Quantitation of intratumoral thymidylate synthase expression predicts for resistance to protracted infusion of 5-fluorouracil and weekly leucovorin in disseminated colorectal cancers: Preliminary report from an ongoing trial

Leichman, Lawrence; Lenz, Heinz Josef; Leichman, Cynthia G.; Groshen, Susan; Danenberg, Kathleen D.; Baranda, Joaquina; Spears, C. P.; Boswell, William D.; Silberman, Howard; Ortega, Alejandro; Stain, Steven C.; Beart, Robert W.; Danenberg, Peter V.

doi:10.1016/0959-8049(95)00326-e

Cited by 91 publications

(41 citation statements)

References 15 publications

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“…Decreased levels of the target enzyme thymidylate synthase (TS) have been repeatedly associated with superior clinical outcome in gastrointestinal cancers, including stomach cancer (Leichman et al, 1995;Boku et al, 1998;Shirota et al, 2001). TS catalyses the formation of thymidylate, a source of DNA replication, from dUMP (Danenberg, 1977).…”

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confidence: 99%

Polymorphisms of glutathione S-transferases (GST) and thymidylate synthase (TS) – novel predictors for response and survival in gastric cancer patients

et al. 2005

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To evaluate the predictive value of a panel of gene polymorphisms involved in metabolism of 5-FU and cisplatin on clinical outcome in advanced gastric cancer patients. A total of 52 patients were enrolled in this study. DNA was extracted from paraffin-embedded tumour specimen. Genotypes were determined using PCR-RFLP. Median survival time was 6.0 months (95% CI 3.9;8.1). Overall response rate was 26%. Patients possessing the glutathione S-transferase P1-105 Valine/Valine (GSTP1-105VV) genotype showed a response rate of 67% compared to 21% in patients harbouring at least one GSTP1-105 Isoleucine (GSTP1-105I) allele (P ¼ 0.038). GSTP1-105VV patients demonstrated a significant superior median survival time of 15.0 months (95% CI 7.8;22.0) compared to 6.0 months (95% CI 5.1;7.0) in patients with at least one GSTP1-105I allele (P ¼ 0.037). Patients possessing a favourable thymidylate synthase (TS) genotype (2R/2R, 2R/3RC, 3RC/3RC) experienced a superior survival time of 10.2 months (95% CI 5.1;15.3) compared to 6.0 months (95% CI 5.0;7.0) in patients with unfavourable TS genotypes (P ¼ 0.099). Patients harbouring the GSTP1-105II genotype and one of the unfavourable TS genotypes showed an inferior median survival time of 6.0 months (95% CI 3.9;8.1) compared to 11 months (95% CI 6,23;15,77) in patients with either GSTP1-105VV or a favourable TS genotype (P ¼ 0.044). Testing for TS and GSTP1 polymorphisms may allow identification of gastric cancer patients who will benefit from 5-FU/cisplatin chemotherapy, sparing others the side effects of this chemotherapy.

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confidence: 99%

Polymorphisms of glutathione S-transferases (GST) and thymidylate synthase (TS) – novel predictors for response and survival in gastric cancer patients

et al. 2005

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“…Variations in intratumoral TS gene expression levels among patients' tumors have been shown to be a statistically significant predictor for response in colorectal cancer patients receiving 5-FU chemotherapy. Those tumors with high TS gene expression are generally non-responsive to protocols that include the TS-directed combination of 5-FU and leucovorin [17,18,20]. However, while high TS gene expression levels effectively predict nonresponse, low TS gene expression did not necessarily predict response: all responding patients had low TS expression, but a subset of patients with low TS gene expression levels did not respond to treatment [17].…”

Section: Discussionmentioning

confidence: 99%

“…For example, high gene expression of TS (determined by reverse transcriptase-polymerase chain reaction [RT-PCR]) has been shown to be associated with a low response to 5-FU (less than 5% response) in metastatic colon cancer. Although high TS expression effectively predicted non-response, low TS expression does not necessarily predict response, as a subset of non-responding patients also exhibited low TS expression [17,18]. Gene expression of TP and DPD has also been proposed to provide the additional predictive information, as tumors with low TS and TP expression were shown to exhibit a response rate of over 80%, while those with high TS and TP had a response rate of zero [19,20].…”

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confidence: 99%

Phase II clinical trial of capecitabine in the treatment of advanced, persistent or recurrent squamous cell carcinoma of the cervix with translational research: A gynecologic oncology group study

García¹,

Blessing

Darcy

et al. 2007

Gynecologic Oncology

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Purpose-To evaluate the anti-tumor activity and adverse events of capecitabine in advanced, persistent or recurrent squamous cell carcinoma of the cervix, and to explore biomarkers with the potential to predict capecitabine response and toxicity. The following member institutions participated in this study: University of Mississippi Medical Center, Indiana University School of Medicine, Wake Forest University School of Medicine, University of California Medical Center at Irvine, University of Texas-Galveston.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptExperimental Design-Eligible, consenting patients were treated with a starting dose of 2500 mg/m 2 /day or 1800 mg/m 2 /day(divided into two doses given every 12 hours) for 14 days of each 21-day cycle. Prior chemotherapy was allowed only in the context of radiation "sensitization". Genotyping in the 5' and 3' ends of thymidylate synthase (TS) was performed in DNA from pretreatment blood. Relative gene expression of TS, dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP) was quantified in RNA extracted from paraffin-embedded tumor.Results-All patients had prior radiotherapy and 22 received a radiation sensitizer. A partial response was observed in 4 of 26 (15%) evaluable patients. An additional 35% of patients achieved stable disease while 42% experienced increasing disease. The most common serious non hematological toxicities were gastrointestinal and dermatologic. Exploratory analyses suggested that: a germline polymorphism in the 3' or the 5' end of TS was not associated with TS gene expression, relative tumor expression of TS, DPD and TP were not correlated, and relative tumor expression of TP may predict severe anemia.Conclusions-Based on the modest response rate, this trial was closed without a second stage of accrual; single agent capecitabine was not selected for further study in advanced persistent or recurrent squamous cell carcinoma of the cervix previously treated with radiation or chemoradiation.

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“…An increase in TS protein levels has been suggested to be an important mechanism of resistance to chemotherapy with fluoropyrimidines [11]. TS has been suggested as a prognostic factor of survival in CRC [12Á16] and a predictor of response to 5-FU therapy [12,13,17,18] In a previous study, we reported that higher levels of TS were associated with shorter survival in CRC patients and with low response rate to therapy [19]. The present study is a continuation of this work, by comparing TS expression with the expression of MLH1 and MSH2.…”

Section: Discussionmentioning

confidence: 99%

Thymidylate synthase and microsatellite instability in colorectal cancer: Implications for disease free survival, treatment response and survival with metastases

et al. 2008

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Quantitation of intratumoral thymidylate synthase expression predicts for resistance to protracted infusion of 5-fluorouracil and weekly leucovorin in disseminated colorectal cancers: Preliminary report from an ongoing trial

Cited by 91 publications

References 15 publications

Polymorphisms of glutathione S-transferases (GST) and thymidylate synthase (TS) – novel predictors for response and survival in gastric cancer patients

Polymorphisms of glutathione S-transferases (GST) and thymidylate synthase (TS) – novel predictors for response and survival in gastric cancer patients

Phase II clinical trial of capecitabine in the treatment of advanced, persistent or recurrent squamous cell carcinoma of the cervix with translational research: A gynecologic oncology group study

Thymidylate synthase and microsatellite instability in colorectal cancer: Implications for disease free survival, treatment response and survival with metastases

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