Thymidilate synthase and p53 primary tumour expression as predictive factors for advanced colorectal cancer patients

Paradiso, Angelo; Simone, G.; Petroni, S.; Leone, Bernardo Amadeo; Vallejo, Carlos; Lacava, J.; Romero, A; Machiavelli, M; Lena, M. De; Allegra, Carmen J.; Johnston, Patrick G.

doi:10.1054/bjoc.1999.0964

Cited by 136 publications

(86 citation statements)

References 30 publications

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“…To overcome the present limitations of commonly used drug-resistance markers which do not satisfactorily predict the clinical outcome of specific subsets of patients, much effort is needed to better identify specific markers of drug action. In this respect promising results seem achievable by analysis of the expression of thymidylate synthase, a crucial enzyme for de novo synthesis of thymidine which is specifically inhibited by 5-FU (Johnston et al, 1991;Paradiso et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Expression of apoptosis-related markers and clinical outcome in patients with advanced colorectal cancer

Paradiso¹,

Simone²,

Lena³

et al. 2001

Br J Cancer

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SummaryThe clinical relevance of bax and bcl-2 protein expression has been investigated in 84 patients with recurrent or metastatic colorectal cancer submitted to a chemotherapy regimen including methotrexate and fluorouracil/leucovorin. Cytoplasmic immunostaining of bax and bcl-2 was present in 65.5% and 38%, respectively, of the tumours. No association was found between bax and bcl-2 or between p53 and bax or bcl-2 protein expression. Moreover, the biomarkers were unrelated to patient and tumour characteristics known to affect the clinical outcome of colorectal cancer patients. In general, the apoptosis-related markers did not appear indicative of short-and long-term clinical response nor of prognosis. Bcl-2-negative lesions were more frequent among patients who reached an objective clinical response, which is in agreement with previously reported data regarding other tumour types. When the interrelationship between p53 and bax expression was examined, a better response rate (40%) was found for patients whose tumours did not express p53 and bax, and a better prognosis (2-year probability of overall survival 75%) for patients with p53-positive and bax-negative tumours. In the present series of patients with advanced colorectal cancer submitted to systemic chemotherapy we did not find a clear association between expression of apoptosis-related markers and clinical outcome, even in the subset of patients in which the apoptotic index as determined by the TUNEL approach was investigated.

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Section: Discussionmentioning

confidence: 99%

Expression of apoptosis-related markers and clinical outcome in patients with advanced colorectal cancer

Paradiso¹,

Simone²,

Lena³

et al. 2001

Br J Cancer

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“…The relation between TS and 5FU has led to a wealth of research regarding the enzyme's role in pre-existing and inducible resistance to the chemotherapeutic drug. With few exceptions (Findlay et al, 1997), existing data suggest increased tumour expression of TS protein predicts for a poorer response to 5FU in advanced colorectal carcinoma (CRC) (Peters et al, 1994;Johnston et al, 1995;Leichmann et al, 1995;Aschele et al, 1999;Paradiso et al, 2000). However, there are still unresolved issues regarding TS expression in CRC and its relation to 5FU therapy.…”

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confidence: 99%

“…Firstly, most previous studies of TS protein expression and 5FU response had only analysed primary tumour tissue Findlay et al, 1997;Paradiso et al, 2000) whereas it is metastatic tumour that is targeted by 5FU therapy in patients with advanced CRC. We are aware of only two previous studies comparing TS expression between primary and metastatic tumour tissue (Peters et al, 1994;Aschele et al, 2000) and the two studies have produced conflicting results.…”

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confidence: 99%

“…Immunohistochemical assessment of TS protein expression provides an obvious method to address this problem. Until now, studies using this technique have only assessed cytoplasmic expression of the enzyme (Johnston et al, 1994Suzuki et al, 1998;Yamachika et al, 1998;Paradiso et al, 2000). Despite the fact that nuclear staining has also been recorded (Johnston et al, 1991), we are unaware of any work into the clinicopathological significance of nuclear expression of TS in vivo.…”

