Relationship Between Thymidylate Synthase and p53 and Response to FEC Versus Taxane Adjuvant Chemotherapy for Breast Carcinoma

Calascibetta, A; Martorana, Annamaria; Cabibi, Daniela; Aragona, F; Sanguedolce, R

doi:10.1179/joc.2011.23.6.354

Cited by 4 publications

(5 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data demonstrated that the level of TS protein was significantly decreased only in wild-type TP53 containing human lung cells (A549 and H460) that had been treated by DOC in a dose-dependent manner. Conversely, TS and TP53 levels were reported in 84 breast tumor samples that were examined using immunohistochemistry ( 27 ). Another study revealed that wild-type TP53 status was associated with low protein expression of TS in human colon carcinoma cell lines LoVo 92 (wild-type TP53) and WiDr T (mutant TP53) ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

High pemetrexed sensitivity of docetaxel-resistant A549 cells is mediated by TP53 status and downregulated thymidylate synthase

Kuo¹,

Chiu

et al. 2017

Oncology Reports

View full text Add to dashboard Cite

The chemoresistance of non-small cell lung cancer (NSCLC) that occurs in docetaxel (DOC) chemotherapy substantially decreases the survival of patients. To overcome DOC-induced chemoresistance, we established DOC-selected A549 lung cancer sublines (A549/D16 and A549/D32) and revealed that both sublines were cross-resistant to vincristine (VCR) and doxorubicin (DXR). Notably, both sublines were more sensitive to pemetrexed (PEM) than parental cells according to MTT and clonogenic assays. The expression levels of thymidylate synthase (TS) and γ-glutamyl hydrolase (GGH) were downregulated in DOC-resistant sublines. When exogenous TS was overexpressed in A549/D16 cells, PEM sensitivity was significantly decreased, however it was not decreased by overexpression of exogenous GGH. PEM treatment induced more apoptotic sub-G1 cells in both DOC-resistant sublines and in the in vivo PEM sensitivities of A549/D16 cells. These findings were further confirmed by a xenografted tumor model. To unmask the mediator of TS downregulation, we investigated human lung cancer cell lines that have various TP53 statuses using DOC treatment. The level of TS protein was significantly decreased in wild-type TP53-containing cells with DOC treatment; TS expression levels were not affected in mutant-TP53 and TP53-null cells under the same conditions. Furthermore, when the expression of TP53 was inhibited in A549 cells, the expression level of TS was increased. Our data indicated that DOC activated wild-type TP53 and suppressed TS expression under continuous DOC exposure. Therefore, the expression of TS remained at low levels in DOC-resistant A549 cancer cells. Our data revealed that for lung cancer with DOC resistance and wild-type TP53 status, the administration of PEM as a second-line agent to overcome DOC-resistance may benefit patients.

show abstract

Section: Discussionmentioning

confidence: 99%

High pemetrexed sensitivity of docetaxel-resistant A549 cells is mediated by TP53 status and downregulated thymidylate synthase

Kuo¹,

Chiu

et al. 2017

Oncology Reports

View full text Add to dashboard Cite

show abstract

“…As a multitargeted antifolate, pemetrexed inhibits several de novo synthesis enzymes for purine and pyrimidine, including TYMS. Previous clinical and in vitro studies showed that cancer cell lines with TYMS expression showed poor sensitivity to cisplatin-and taxane-based chemotherapy regimens (24,25). Pemetrexed treatment in non-small cell lung cancer patients indicated that low TYMS mRNA expression was associated with increased ORR (26), and TYMS was an appropriate biomarker for pemetrexed chemotherapy response in non-small cell lung cancer (9,10,27).…”

