Abstract

The long term goal of this Interactive ROl program is to improve the long term survival of patients with colorectal cancer metastatic to the liver.
The specific aims of this portion of the IRPG are to understand mechanisms of resistance to fluoropyrimidines in human colon cancer, to develop new therapies based on this experimental data and to provide pharmacologic monitoring for new treatment regimens that are tested in the clinic (Kemeny R0l). The approach will be to use human colon carcinoma cell lines and fresh tumor samples from patients on study to determine mechanisms of natural and acquired resistance to fluoropyrimidines. Samples of colon cancer will be obtained at pump placement (Cohen R0l and Kemeny ROI) from either untreated patients or patients resistant to systemic FUra regimens and mechanisms of fluoropyrimidine resistance studied. In addition, we will also obtain tumor samples from patients at relapse following HAI FUDR for studies of acquired resistance to this drug. Drugs selected that are in various stages of development for HAI are fluoruridine, teroxirone and D1694, a thymidylate synthase inhibitor. Phase I trials are planned for fluoruridine and teroxirone (Kemeny, R0l), as well as hepatic extraction studies, with pharmacologic monitoring.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA061586-01
Application #
3204943
Study Section
Special Emphasis Panel (SRC (57))
Project Start
1993-08-01
Project End
1997-07-31
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065

  Publications

Iwamoto, Marian; Banerjee, Debabrata; Menon, Lata G et al. (2004) Overexpression of E2F-1 in lung and liver metastases of human colon cancer is associated with gene amplification. Cancer Biol Ther 3:395-9
Bertino, Joseph R; Banerjee, Debabrata (2003) Is the measurement of thymidylate synthase to determine suitability for treatment with 5-fluoropyrimidines ready for prime time? Clin Cancer Res 9:1235-9
Mayer-Kuckuk, Philipp; Doubrovin, Mikhail; Gusani, Niraj J et al. (2003) Imaging of dihydrofolate reductase fusion gene expression in xenografts of human liver metastases of colorectal cancer in living rats. Eur J Nucl Med Mol Imaging 30:1281-91
Mayer-Kuckuk, Philipp; Banerjee, Debabrata; Malhotra, Sundeep et al. (2002) Cells exposed to antifolates show increased cellular levels of proteins fused to dihydrofolate reductase: a method to modulate gene expression. Proc Natl Acad Sci U S A 99:3400-5
Banerjee, Debabrata; Mayer-Kuckuk, Philipp; Capiaux, Gina et al. (2002) Novel aspects of resistance to drugs targeted to dihydrofolate reductase and thymidylate synthase. Biochim Biophys Acta 1587:164-73
Banerjee, Debabrata; Bertino, Joseph R (2002) Myeloprotection with drug-resistance genes. Lancet Oncol 3:154-8
Mayer-Kuckuk, Philipp; Banerjee, Debabrata; Kemeny, Nancy et al. (2002) Molecular therapies for colorectal cancer metastatic to the liver. Mol Ther 5:492-500
Longo, G S; Izzo, J; Gorlick, R et al. (2001) Characterization and drug sensitivity of four newly established colon adenocarcinoma cell lines to antifolate inhibitors of thymidylate synthase. Oncol Res 12:309-14
Banerjee, D; Gorlick, R; Liefshitz, A et al. (2000) Levels of E2F-1 expression are higher in lung metastasis of colon cancer as compared with hepatic metastasis and correlate with levels of thymidylate synthase. Cancer Res 60:2365-7
Gorlick, R; Bertino, J R (1999) Drug resistance in colon cancer. Semin Oncol 26:606-11

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