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confidence: 99%

“…There has also been interest in associations between TS and p53 on a more clinical level. At least two previous studies have shown that p53 protein expression may be used to supplement tumour TS protein expression as a predictor of response to 5FU therapy (Lenz et al, 1998a;Paradiso et al, 2000). Whether there is any relation between nuclear TS protein expression and p53 protein expression in vivo and whether the two may supplement one another in predicting for response of advanced CRC to 5FU therapy are unknown.…”

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confidence: 99%

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Nuclear thymidylate synthase expression, p53 expression and 5FU response in colorectal carcinoma

et al. 2001

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Summary Thymidylate synthase (TS) is a key enzyme in DNA synthesis and is inhibited by metabolites of the chemotherapeutic agent 5-fluorouracil (5FU). Nuclear expression of TS in human tissue in vivo has not been characterised and its clinicopathological correlates in malignancy are unknown. 52 cases of primary colorectal carcinoma (CRC) and 24 cases of matched metastatic carcinoma were studied immunohistochemically using the monoclonal antibody TS106. The degree of nuclear TS immunostaining correlated closely with levels of TS mRNA expression amongst 10 CRCs studied. Strong nuclear immunostaining was seen in normal basal crypt colonocytes and germinal centre cells, and in a varying proportion of adenocarcinoma cells. Amongst the primary carcinomas, higher TS nuclear expression was associated with prominent extracellular mucin production and right-sided location. Higher TS nuclear expression also showed a significant association with poorer response to protracted venous infusional 5FU therapy. There was no clear association between TS nuclear expression and Ki67 or p53 expression assessed immunohistochemically. There was a strong positive correlation between TS nuclear expression in primary and metastatic CRC but the latter generally showed higher expression than matched primary tumour tissue. These findings confirm the nuclear expression of TS protein in human cells in vivo and provide new insight into how such expression may relate to the behaviour of CRCs.

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The Use of Molecular Profiling of Early Colorectal Cancer to Predict Micrometastases

Bilchik

Nora²,

Saha³

et al. 2002

Arch Surg

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Background: Approximately one third of nodenegative colorectal cancers (CRCs) recur, suggesting the failure to detect occult disease. Lymphatic mapping followed by focused analysis of the sentinel node is highly accurate in identifying micrometastases. Hypothesis: Because aberrant genetic changes occur early in tumor progression and are associated with lymphatic metastases, we hypothesized that the molecular profiling of specific tumor markers in the primary tumor might predict that tumor's metastatic potential. Design: A prospective patient series. Patients and Interventions: Forty consecutive patients with early CRC underwent lymphatic mapping after subserosal injection of 1 mL of isosulfan blue dye. All lymph nodes were examined by hematoxylin-eosin (HE) staining, and multiple sections of each sentinel node were examined by HE and cytokeratin immunohistochemistry (CK-IHC) staining. Primary tumors were analyzed for p53 expression using IHC staining and for ␤-human chorionic gonadotropin (␤-hCG), hepatocyte growth factor receptor (c-Met), and universal melanoma antigen (uMAGE) messenger RNA expression using reversetranscriptase polymerase chain reaction and electrochemiluminescence. Results: Nine patients (23%) had positive nodes by routine HE staining. Of the remaining 31 patients with negative nodes on HE staining, 8 tumors (26%) were upstaged by CK-IHC identification of occult micrometastases. There was a direct correlation between the number of markers and the T stage (P=.001). The expression of p53, ␤-hCG, c-Met, and uMAGE in primary tumors was significantly higher in the presence of nodal micrometastases vs no metastases (P=.03). Conclusions: Sentinel lymphatic mapping is an accurate method of detecting micrometastases in CRC. Molecular profiling of primary CRC tumors, similar to that used for breast cancer, may be important in predicting metastatic potential and determining which patients may benefit from adjuvant therapy.

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Thymidilate synthase and p53 primary tumour expression as predictive factors for advanced colorectal cancer patients

Cited by 136 publications

References 30 publications

Expression of apoptosis-related markers and clinical outcome in patients with advanced colorectal cancer

Expression of apoptosis-related markers and clinical outcome in patients with advanced colorectal cancer

Nuclear thymidylate synthase expression, p53 expression and 5FU response in colorectal carcinoma

The Use of Molecular Profiling of Early Colorectal Cancer to Predict Micrometastases

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