Thymidylate Synthase: A Critical Target for Cancer Chemotherapy

Rose, Michal G.; Farrell, Michael; Schmitz, John C.

doi:10.3816/ccc.2002.n.003

Cited by 120 publications

(98 citation statements)

References 47 publications

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“…FUMP is then metabolized into 5-fluorouridine triphosphate (FUTP), which can be incorporated into RNA and into 5-flurodeoxyuridine triphosphate (FdUTP), which can be incorporated into DNA (10). Although the incorporation into RNA and DNA is certainly an important aspect of the mechanism of action of 5FU, the potential mechanism that has received the most focus is the inhibition of TS by the formation of ternary complexes, as a number of chemotherapeutic drugs similarly inhibit TS, including methotrexate (11), pemetrexate and raltitrexed (12). TS is the enzyme required to convert deoxyuridine monophosphate (dUMP) to thymidine monophosphate (dTMP); the inhibition of TS causes a lack of dTMP, leading to the inhibition of DNA de novo synthesis and cell death, a phenomenon termed 'thymineless death' (13).…”

Section: Introductionmentioning

confidence: 99%

5FU resistance caused by reduced fluoro-deoxyuridine monophosphate and its reversal using deoxyuridine

et al. 2017

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Abstract. The mechanism of 5-fluorouracil (5FU) resistance was investigated, focusing on the level of thymidylate synthase (TS) ternary complex formed with fluoro-deoxyuridine monophosphate (FdUMP). MKN45 and 5FU-resistant MKN45/F2R cells were treated with 5FU and fluoro-deoxyuridine (FdU) in combination with deoxyuridine (dU) and thymidine (dT). Subsequently, the levels of ternary complex were determined by western blotting and the cell viability was calculated using an MTT assay. MKN45/F2R cells exhibited 5FU resistance (56.2-fold relative to MKN45 cells), and demonstrated decreased orotate phosphoribosyltransferase (OPRT) and increased TS levels, requiring a higher concentration of 5FU to induce ternary complex formation than MKN45 cells. Following transfection of small interfering RNA against OPRT, MKN45 exhibited increased resistance to 5FU and decreased ternary complex formation subsequent to treatment with 5FU, indicating that decreased OPRT led to increased 5FU resistance. However, MKN45/F2R also exhibited resistance to FdU, which can be converted to FdUMP without OPRT, and there was decreased ternary complex formation after treatment with FdU, indicating that the 5FU-resistant cells had the ability to decrease intracellular FdUMP. The addition of dU and thymidine dT to 5FU promoted the formation of ternary complexes and reversed 5FU resistance in MKN45/F2R cells, although dT inhibited the efficacy of raltitrexed (another TS inhibitor). These results suggested that 5FU-resistant cells had the ability to reduce intracellular FdUMP irrespective of decreased OPRT, which led to resistance to 5FU. This resistance was then inhibited by treatment with dT or dU. IntroductionDespite recent advances in the development of diagnostic tools for gastric cancer, many patients with gastric cancer continue to be diagnosed at a late stage, and even following curative surgery, recurrent tumors frequently occur. Therefore, gastric cancer remains a major cause for cancer-associated mortality worldwide (1) and the development of novel drug therapies for gastric cancer is important.5FU is currently a key drug for adjuvant therapy following curative surgery (2-4) and for the treatment of metastatic gastric cancer (5,6). Three mechanisms have been proposed for its action: Incorporation into RNA (7), incorporation into DNA (8) and the inhibition of thymidine synthase (TS) leading to the inhibition of DNA de novo synthesis by forming a ternary complex composed of TS, 5,10-methylenetetrahydrofolate (CH2THF) and fluoro-deoxyuridine monophosphate (FdUMP) (9). The first step in the activation of 5FU is the phosphorylation of 5FU by orotate phosphoribosyltransferase (OPRT), which metabolizes 5FU to 5-fluorouridine monophosphate (FUMP). FUMP is then metabolized into 5-fluorouridine triphosphate (FUTP), which can be incorporated into RNA and into 5-flurodeoxyuridine triphosphate (FdUTP), which can be incorporated into DNA (10). Although the incorporation into RNA and DNA is certainly an important aspect of the mechanism of action of 5FU,...

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Section: Introductionmentioning

confidence: 99%

5FU resistance caused by reduced fluoro-deoxyuridine monophosphate and its reversal using deoxyuridine

et al. 2017

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“…[10][11][12][13][14][15][16][17][18] Increased thymidylate synthase expression is one the most important mechanisms underlying the resistance to 5-fluorouracil (FU) in colorectal cancer. 19,20 Interestingly, activation of CASR reportedly downregulates the expression of thymidylate synthase and survivin, and upregulates cellular sensitivity to 5-FU in human colorectal cancer cell lines. 15 Moreover, it has been reported that vitamin D mediates its action in human colorectal cancer cells in a CASR-dependent manner and downregulates malignant cell behavior.…”

