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

Richard Gorlick, Ralf Metzger, Kathleen D. Danenberg, Dennis Salonga, Joseph S. Miles, Guiseppe S A Longo, Jenny Fu, Debabrata Banerjee, David Klimstra, Suresh Jhanwar, Peter V. Danenberg, Nancy Kemeny, Joseph R. Bertino

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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.

Original languageEnglish (US)
Pages (from-to)1465-1469
Number of pages5
JournalJournal of Clinical Oncology
Volume16
Issue number4
StatePublished - Apr 1998
Externally publishedYes

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Thymidylate Synthase
Adenocarcinoma
Neoplasm Metastasis
Gene Expression
Lung
Liver
Fluorouracil
Colorectal Neoplasms
Actins
Immunohistochemistry
Messenger RNA
Proteins
Gene Dosage
Southern Blotting
Reverse Transcriptase Polymerase Chain Reaction
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Gorlick, R., Metzger, R., Danenberg, K. D., Salonga, D., Miles, J. S., Longo, G. S. A., ... Bertino, J. R. (1998). Higher levels of thymidylate synthase gene expression are observed in pulmonary as compared with hepatic metastases of colorectal adenocarcinoma. Journal of Clinical Oncology, 16(4), 1465-1469.

Higher levels of thymidylate synthase gene expression are observed in pulmonary as compared with hepatic metastases of colorectal adenocarcinoma. / Gorlick, Richard; Metzger, Ralf; Danenberg, Kathleen D.; Salonga, Dennis; Miles, Joseph S.; Longo, Guiseppe S A; Fu, Jenny; Banerjee, Debabrata; Klimstra, David; Jhanwar, Suresh; Danenberg, Peter V.; Kemeny, Nancy; Bertino, Joseph R.

In: Journal of Clinical Oncology, Vol. 16, No. 4, 04.1998, p. 1465-1469.

Research output: Contribution to journalArticle

Gorlick, R, Metzger, R, Danenberg, KD, Salonga, D, Miles, JS, Longo, GSA, Fu, J, Banerjee, D, Klimstra, D, Jhanwar, S, Danenberg, PV, Kemeny, N & Bertino, JR 1998, 'Higher levels of thymidylate synthase gene expression are observed in pulmonary as compared with hepatic metastases of colorectal adenocarcinoma', Journal of Clinical Oncology, vol. 16, no. 4, pp. 1465-1469.
Gorlick, Richard ; Metzger, Ralf ; Danenberg, Kathleen D. ; Salonga, Dennis ; Miles, Joseph S. ; Longo, Guiseppe S A ; Fu, Jenny ; Banerjee, Debabrata ; Klimstra, David ; Jhanwar, Suresh ; Danenberg, Peter V. ; Kemeny, Nancy ; Bertino, Joseph R. / Higher levels of thymidylate synthase gene expression are observed in pulmonary as compared with hepatic metastases of colorectal adenocarcinoma. In: Journal of Clinical Oncology. 1998 ; Vol. 16, No. 4. pp. 1465-1469.
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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.",
author = "Richard Gorlick and Ralf Metzger and Danenberg, {Kathleen D.} and Dennis Salonga and Miles, {Joseph S.} and Longo, {Guiseppe S A} and Jenny Fu and Debabrata Banerjee and David Klimstra and Suresh Jhanwar and Danenberg, {Peter V.} and Nancy Kemeny and Bertino, {Joseph R.}",
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T1 - Higher levels of thymidylate synthase gene expression are observed in pulmonary as compared with hepatic metastases of colorectal adenocarcinoma

AU - Gorlick, Richard

AU - Metzger, Ralf

AU - Danenberg, Kathleen D.

AU - Salonga, Dennis

AU - Miles, Joseph S.

AU - Longo, Guiseppe S A

AU - Fu, Jenny

AU - Banerjee, Debabrata

AU - Klimstra, David

AU - Jhanwar, Suresh

AU - Danenberg, Peter V.

AU - Kemeny, Nancy

AU - Bertino, Joseph R.

PY - 1998/4

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N2 - 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.

AB - 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.

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