Thymidylate synthase is a predictor for response and resistance in hepatic artery infusion chemotherapy

doi:10.1016/S0304-3835(97)00220-6

Cancer Letters

Volume 118, Issue 1, 16 September 1997, Pages 29-35

https://doi.org/10.1016/S0304-3835(97)00220-6 Get rights and content

Abstract

The value of intratumoral thymidylate synthase (TS) quantitation as a predictive parameter for hepatic artery infusion (HAI) chemotherapy in patients with colorectal liver metastases was investigated. Relative TS mRNA levels were determined in 29 tumor samples using a quantitative RT-PCR amplification method. The median level of expression was 3.0 × 10⁻³ (no units) and varied considerably among the tumors over a range of 135-fold. Patients with low TS levels were 4.1-fold more likely to respond (P < 0.03) compared to patients with high TS levels. Our results indicate that TS quantitation is a valuable predictive marker for tumor response to HAI therapy.

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To comprehensively elucidate overall protein alterations associated with acute radiation-induced rectal injury in rats.
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Administration of adjuvant oral tegafur/uracil chemotherapy post hepatocellular carcinoma resection: A randomized controlled trial
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Citation Excerpt :
Theoretically, the lower activities of TS and DPD in tumors produce the better response to 5-FU.20–22 In fact, low TS patients who received hepatic artery infusion chemotherapy had 4.1 times higher response for colorectal liver metastases than those of high TS patients.23 Furthermore, in patients with neck and head cancer, complete responders had a significantly lower DPD activity than those of partial or no responders.24
Recurrence of hepatocellular carcinoma (HCC) after surgery is frequent, and is an important factor adversely influencing the long-term survival of patients. This prospective study evaluated whether adjuvant chemotherapy with oral tegafur/uracil (UFT) reduces the recurrence rate of HCC. In addition, expression of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) were investigated in resected tumors and nontumorous tissues, and the relationship between their expression and the effectiveness of UFT was examined.
A total of 117 patients who underwent curative hepatic resection for HCC were randomly allocated to UFT 400 mg/d (n = 24, UFT group) or surgery alone (n = 56, control group). The primary endpoint was the recurrence-free survival rate, and the secondary endpoint was the overall survival rate. Expression of the DPD and TS genes were quantified with TaqMan reverse transcription-polymerase chain reaction assay using β-actin as an internal standard. The cut-off value was set at the mean value of TS and DPD expression.
Among the 61 patients in the UFT group, 37 patients (60.6%) discontinued UFT within 1 month. Recurrence-free survival (p = 0.16) and overall survival (p = 0.29) were similar in the two groups. In the UFT group, recurrence-free survival did not differ significantly between high-TS (TS > 3.6) and high-DPD (DPD > 8.9; n = 10), and low-TS (TS ≤ 3.6) and low-DPD (DPD ≤ 8.9; n = 9) groups. However, there was a significant difference between the two groups in overall survival (p = 0.04).
Peroral UFT administration fails to prolong the recurrence-free rates and overall survival rates, in comparison with surgery alone. However, oral administration of UFT may improve the survival of HCC patients when the levels of TS and DPD mRNA are low in the tumor tissue.
Response prediction in metastasised colorectal cancer using intratumoural thymidylate synthase: Results of a randomised multicentre trial
2012, European Journal of Cancer
Citation Excerpt :
Several studies in mCRC demonstrated that high intratumoural TS levels correlated with resistance to fluoropyrimidine treatment.8,9 Similar observations were reported for liver metastases of CRC treated with fluoropyrimidine-based hepatic arterial infusion and other gastrointestinal malignancies.10–13 Despite these promising results as a predictor of response to 5-FU based chemotherapy TS has not been recommended for routine clinical practise nor have other markers.14
Molecular markers to predict response to 5-fluorouracil (FU)-based treatment of recurrent or metastasised colorectal cancer (mCRC) are not established. The aim of this trial was to determine the value of thymidylate synthase (TS), a key enzyme of DNA synthesis and target of 5-FU, to predict response to chemotherapy of mCRC.
Tumour tissue was obtained from 168 patients with mCRC for relative thymidylate synthase (TS) mRNA quantitation. Patients were randomised to receive either 5-FU/folinic acid (FA, FUFA) alone or in combination with irinotecan 5-fluorouracil/folinic acid and irinotecan (FOLFIRI) stratified by TS (low versus high). Primary end-point was overall response to first-line treatment among TS high patients. All parties, except for the randomisation centre, were blinded for TS status.
