Thymidylate synthase: a critical target for cancer chemotherapy

Our plain-English summary of Thymidylate synthase: a critical target for cancer chemotherapy, by M.G. Rose, M.P. Farrell, J.C. Schmitz (Clinical Colorectal Cancer, 2002).

The study

• Authors: M.G. Rose, M.P. Farrell, J.C. Schmitz
• Journal: Clinical Colorectal Cancer
• Published: 2002;1(4):220-9
• Type of article: Review
• Cited by: 98 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Thymidylate synthase (TS) is a key enzyme in the synthesis of 2'-deoxythymidine-5'-monophosphate, an essential precursor for DNA biosynthesis. For this reason, this enzyme is a critical target in cancer chemotherapy. As the first TS inhibitor in clinical use, 5-fluorouracil (5-FU) remains widely used for the treatment of colorectal, pancreatic, breast, head and neck, gastric, and ovarian cancers. The reduced folate, leucovorin, has been shown to enhance the activity of 5-FU in colorectal cancer. However, response rates of the combination remain in the 25%-30% range, and much effort has been focused on designing new, more potent TS inhibitors. Raltitrexed is a folate analogue that is approved as first-line therapy for advanced colorectal cancer in Europe, Australia, Canada, and Japan, although it remains an investigational agent in the United States. Pemetrexed is an antifolate analogue that has shown promising activity in several solid tumor types, including mesothelioma. ZD9331, a highly specific TS inhibitor that dose not require polyglutamation for its activation, has shown activity in patients with refractory ovarian and colorectal cancer. Capecitabine is an oral fluoropyrimidine carbamate that was designed to generate 5-FU preferentially in tumor cells; this agent was recently approved by the US Food and Drug Administration as first-line therapy for patients with advanced colorectal cancer. As the number of TS inhibitors available for general clinical use increases, further research is needed to elucidate the critical molecular and biochemical elements that determine the efficacy and tumor specificity of each compound.

In plain English

This article was a review, not an original study. The authors reviewed drugs that block thymidylate synthase, an enzyme cells need to make DNA. It emphasized how the drugs work, their side effects and their results in patients. The article did not discuss asbestos. Citing other studies, the authors reported response rates of 10%-15% for 5-fluorouracil (5-FU) alone and 25%-30% with leucovorin. In a European trial of 439 patients with advanced colorectal cancer, response rates were 20% with raltitrexed and 16.6% with 5-FU/leucovorin. A North American trial found longer survival with 5-FU/leucovorin (12.7 versus 9.7 months). The review's mesothelioma numbers came from another group's ongoing phase I trial of pemetrexed with carboplatin. Of 22 patients enrolled so far, 14 had improved symptoms and 10 showed response on CT scans. The review also cited preliminary phase II results showing encouraging activity in mesothelioma, breast and gastric cancers. A combined analysis of two trials (1207 patients) found response rates of 26% with capecitabine and 17% with 5-FU/leucovorin. The authors concluded that future work must identify what determines each drug's activity and selectivity.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review of published preclinical and clinical studies of thymidylate synthase (TS) inhibitor drugs
• Who was studied: No patients were studied directly. The review covered published laboratory studies and clinical trials of TS inhibitors in various cancers, mainly colorectal cancer.
• Exposure: Chemotherapy drugs that inhibit TS: 5-fluorouracil (with or without leucovorin), CB3717, raltitrexed, pemetrexed, GS7904L, ZD9331, AG331, nolatrexed and capecitabine, and capecitabine combined with radiation therapy. No asbestos exposure was discussed.
• Main results:
  • Reported from other studies: response rates were 10%-15% with single-agent 5-FU and 25%-30% with 5-FU plus leucovorin.
  • Reported from a European phase III trial of 439 patients with previously untreated advanced colorectal cancer: the response rate was 20% with raltitrexed versus 16.6% with 5-FU/leucovorin.
  • Reported from a North American phase III trial: time to progression and overall survival were significantly longer with 5-FU/leucovorin than with raltitrexed (survival 12.7 versus 9.7 months).
  • Reported from an ongoing phase I trial by Calvert et al of pemetrexed with carboplatin in malignant mesothelioma: of 22 patients enrolled so far, 14 had improved symptoms and 10 showed response by CT scan.
  • Reported from other studies: preliminary phase II results showed encouraging activity of pemetrexed in patients with mesothelioma, breast and gastric cancers.
  • Reported from an integrated analysis of two phase III trials (1207 patients with metastatic colorectal cancer): overall response rates were 26% with capecitabine versus 17% with 5-FU/leucovorin.
• The authors' conclusion: The authors concluded that future work needs to identify the factors that determine the antitumor activity and selectivity of each TS inhibitor.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Colon cancer.

Medical terms in this study, explained in our Lexicon: Chemotherapy, Fluorouracil (5-FU), Ovarian Cancer, Colorectal Cancer, Raltitrexed, First-line Therapy, Pemetrexed (Alimta), Antifolate.

Related studies

• Thymidylate synthase and folyl-polyglutamate synthase are not clinically useful markers of response to pemetrexed in patients with malignant pleural mesothelioma — D.E. Lustgarten, C. Deshpande, et al. (2013)
• The issue of studies evaluating biomarkers which predict outcome after pemetrexed-based chemotherapy in malignant pleural mesothelioma — F. Mairinger, C. Vollbrecht, et al. (2013)
• Reduced folate carrier and folylpolyglutamate synthetase, but not thymidylate synthase predict survival in pemetrexed-treated patients suffering from malignant pleural mesothelioma — F. Mairinger, C. Vollbrecht, et al. (2013)
• Raltitrexed: current clinical status and future directions — E. Van Cutsem, D. Cunningham, et al. (2002)
• Downregulation of thymidylate synthase and E2F1 by arsenic trioxide in mesothelioma — S.K. Lam, Y.Y. Li, et al. (2015)
• Downregulation of thymidylate synthase by RNAi molecules enhances the antitumor effect of pemetrexed in an orthotopic malignant mesothelioma xenograft mouse model — A.S. Abu Lila, C. Kato, et al. (2016)

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