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Downstream molecular determinants of response to 5-fluorouracil and antifolate thymidylate synthase inhibitors
B Van Triest1, H M Pinedo, G Giaccone
1Department of Oncology, University Hospital VU, Amsterdam, The Netherlands.
Abstract:
Thymidylate synthase (TS) is an essential enzyme for the de novo synthesis of thymidylate and subsequently DNA synthesis. TS has been used as a target for cancer chemotherapy in the development of fluoropyrimidines such as 5-fluorouracil (5-FU) and 5-fluorodeoxyuridine and of novel folate-based TS inhibitors such as ZD1694 (Tomudex, Raltitrexed), ZD9331, LY231514 (ALIMTA, Pemetrexed), AG337 (Thymitaq, Nolatrexed) and AG331. Although TS has been considered as a target for chemotherapy, the precise mechanism by which TS inhibition leads to cell death is still not completely resolved. TS inhibition results in depletion of dTTP, an essential precursor for DNA, and an increase in dUTP. This results in the so-called thymine-less death due to misincorporation of dUTP into DNA; its excision, catalysed by uracil-DNA glycosylase, results in DNA damage. Both this imbalance in dTTP/dUTP and DNA damage can result in induction of downstream events, leading to apoptosis. On the other hand a specific interaction exists between oncogenes and TS, by binding of TS protein to the p53 and c-myc RNA, while wt p53 can also inhibit TS promotor activity. TS inhibition by either 5-FU or antifolates can also result in a depression of TS protein mediated inhibition of TS mRNA translation leading to induction of more TS protein synthesis, and p53 protein may further deregulate this process. These complex indirect and direct interactions between oncogenes and TS may have as yet unclear clinical implications, since most data are based on in vitro or in vivo studies and some results are contradictive. In some preliminary clinical studies evidence was postulated for a combined prognostic role for TS and p53. This knowledge should be used to design clinical studies with the aim to deliver effective treatment to potentially sensitive patients both in the adjuvant setting and in advanced stage disease.
Insights
Thymidylate synthase (TS) inhibition disrupts DNA synthesis, causing thymine-less death and DNA damage. Complex interactions with oncogenes like p53 suggest potential prognostic roles and targeted cancer therapy strategies.
Area of Science:
- Biochemistry and Molecular Biology
- Cancer Research and Pharmacology
Background:
- Thymidylate synthase (TS) is a crucial enzyme for DNA synthesis, making it a key target for cancer chemotherapy.
- Established TS inhibitors include fluoropyrimidines (e.g., 5-FU) and novel folate-based drugs (e.g., Raltitrexed, Pemetrexed).
Purpose of the Study:
- To elucidate the precise mechanisms by which TS inhibition leads to cancer cell death.
- To explore the intricate interactions between TS, oncogenes (p53, c-myc), and their implications for cancer therapy.
Main Methods:
- Review of existing literature on TS inhibition, DNA synthesis, and oncogene interactions.
- Analysis of in vitro and in vivo study data regarding TS targeting and its downstream effects.
Main Results:
- TS inhibition causes dTTP depletion and dUTP accumulation, leading to 'thymine-less death' via dUTP misincorporation and DNA damage.
- TS interacts with oncogenes, including binding to p53 and c-myc RNA, and p53 can regulate TS promoter activity.
- TS inhibition can paradoxically increase TS protein synthesis, a process potentially modulated by p53.
Conclusions:
- The complex interplay between TS and oncogenes has unclear clinical implications, with some studies suggesting a combined prognostic role for TS and p53.
- Further clinical studies are warranted to leverage this knowledge for designing targeted therapies for sensitive cancer patients in both adjuvant and advanced settings.