The role of thymidylate synthase expression in prognosis and outcome of adjuvant chemotherapy in patients with rectal cancer.

Johnston, Patrick G.; Fisher, Edwin R.; Rockette, Howard E.; Fisher, Bernard; Wolmark, Norman; Drake, James C.; Ba, Chabner; Allegra, Carmen J.

doi:10.1200/jco.1994.12.12.2640

Cited by 353 publications

(251 citation statements)

References 16 publications

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“…Thirdly, it is also possible that adjuvant chemotherapy did not affect survival regardless of TS expression, which may explain the lack of difference in survival between high-TS and low-TS groups in the current study. Alternatively, there is a possibility that the gastric cancer patients with high TS expression might experience a greater survival benefit from adjuvant chemotherapy compared to patients with low TS expression, as shown in other studies with rectal cancer and breast cancer (Johnston et al, 1994;Pestalozzi et al, 1997). In the current study, there was no significant difference in survival according to important prognostic variables such as Lauren's classification, lymph node metastasis and pathologic stage.…”

Section: Discussionmentioning

confidence: 96%

“…The discrepant findings between the current study and the previous reports in terms of prognostic implications of TS could be explained as follows. First, the TS expression in primary tumours of gastric cancer patients may not reflect the ability of the tumour to induce TS protein or undergo TS gene amplification with exposure to chemotherapeutic agents (Johnston et al, 1994;Pestalozzi et al, 1997). Secondly, all patients in this study were treated with doxorubicin as well as 5-FU, while other studies demonstrating increased risk of recurrence and poor survival in gastric cancer patients with high TS expression used 5-FU or tegafur-uracil with or without mitomycin-C (Kuniyasu et al, 1998;Suda et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

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Expression of thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection

Lim

Nam

et al. 2001

Br J Cancer

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SummaryWe evaluated the expression of thymidylate synthase (TS) in locally advanced gastric cancer patients treated with adjuvant chemotherapy after curative resection and investigated the association between TS expression and clinicopathologic characteristics including prognosis of the patients. TS expression was evaluated by immunohistochemical staining using TS106 monoclonal antibody in 103 locally advanced gastric cancer patients (stage IB-IV) who underwent 5-fluorouracil (5-FU) and doxorubicin-based adjuvant chemotherapy after curative resection. 65 patients (63%) had primary tumours with high TS expression (≥ 25% of tumour cells positive), and 38 patients (37%) demonstrated low TS expression (< 25% of tumour cells positive or no staining). High TS expression was associated with male gender (P = 0.002), poorly differentiated histology (P = 0.015), and mixed type in Lauren's classification (P = 0.027). There were no statistically significant differences in 4-year disease-free survival (60.0% vs 57.2%, P = 0.548) and overall survival (59.6% vs 59.3%, P = 0.792) between high-TS group and low-TS group. In conclusion, although high TS expression was associated with poorly differentiated histology and mixed type in Lauren's classification, it did not predict poor disease-free and overall survival in gastric cancer patients treated with 5-FU and doxorubicin-based adjuvant chemotherapy after curative resection. Further prospective studies including the evaluation of other biological markers associated with the resistance to 5-FU and doxorubicin are necessary. 186-192 © 2001 Cancer Research Campaign doi: 10.1054/ bjoc.2000.1553, available online at http://www.idealibrary.com on http://www.bjcancer.com based adjuvant chemotherapy after curative surgical resection at Ajou University Medical Center in Suwon, Korea, between July 1994 and October 1996. All patients had a postsurgical pathologic stage ranging from IB to IV without evidence of distant metastasis according to the American Joint Committee on Cancer TNM classification (American Joint Committee on Cancer, 1997). Curative resection was defined by the General Rules for the Gastric Cancer Study in Surgery and Pathology of the Japanese Research Society for Gastric Cancer as: no involvement of surgical stumps; sufficient lymphatic dissection (R number ≥ N number); no distant metastasis; removal of involved adjacent organs and structures by combined en-bloc resection; and no gross residual disease (Japanese Research Society for Gastric Cancer, 1981). None of these patients received chemotherapy prior to surgery.Although all patients received 5-FU and doxorubicin-based adjuvant chemotherapy, the regimens were not uniform. The most commonly administered regimen was FA (5-FU, doxorubicin) with OK-432 (51 patients), followed by FAM (5-FU, doxorubicin, mitomycin-C) (33 patients), FA (11 patients), and FA with lentinan (eight patients). Chemotherapy was usually started 2-3 weeks after surgery. In the FA regimen with or without immunotherapy (OK-432 or lentinan), 5-FU (...

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Expression of thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection

Lim

Nam

et al. 2001

Br J Cancer

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“…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%

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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“…However, it is likely that thymidylate synthase is the main target for the nucleoside of 5-FU, which binds to the active site of the enzyme in a similar manner to dUMP. This is followed by incorporation of the folate co-factor (Pestalozzi et al, 1997), gastric cancer (Lenz et al, 1995) and primary rectal cancer (Johnston et al, 1994) all reach similar conclusions, with TS expression being measured either immunohistochemically, or using PCR to measure genetic expression of TS mRNA.…”

Section: Nucleoside Analoguesmentioning

confidence: 63%

“…patients with high TS levels have a better outcome with that therapy. This has been seen both in 278 node-positive breast cancer patients receiving CMF (cyclophosphamide, methotrexate, 5-FU) (Pestalozzi et al, 1997) and in 194 patients with Dukes' B and C rectal cancer receiving MOF (methyl CCNU, 5-FU vincristine) chemotherapy (Johnston et al, 1994). The reasons for the apparent paradox are not clear, but the data reported to date would certainly justify further translational studies to clarify the predictive role of TS expression; it remains quite possible that this will vary according to the type of tumour being treated.…”

Section: Nucleoside Analoguesmentioning

confidence: 99%

New antimetabolites in cancer chemotherapy and their clinical impact

1998

Br J Cancer

133

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Summary It is almost 50 years since antimetabolites were first found to have clinical antitumour activity, with Farber's discovery that aminopterin could cause remission in acute leukaemia. In the following 10 years, methotrexate, 6-mercaptopurine and 5-fluorouracil (5-FU) found their way into clinical practice. Subsequently, cytosine arabinoside was found to have activity in acute leukaemia, but, until recently, other significant developments have involved optimizing the efficacy of existing antimetabolites, including the use of leucovorin with methotrexate or 5-FU. Recently, new antimetabolites have become a fertile area for anti-cancer drug research. Gemcitabine (GEMZAR®) has emerged as an important new agent in several tumour types, including pancreatic, non-small-cell lung, bladder, breast and ovarian cancers. Capecitabine is an intriguing new prodrug, offering tumour selectivity and prolonged tumour exposure to 5-FU. More potent thymidylate synthase inhibitors have also emerged; raltitrexed is now commercially available for the treatment of colorectal cancer. Others under development include LY231514, which has other sites of action, hence the acronym MTA (multi-targeted antifolate). A novel target is glycinamide ribonucleotide formyltransferase (GARFT) and LY309887 and AG2034 are undergoing clinical investigation as GARFT inhibitors. A critical element with LY309887 appears to be co-administration of folate. It seems entirely possible that several novel antimetabolites will establish themselves in clinical practice in future for the treatment of solid tumours.

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The role of thymidylate synthase expression in prognosis and outcome of adjuvant chemotherapy in patients with rectal cancer.

Cited by 353 publications

References 16 publications

Expression of thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection

Expression of thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection

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

New antimetabolites in cancer chemotherapy and their clinical impact

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