancers, including colorectal cancers (Isshi et al, 2002;Fujii et al, 2003;Ichikawa et al, 2003a;Matsuyama et al, 2006) and bladder carcinomas (Mizutani et al, 2004). However, these studies were performed using relatively small number of patients, and then were evaluated by biochemical assays for OPRT enzyme activity or reverse transcriptional PCR (RT -PCR) assays for OPRT gene expression.…”

Delivery of PAR-4 plasmid in vivo via nanoliposomes sensitizes colon tumor cells subcutaneously implanted into nude mice to 5-FU

“…5-fluorouracil (5-FU), or a related fluoropyrimidine, has been used as a component of the therapeutic regimen for colon cancer patients for four decades. [3][4][5] However, despite a combination of 5-FU with other chemotherapeutic agents, the clinical response rate for patients with liver metastases remains 20-39%, 6 indicating a need for a more effective regimen. The Par-4 protein was first identified in prostate cancer cells that were induced to undergo apoptosis.…”

Targeted therapy of cancer: new roles for pathologists in colorectal cancer

“…1,[8][9][10][19][20][21][22] Recently, additional enzymes important in 5-FU effects have been identified, including mRNA expression of TNFRSF1B, SLC35F5, and orotate phosphoribosyltransferase. [23][24][25] At the DNA level, a tandem repeat of 28 bp is present in the 5 0 -untranslated region of the TS gene and is linked to its expression and enzymatic activity in tumors. An increase in mRNA and protein has been reported in patients with three repeats (3R) as compared with two repeats (2R).…”