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confidence: 99%

Epigenetic inactivation of calcium-sensing receptor in colorectal carcinogenesis

et al. 2011

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Ca 2 þ is a chemopreventive agent for colon cancer. Ion transport systems are often altered in human cancer. The aim of this study was to clarify the alterations of calcium-sensing receptor (CASR), a member of the G proteincoupled receptor family, in colorectal carcinogenesis. We analyzed the expression of CASR in colorectal cancer cell lines and in cancer and adenoma tissues by RT-PCR and immunostaining. In addition, we analyzed methylation of the CASR promoter by using bisulfite sequence analysis and methylation-specific PCR. CASR mRNA and protein expression was significantly downregulated in most of the cancer cell lines. CpG islands were densely methylated in cancer cell lines with reduced CASR mRNA expression. Treatment with a demethylating agent, 5-aza-2 0 -deoxycytidine, and/or a histone deacetylase inhibitor, trichostatin A, restored CASR expression in the cancer cell lines. Disruption of CASR expression in CASR-unmethylated HCT-8 cells blocked the enhancing effect of Ca 2 þ on the cytotoxic response to 5-fluorouracil. CASR expression was observed in normal colonic epithelial cells and was retained in most adenoma tissues. CASR mRNA and protein expression was significantly downregulated in cancer tissues. There was an inverse relationship between CASR expression and degree of differentiation. Immunohistochemical CASR staining was reduced more predominantly in less-differentiated cancer tissues and/or in cancer cells at the invasive front, where nuclear/ cytoplasmic b-catenin was often localized. CASR methylation was detected in 69% of colorectal cancer tissues and 90% of lymph node metastatic tissues and was significantly correlated with reduced CASR expression. CASR methylation was also detected in 32% of advanced adenoma tissues but was detected in only 9% of adenoma tissues and was not detected in hyperplastic polyp tissues. CASR methylation seems to occur at an early stage and progress in colorectal carcinogenesis. The results suggest that epigenetic inactivation of CASR has an important role in colorectal carcinogenesis.

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“…The antitumour activity of 5-FU is (Rose et al, 2002): 5-fluoro-2 0 -deoxyuridine-5 0 -monophosphate (FdUMP) is one of the critical nucleotide metabolites generated in tumour cells and other sensitive tissues (Figure 1). FdUMP potently inhibits thymidylate synthetase by competitive binding, resulting in a thymine-depleted state ('thymine-less death').…”

Section: Discussionmentioning

confidence: 99%

Prophylactic options in patients with 5-fluorouracil-associated cardiotoxicity

et al. 2003

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At present, the various mechanisms involved in 5-fluorouracil (5-FU)-correlated cardiotoxicity remain to be elucidated and a universally accepted prophylaxis or treatment for this specific toxicity is not available. Although it may improve time to progression, survival and clinical benefit, a 5-FU-based regimen usually has to be discontinued if a patient experiences cardiotoxicity. Here, we describe our experience with three cases of 5-FU-associated cardiotoxicity. The angina-like pain that appeared approximately 95 h after beginning 5-FU therapy was apparently independent of the drug's administration modality. In the two patients receiving 5-FU 12-h flat continuous infusion from 22.00 to 10.00 h (5-FU 12-h c.i.) in combination with other drugs, the dose of 5-FU was reduced by 10 -20% and patients received prophylactic transepidermal nitroglycerin. In the third patient, 5-FU administration modality was changed and prophylactic therapy was not given. By taking these precautions, the patients no longer complained of anginal pain and none of them discontinued chemotherapy. (Kohne et al, 1998). The spectrum of toxicities associated with 5-FU involves the gastrointestinal tract, the bone marrow, the skin and the central nervous system. Last, but not the least, 5-FU may give cardiac toxicity that is less familiar to physicians and this may present as precordial pain, atrial arrhythmias, electrocardiogram (EKG) ST-T wave changes, ventricular dysfunction and cardiogenic shock.The overall incidence of 5-FU cardiotoxicity varies from 1.2 to 18% of patients and is usually underestimated, since silent EKG alterations often occur (Klaus Becker et al, 1999). The different mechanisms involved in 5-FU-associated cardiotoxicity are not yet fully understood and no unequivocally effective prophylaxis or treatment for this specific toxicity exists. Here, we describe three cases of 5-FU-associated cardiotoxicity, its clinical management and the prophylactic treatment used. PATIENTS AND METHODS Case 1A 57-year-old male, with positive family history for acute myocardial infarction (AMI) but with no history of cardiovascular disease, came to our observation after undergoing an anterior resection of the rectum for a stage III rectal -sigmoid adenocarcinoma (RSA) ( Table 1). Physical examination, chest X-rays, blood pressure and EKG were all within normal limits. The patient received four cycles of adjuvant chemotherapy with 5-FU (370 mg m À2 day À1 ) and folinic acid (FA) (50 mg tot À1 ) i.v. for 5 days, every 3 weeks.During adjuvant chemotherapy, disease progressed with liver metastasis and the patient's therapy was changed to irinotecan (180 mg m À2 ) day 1 and 5-Fu 12-h flat continuous infusion from 22.00 to 10.00 h (5-FU 12-h c.i.) (900 mg m À2 day À1 ) for 4 days, every 2 weeks. Approximately 93 h after starting the first cycle of the second 5-FU regimen, the patient presented angina-like pain that lasted a few minutes and disappeared with oral nitroglycerin. The blood pressure was 160/115 mmHg and the heart rate was 105 beats min...

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Thymidylate Synthase: A Critical Target for Cancer Chemotherapy

Cited by 120 publications

References 47 publications

5FU resistance caused by reduced fluoro-deoxyuridine monophosphate and its reversal using deoxyuridine

5FU resistance caused by reduced fluoro-deoxyuridine monophosphate and its reversal using deoxyuridine

Epigenetic inactivation of calcium-sensing receptor in colorectal carcinogenesis

Prophylactic options in patients with 5-fluorouracil-associated cardiotoxicity

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