Higher levels of thymidylate synthase gene expression are observed in pulmonary as compared with hepatic metastases of colorectal adenocarcinoma Journal Article

Authors: Gorlick, R.; Metzger, R.; Danenberg, K. D.; Salonga, D.; Miles, J. S.; Longo, G. S. A.; Fu, J.; Banerjee, D.; Klimstra, D.; Jhanwar, S.; Danenberg, P. V.; Kemeny, N.; Bertino, J. R.
Article Title: Higher levels of thymidylate synthase gene expression are observed in pulmonary as compared with hepatic metastases of colorectal adenocarcinoma
Abstract: Purpose: It has be observed previously that the pulmonary metastases of colorectal adenocarcinoma are less responsive to therapy with fluorouracil (FUra) as compared with other sites of metastasis (liver, local). To investigate the basis of this chemoresistance, the levels of thymidylate synthase (TS) mRNA and protein were measured, as TS expression has been shown to be predicted of response to therapy in colorectal cancer. Materials and Methods: Tumors were obtained from 19 patients with metastatic colorectal cancer (12 hepatic and seven pulmonary). TS expression was measured by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) and TS protein levels were measured by Western blotting. The presence of TS amplification was assessed by Southern blotting. Levels of p53 protein were determined using immunohistochemistry. Results: TS mRNA expression was shown to be significantly higher in the pulmonary metastases (mean TS/β-actin ratio, 19.7; n = 7) as compared with the hepatic metastases (mean TS/β- actin ratio, 4.7; n = 11) of colorectal cancer. Lower TS expression was observed in patients with hepatic metastases who had received prior FUra versus patients who had not been treated. High levels of TS expression in some samples was associated with low-level (two to three germ copies) increases in TS gene copy numbers and this was observed more frequently in the pulmonary metastatic samples. The increased germ copy numbers occurred both in samples with wild-type p53 and those with mutant p53 tumor-suppressor germ as determined by immunohistochemistry. Conclusion: High levels of TS enzyme may be the basis of the lack of response of pulmonary metastases to FUra treatment.
Keywords: immunohistochemistry; adult; clinical article; controlled study; human tissue; protein expression; aged; middle aged; fluorouracil; liver neoplasms; methotrexate; polymerase chain reaction; adenocarcinoma; reverse transcription polymerase chain reaction; antineoplastic combined chemotherapy protocols; lung neoplasms; protein p53; irinotecan; colorectal carcinoma; colorectal neoplasms; liver metastasis; lung metastasis; blotting, western; gene expression regulation, neoplastic; dna; messenger rna; rna, messenger; folinic acid; immunoblotting; thymidylate synthase; gene expression regulation, enzymologic; southern blotting; humans; human; male; female; priority journal; article
Journal Title: Journal of Clinical Oncology
Volume: 16
Issue: 4
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 1998-04-01
Start Page: 1465
End Page: 1469
Language: English
PUBMED: 9552053
PROVIDER: scopus
DOI: 10.1200/JCO.1998.16.4.1465
Notes: Article -- Export Date: 12 December 2016 -- Source: Scopus
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MSK Authors
  1. Debabrata Banerjee
    124 Banerjee
  2. Richard G Gorlick
    120 Gorlick
  3. Joseph Bertino
    256 Bertino
  4. David S Klimstra
    843 Klimstra
  5. Suresh C Jhanwar
    207 Jhanwar
  6. Nancy Kemeny
    346 Kemeny