Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin.

Leichman, Cynthia G.; Lenz, Heinz‐Josef; Leichman, Lawrence; Danenberg, Kathleen D.; Baranda, Joaquina; Groshen, Susan; Boswell, William D.; Metzger, Ralf; Tan, Matthew; Danenberg, Peter V.

doi:10.1200/jco.1997.15.10.3223

Cited by 419 publications

(242 citation statements)

References 19 publications

Supporting

Mentioning

216

Contrasting

Unclassified

Order By: Relevance

“…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: 64%

“…In studies in gastric cancer (Lenz et al, 1995) and in head and neck cancer , 65 and 70 patients, respectively, received 5-FU-based neoadjuvant chemotherapy, and in both cases there was a significant (P < 0.001, P = 0.02, respectively) inverse correlation between TS expression level and response. A similar conclusion was drawn in a smaller study of 22 patients with advanced colorectal cancer (Leichman et al, 1995), in which a significant association (P = 0.004) between high TS expression and lack of response to infusional 5-FU was noted.…”

Section: Nucleoside Analoguesmentioning

confidence: 99%

See 1 more Smart Citation

New antimetabolites in cancer chemotherapy and their clinical impact

1998

Br J Cancer

136

View full text Add to dashboard Cite

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.

show abstract

Section: Nucleoside Analoguesmentioning

confidence: 64%

Section: Nucleoside Analoguesmentioning

confidence: 99%

New antimetabolites in cancer chemotherapy and their clinical impact

1998

Br J Cancer

136

View full text Add to dashboard Cite

show abstract

“…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%

“…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]. These non-responders therefore may have other mechanisms of resistance that the favorable condition of low TS gene expression is insufficient to overcome.…”

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].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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.

show abstract

Colorectal Cancer

Hobday

Erlichman

2014

TNM Online

View full text Add to dashboard Cite

Colorectal cancer is the second leading cause of site‐specific cancer mortality in Western nations. Over 130,000 new cases and 56,500 deaths were expected in the United States in 1998. Approximately 70–80% of patients will present with apparently localized disease that is surgically resectable. A proportion of these patients harbor occult micrometastases and will relapse after initial therapy. Randomized, Phase III clinical trials evaluating adjuvant chemotherapy (combined with radiotherapy in rectal cancer) for patients with local/regional lymph‐node involvement have clearly shown some of these patients can be cured with adjuvant therapy. A recent pooled analysis as well as the individual prospective randomized clinical trials of adjuvant chemotherapy in patients with Stage II disease (no involvement of local/regional lymph nodes) have not clearly shown a survival benefit in these patients. Yet a significant minority of these patients will relapse and eventually die of their disease. A review by the National Surgical Adjuvant Breast and Bowel Project (NSABP) of four consecutive adjuvant chemotherapy trials in Stages II and III colorectal cancer argues that adjuvant chemotherapy does improve survival for Stage II patients. The use of molecular markers that have prognostic significance in addition to pathologic and clinical factors has the potential to identify high‐risk patients who may benefit from therapy. This may allow treatment of those at highest risk while sparing those with minimal risk the toxicity and expense of adjuvant chemotherapy. Prognostic factors can also serve a useful role in advanced disease. Some factors may be predictive of response to therapy, thereby aiding in the choice of palliative treatment. In a small subset of patients with metastatic colorectal cancer, patient‐and tumor‐related factors impact on the potential for curative resection of metastatic disease.

show abstract

Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin.

Cited by 419 publications

References 19 publications

New antimetabolites in cancer chemotherapy and their clinical impact

New antimetabolites in cancer chemotherapy and their clinical impact

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

Colorectal Cancer

Contact Info

Product

Resources

About