Biopsies (n = 168) were taken without complications. TS levels were available for 147 patients (87.5%). Analysing response to FUFA and FOLFIRI in the per protocol set (n = 119) after un-blinding TS in the data base revealed a trend to better overall response to FOLFIRI (9/19, 47%) in TS high compared to FUFA (5/23, 22%, p = 0.077). In patients with biopsies taken from liver lesions (n = 91) overall response to FOLFIRI and FUFA in TS high was 53% (9/17) and 18% (3/17), respectively (p = 0.035). In patients with low TS, no remarkable difference in overall response to FOLFIRI and FUFA was observed.
Taking a pre-treatment biopsy is a safe and feasible procedure in mCRC. After validation of our data in a larger group TS determination may have the potential to better help direct systemic treatment in patients with primarily non-resectable mCRC.
Improving the Efficacy and Safety of Anticancer Agents - the Role of Pharmacogenetics
2006, Novel Anticancer Agents
This chapter discusses the role of pharmacogenetics in improving the efficacy and safety of anticancer agents. The role of pharmacogenetics in the optimization of the efficacy and safety of cancer chemotherapy is important in oncology. The enzymes involved in cancer chemotherapy, including TPMT, DPD, TS, ABC group of transporters, UGT, MTHFR, and cytochrome P450 3A (CYP3A) are elaborated. TPMT catalyzes the S-methylation of thiopurine drugs such as 6-mercaptop-urine (6-MP), 6-thioguanine, and azathioprine to inactive metabolites. TPMT enzyme activity and immunoreactive protein levels in human tissues are controlled by a common genetic polymorphism. Molecular analysis of TPMT genotype is able to identify patients at risk for acute toxicity from thiopurines. DPD catalyzes the rate-limiting step in the catabolism of pyrimidines such as thymine and uracil and the fluoropyrimidine, 5-fluorouracil (5-FU). 5-FU is used in the treatment of breast, head, neck, and colorectal cancers. The ATP-binding cassette (ABC) transporter family comprises several drug transport proteins. The CYP3A enzymes account for approximately half of the metabolism carried out by cytochrome P450 enzymes. It is found that once the functional significance of a drug disposition pathway has been established, anticancer agents can be optimized and individualized by pharmacogenetic approaches into the routine care of patients receiving anticancer drugs.
Molecular predictors of lymph node metastasis in colon cancer: Increased risk with decreased thymidylate synthase expression
2005, Journal of Gastrointestinal Surgery
Citation Excerpt :
Previous studies examining the prognostic role of TS expression have reached somewhat conflicting results. There is some suggestion that cancers with higher levels of TS expression are associated with poorer survival and a poorer response to adjuvant chemotherapy.14–17 There are, however, a number of studies that have shown improved prognosis with higher TS expression, in agreement with our data.18,19
TNM staging in colon cancer has several limitations. Prognostic molecular markers are now being developed to address these limitations. The aim of this study was to identify a combination of genes and markers whose expression is predictive of nodal status and outcome in colon cancer. The expression of 12 genetic markers were examined in 66 node-positive and 65 node-negative T3 colon cancers. Gene expression was quantified using real-time polymerase chain reaction. Microsatellite instability status was available through the registry. Association with lymph node status was examined using univariate and multivariate logistic regression. Thymidylate synthase expression was statistically significantly associated with lymph node status (odds ratio 0.36; 95% confidence interval: 0.16–0.81). Microsatellite instability and the other genes were not associated with nodal status. Multiple logistic regression did not identify a significant multivariate predictive model. Decreased expression of thymidylate synthase is associated with a higher risk of lymph node metastasis in patients with T3 colon cancers. Microsatellite instability and the expression of other genes are not predictive of nodal status in this population. Thymidylate synthase gene expression may help identify patients at greater risk for progression of disease.
Are colon and rectal cancer two different tumor entities? A proposal to abandon the term colorectal cancer
2018, International Journal of Molecular Sciences

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Thymidylate synthase is a predictor for response and resistance in hepatic artery infusion chemotherapy

Abstract

Eur. J. Cancer

Eur. J. Cancer

Blood

Colorectal cancer; hepatic-directed therapy: the role of surgery, regional chemotherapy, and novel modalities

Long-term survivors of colorectal cancer with unresectable hepatic metastases

Dis. Colon Rect.

Quantitation of thymidylate synthase, dihydrofolate reductase, and DT-diaphorase gene expression in human tumors using the polymerase chain reaction

Cancer Res.

Colorectal cancer biology: clinical implications

The role of thymidylate synthase expression in the prognosis and outcome of adjuvant chemotherapy in patients with rectal cancer

J. Clin. Oncol.

p53 status and thymidylate synthase levels are predictors of chemotherapy efficacy in patients with advanced colorectal cancer

Thymidylate synthase mRNA level in adenocarcinoma of the stomach: a predictor for primary tumor response and overall survival

J. Clin. Oncol.