Section: Tyms Expression --------------------------------------------mentioning

confidence: 99%

Thymidylate synthase predicts poor response to pemetrexed chemotherapy in patients with advanced breast cancer

et al. 2018

View full text Add to dashboard Cite

Pemetrexed is a candidate chemotherapy regimen for anthracycline- and taxane-pretreated advanced breast cancer. However, to the best of our knowledge, no efficient treatment efficacy biomarkers have been identified. In the present study, the potential correlation between thymidylate synthase (TYMS) expression and clinical response to pemetrexed was examined in advanced breast cancer. A retrospective collection was performed by using 77 advanced breast cancer subjects, who received at least three cycles of pemetrexed treatment in the Second Hospital of Shandong University hospital. TYMS expression was detected using immunohistopathological staining. The correlations between TYMS and therapeutic efficacies of different chemotherapy treatment were analyzed. The objective response rate (ORR) and disease control was 31.17 and 64.94%, respectively. Immunohistochemical staining demonstrated that TYMS expression was observed in the cytoplasm and nuclei of breast cancer cells. High TYMS expression was observed in 32 specimens. Elevated TYMS expression was correlated with higher histological grade and lymph node metastasis (P<0.05). Furthermore, significantly higher TYMS expression was observed in treatment-resistant patients than response ones (P<0.05). Patients with low expression level of TYMS exhibit significantly higher ORR. Cox regression analysis indicated that elevated TYMS expression was a detrimental factor for pemetrexed treatment for advanced breast cancer patients. The present results suggested that TYMS expression levels predicts therapeutic sensitivity of pemetrexed chemotherapy in advanced breast cancer, indicating that it may be a useful biomarker to choose chemotherapy regimens.

show abstract

“…The optimal pH range in leukemia is 7.0-8.1 [147]. TS is also a prognostic biomarker in tumors and is associated with drug resistanc [148][149][150][151][152][153].…”

Section: Dihydroorotase Inhibitorsmentioning

confidence: 99%

“…TS is also a prognostic biomarker in tumors and is associated with drug resistance [ 148 , 149 , 150 , 151 , 152 , 153 ].…”

Section: The Pyrimidine Synthesis Pathwaymentioning

confidence: 99%

Role of pH in Regulating Cancer Pyrimidine Synthesis

Al‐Qahtani

Koltai²,

Ibrahim

et al. 2022

JoX

View full text Add to dashboard Cite

Replication is a fundamental aspect of cancer, and replication is about reproducing all the elements and structures that form a cell. Among them are DNA, RNA, enzymes, and coenzymes. All the DNA is doubled during each S (synthesis) cell cycle phase. This means that six billion nucleic acids must be synthesized in each cycle. Tumor growth, proliferation, and mutations all depend on this synthesis. Cancer cells require a constant supply of nucleotides and other macromolecules. For this reason, they must stimulate de novo nucleotide synthesis to support nucleic acid provision. When deregulated, de novo nucleic acid synthesis is controlled by oncogenes and tumor suppressor genes that enable increased synthesis and cell proliferation. Furthermore, cell duplication must be achieved swiftly (in a few hours) and in the midst of a nutrient-depleted and hypoxic environment. This also means that the enzymes participating in nucleic acid synthesis must work efficiently. pH is a critical factor in enzymatic efficiency and speed. This review will show that the enzymatic machinery working in nucleic acid synthesis requires a pH on the alkaline side in most cases. This coincides with many other pro-tumoral factors, such as the glycolytic phenotype, benefiting from an increased intracellular pH. An increased intracellular pH is a perfect milieu for high de novo nucleic acid production through optimal enzymatic performance.

show abstract

Relationship Between Thymidylate Synthase and p53 and Response to FEC Versus Taxane Adjuvant Chemotherapy for Breast Carcinoma

Cited by 4 publications

References 8 publications

High pemetrexed sensitivity of docetaxel-resistant A549 cells is mediated by TP53 status and downregulated thymidylate synthase

High pemetrexed sensitivity of docetaxel-resistant A549 cells is mediated by TP53 status and downregulated thymidylate synthase

Thymidylate synthase predicts poor response to pemetrexed chemotherapy in patients with advanced breast cancer

Role of pH in Regulating Cancer Pyrimidine Synthesis

Contact Info

Product

Resources

About