Predictive value of thymidylate synthase expression in resected metastases of colorectal cancer

Corsi, Domenico; Ciaparrone, Marco; Zannoni, Gian Franco; Mancini, Marco; Cassano, Alessandra; Specchia, ML; Pozzo, Carmelo; Martini, Maurizio; Barone, Carlo

doi:10.1016/s0959-8049(01)00402-6

Cited by 33 publications

(12 citation statements)

References 25 publications

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“…A possible reason for the chemoresistance in patients with high TS is that the protein levels measured in primary CRC may not be an accurate reflection of the TS levels in metastatic or micrometastatic deposits (which represent the mechanism of relapse in patients with local and locally advanced disease) [40,41,42]. Another possible explanation is that the situation of circulating cells is clearly different from the situation of an established tumor in many respects.…”

Section: Discussionmentioning

confidence: 99%

Predictive Role of Thymidylate Synthase, Dihydropyrimidine Dehydrogenase and Thymidine Phosphorylase Expression in Colorectal Cancer Patients Receiving Adjuvant 5-Fluorouracil

Ciaparrone¹,

Quirino²,

Schinzari³

et al. 2006

Oncology

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Objective: The combined assessment of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP) gene expressions in metastatic colorectal cancer has been reported to be able to predict the efficacy of fluoropyrimidine-based chemotherapy. In order to evaluate the prognostic role in the adjuvant setting, we investigated the TS, DPD and TP expression in primary tumors of colorectal cancer patients treated with 5-fluorouracil (5-FU). Methods: TS, DPD and TP expression levels were determined by immunohistochemistry in paraffin-embedded primary tumor tissues from 62 patients with Dukes’ stage B and C colorectal cancers who underwent surgery and received adjuvant systemic chemotherapy with 5-FU. The median follow-up was 90 months (range 17–127). Results: Dukes’ stage C cancer and high TS expression were independent markers of poor prognosis for disease-free survival (DFS; p = 0.0009 and p = 0.007, respectively) and overall survival (OS; p = 0.0005 and p = 0.011, respectively). By multivariate analysis, patients with high DPD expression had significantly shorter DFS (p = 0.007) and OS (p = 0.005) compared to patients with low DPD expression. In the combined analysis of 2 markers, patients with low TS and low DPD had the best outcome in terms of DFS (p = 0.007) and OS (p = 0.03). The analysis of all 3 proteins showed that the patients with low expression of all 3 markers had significantly longer DFS (p = 0.04) and OS (p = 0.01) than patients with a high value of any one of the protein expressions. However, the joint analysis of 3 markers (group with TS–/DPD–/TP–) could not identify a subgroup of patients with a better prognosis compared to the analysis of 2 markers (group with TS–/DPD–). The analysis of Dukes’ stage C cancer patients confirmed a significant benefit in terms of DFS and OS (p = 0.001 and p = 0.006, respectively) when all 3 markers had low expression. We also found a positive significant correlation between TS and TP protein expression (p = 0.033). Conclusions: This retrospective investigation suggests that the combined assessment of TS and DPD may be useful to evaluate the prognosis of patients with Dukes’ B and C colon carcinoma receiving 5-FU adjuvant chemotherapy. The role of TP as a predictor for 5-FU-based therapy needs further investigations.

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Section: Discussionmentioning

confidence: 99%

Predictive Role of Thymidylate Synthase, Dihydropyrimidine Dehydrogenase and Thymidine Phosphorylase Expression in Colorectal Cancer Patients Receiving Adjuvant 5-Fluorouracil

Ciaparrone¹,

Quirino²,

Schinzari³

et al. 2006

Oncology

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“…Also, because most of CRC relapse or transfer in the following 3 years of operation, it is necessary to give patients adjuvant chemotherapy [24,25] . As to the elderly patients, several factors must be taken into consideration when chemotherapy is given, such as suitable chemotherapy regimen with good efficiency and low side effects [26,27] , the importance of the first cycle [28] , liver and kidney function testing and blood cell calculation before every cycle with heart and lung function evaluated if necessary, active support simultaneously, less or no anti-HT3 used to decrease the rate of constipation, long-cycle and convenient scheme to decrease the in-patient time, and changing scheme when it is inefficient [29] . In this study, univariate and multivariate analyses showed that the patients aged 70-75 years had a longer survival than those aged 75-91 years, which conformed with the study that aging was a risk factor for prognosis [30] .…”

Section: Discussionmentioning

confidence: 99%

Prognostic factors in 165 elderly colorectal cancer patients

Kang¹

2003

WJG

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AIM:To analyse the prognostic factors in 165 colorectal patients aged 70. METHODS:One hundred and sixty-five elderly patients with colorectal cancer diagnosed by histology were entered into the retrospective study between 1994 and 2001. Patients were given optimal operation alone, chemotherapy after operation, or chemotherapy alone according to tumor stage, histology, physical strength, and co-morbid problems. Survival rate was calculated by Kaplan-Meier method, and compared with meaningful variances by Log-rank method. Prognostic factors were analyzed by Cox regression. RESULTS:The 1,2,3,4,5 year survival rate (all-cause mortality) was 87.76 %, 65.96 %, 52.05 %, 42.77 %, 40.51 %, respectively. The mean survival time was 41.89±2.33 months (95 % CI: 37.33-46.45 months), and the median survival time was 37 months. Univariate analysis showed that factors such as age, nodal metastasis, treatment method, Duke's stage, gross findings, kind of histology, and degree of differentiation had influences on the survival rate. Multivariate analysis showed that factors such as treatment method, Duke's stage, kind of histology and degree of differentiation were independent prognostic factors. CONCLUSION:This study suggests that the prognosis of elderly colorectal cancer patients is influenced by several factors. Most of elderly patients can endure surgery and/or chemotherapy, and have a long-time survival and good quality of life. Nan KJ, Qin HX, Yang G.

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“…It is noteworthy that the bcl-XL positivity tended to be stronger in the invasive components of tumors. These findings may suggest that bcl-XL play a important role in colorectal tumor progression (Maurer, Friess et al, 1998) (Cascinu, Aschele et al, 1999, Cascinu, Catalano et al, 2000, Corsi, Ciaparrone et al, 2002, Johnston, Fisher et al, 1994, Johnston, Lenz et al, 1995, Paradiso, Simone et al, 2000 and TS mRNA (Johnston, Lenz et al, 1995, Leichman, Lenz et al, 1997 least likely benefit from 5-FUbased postoperative adjuvant chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…Anti-cancer effects of 5-FU are biochemically mediated through its metabolic conversion by two additional enzymes (thymidine phosphorylase and thymidine kinase) into fluorodeoxyuridine monophosphate (FdUMP), which eventually forms a ternary covalent complex with TS and reduced folic acid, to result in It has been suggested that high expression of TS is associated with the 5-FU resistance of colorectal cancer cells and a poor prognosis of patients (Cascinu, Aschele et al, 1999, Cascinu, Catalano et al, 2000, Corsi, Ciaparrone et al, 2002, Johnston, Fisher et al, 1994, Johnston, Lenz et al, 1995, Leichman, Lenz et al, 1997, Lenz, Hayashi et al, 1998, Paradiso, Simone et al, 2000, Tomiak, Vincent et al, 2001, Yamachika, Nakanishi et al, 1998. Immunohistochemical analysis of TS expression has been done in a number of reports, but all in retrospective analyses (Cascinu, Aschele et al, 1999, Cascinu, Catalano et al, 2000, Corsi, Ciaparrone et al, 2002, Johnston, Fisher et al, 1994, Johnston, Lenz et al, 1995, Paradiso, Simone et al, 2000, Tomiak, Vincent et al, 2001, Yamachika, Nakanishi et al, 1998. Inhibition of apoptosis is one of the mechanisms responsible for the chemoresistance of cancer cells (Dive and Hickman 1991).…”

Section: Introductionmentioning

confidence: 99%

IMMUNOHISTOCHEMICAL DEMONSTRATION OF THYMIDYLATE SYNTHASE (TS), p53 PROTEIN AND BCL-XL PROTEIN IN COLORECTAL CANCER WITH PREOPERATIVE PERORAL CHEMOTHERAPY

Kamoshida

Matsuoka

Matsuyama

et al. 2003

ACRT

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of apoptosis, p53 protein, selection of patients, thymidylate synthase (TS). AbstractHigh expression of thymidylate synthase (TS), p53 protein and bcl-XL protein has been suggested to be associated with chemoresistance of colorectal malignancies. The significance of TS, p53 protein and bcl-XL protein as predictive parameters of effects of 5-fluorouracil (5-FU)-based chemotherapy on colorectal cancers was evaluated.Immunoperoxidase staining of TS, p53 protein and bcl-XL protein was performed on formalin-fixed, paraffin-embedded, 1opsied and resected specimens from 37 patients with advanced colorectal cancers, preoperatively treated with 5-FU derivatives per os. When more than one third of the cancer cells were stained, the lesions were considered high for antigen expression. High TS expression in the resected tumors was seen in 23 (74%) of 31 histologic non-responders but none in six responders. TS expression in preoperative biopsies and resected specimens was concordant in 80% of cases when two or more biopsy specimens were available.The rate of high TS expression was comparable in the control non-treated group. There was no difference between chemotherapeutic effects and the expression of p53 protein or bcl-XL protein.

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Predictive value of thymidylate synthase expression in resected metastases of colorectal cancer

Cited by 33 publications

References 25 publications

Predictive Role of Thymidylate Synthase, Dihydropyrimidine Dehydrogenase and Thymidine Phosphorylase Expression in Colorectal Cancer Patients Receiving Adjuvant 5-Fluorouracil

Predictive Role of Thymidylate Synthase, Dihydropyrimidine Dehydrogenase and Thymidine Phosphorylase Expression in Colorectal Cancer Patients Receiving Adjuvant 5-Fluorouracil

Prognostic factors in 165 elderly colorectal cancer patients

IMMUNOHISTOCHEMICAL DEMONSTRATION OF THYMIDYLATE SYNTHASE (TS), p53 PROTEIN AND BCL-XL PROTEIN IN COLORECTAL CANCER WITH PREOPERATIVE PERORAL CHEMOTHERAPY

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