Imaging of dihydrofolate reductase fusion gene expression in xenografts of human liver metastases of colorectal cancer in living rats

Philipp Mayer-Kuckuk, Mikhail Doubrovin, Niraj J. Gusani, Terence Gade, Julius Balatoni, Tim Akhurst, Ronald Finn, Yuman Fong, Jason A. Koutcher, Steven Larson, Ronald Blasberg, Juri Gelovani Tjuvajev, Joseph R. Bertino, Debabrata Banerjee

Research output: Contribution to journalArticle

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Abstract

Radionuclide imaging has been demonstrated to be feasible to monitor transgene expression in vivo. We hypothesized that a potential application of this technique is to non-invasively detect in deep tissue, such as cancer cells metastatic to the liver, a specific molecular response following systemic drug treatment. Utilizing human colon adenocarcinoma cells derived from a patient's liver lesion we first developed a nude rat xenograft model for colorectal cancer metastatic to the liver. Expression of a dihydrofolate reductase-herpes simplex virus 1 thymidine kinase fusion (DHFR-HSV1 TK) transgene in the hepatic tumors was monitored in individual animals using the tracer [ 124I]2′-fluoro-2′-deoxy-5-iodouracil-β -D-arabinofuranoside (FIAU) and a small animal micro positron emission tomograph (microPET), while groups of rats were imaged using the tracer [ 131I]FIAU and a clinical gamma camera. Growth of the human metastatic colorectal cancer cells in the rat liver was detected using magnetic resonance imaging and confirmed by surgical inspection. Single as well as multiple lesions of different sizes and sites were observed in the liver of the animals. Next, using a subset of rats bearing hepatic tumors, which were retrovirally bulk transduced to express the DHFR-HSV1 TK transgene, we imaged the fusion protein expression in the hepatic tumor of living rats using the tracer [124I]FIAU and a micro-PET. The observed deep tissue signals were highly specific for the tumors expressing the DHFR-HSV1 TK fusion protein compared with parental untransduced tumors and other tissues as determined by gamma counting of tissue samples. A subsequent study used the tracer [ 131I]FIAU and a gamma camera to monitor two groups of transduced hepatic tumor-bearing rats. Prior to imaging, one group was treated with trimetrexate to exploit DHFR-mediated upregulation of the fusion gene product. Imaging in the living animal as well as subsequent gamma counting of tissue samples showed increased signal and tracer accumulation, respectively, as compared to the group not treated with the antifolate. It is concluded that the two examined nucleotide imaging methods are feasible techniques for monitoring of DHFR-HSV TK fusion protein expression in hepatic colorectal tumor tissue in living animals.

Original languageEnglish (US)
Pages (from-to)1281-1291
Number of pages11
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Volume30
Issue number9
DOIs
StatePublished - Sep 1 2003

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Tetrahydrofolate Dehydrogenase
Heterografts
Colorectal Neoplasms
Neoplasm Metastasis
Gene Expression
Liver
Thymidine Kinase
Human Herpesvirus 1
Transgenes
Neoplasms
Gamma Cameras
Trimetrexate
Nude Rats
Folic Acid Antagonists
Proteins
Gene Fusion
Radionuclide Imaging
Colon
Adenocarcinoma
Up-Regulation

All Science Journal Classification (ASJC) codes

  • Radiology Nuclear Medicine and imaging

Cite this

Mayer-Kuckuk, Philipp ; Doubrovin, Mikhail ; Gusani, Niraj J. ; Gade, Terence ; Balatoni, Julius ; Akhurst, Tim ; Finn, Ronald ; Fong, Yuman ; Koutcher, Jason A. ; Larson, Steven ; Blasberg, Ronald ; Tjuvajev, Juri Gelovani ; Bertino, Joseph R. ; Banerjee, Debabrata. / Imaging of dihydrofolate reductase fusion gene expression in xenografts of human liver metastases of colorectal cancer in living rats. In: European Journal of Nuclear Medicine and Molecular Imaging. 2003 ; Vol. 30, No. 9. pp. 1281-1291.
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abstract = "Radionuclide imaging has been demonstrated to be feasible to monitor transgene expression in vivo. We hypothesized that a potential application of this technique is to non-invasively detect in deep tissue, such as cancer cells metastatic to the liver, a specific molecular response following systemic drug treatment. Utilizing human colon adenocarcinoma cells derived from a patient's liver lesion we first developed a nude rat xenograft model for colorectal cancer metastatic to the liver. Expression of a dihydrofolate reductase-herpes simplex virus 1 thymidine kinase fusion (DHFR-HSV1 TK) transgene in the hepatic tumors was monitored in individual animals using the tracer [ 124I]2′-fluoro-2′-deoxy-5-iodouracil-β -D-arabinofuranoside (FIAU) and a small animal micro positron emission tomograph (microPET), while groups of rats were imaged using the tracer [ 131I]FIAU and a clinical gamma camera. Growth of the human metastatic colorectal cancer cells in the rat liver was detected using magnetic resonance imaging and confirmed by surgical inspection. Single as well as multiple lesions of different sizes and sites were observed in the liver of the animals. Next, using a subset of rats bearing hepatic tumors, which were retrovirally bulk transduced to express the DHFR-HSV1 TK transgene, we imaged the fusion protein expression in the hepatic tumor of living rats using the tracer [124I]FIAU and a micro-PET. The observed deep tissue signals were highly specific for the tumors expressing the DHFR-HSV1 TK fusion protein compared with parental untransduced tumors and other tissues as determined by gamma counting of tissue samples. A subsequent study used the tracer [ 131I]FIAU and a gamma camera to monitor two groups of transduced hepatic tumor-bearing rats. Prior to imaging, one group was treated with trimetrexate to exploit DHFR-mediated upregulation of the fusion gene product. Imaging in the living animal as well as subsequent gamma counting of tissue samples showed increased signal and tracer accumulation, respectively, as compared to the group not treated with the antifolate. It is concluded that the two examined nucleotide imaging methods are feasible techniques for monitoring of DHFR-HSV TK fusion protein expression in hepatic colorectal tumor tissue in living animals.",
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Mayer-Kuckuk, P, Doubrovin, M, Gusani, NJ, Gade, T, Balatoni, J, Akhurst, T, Finn, R, Fong, Y, Koutcher, JA, Larson, S, Blasberg, R, Tjuvajev, JG, Bertino, JR & Banerjee, D 2003, 'Imaging of dihydrofolate reductase fusion gene expression in xenografts of human liver metastases of colorectal cancer in living rats', European Journal of Nuclear Medicine and Molecular Imaging, vol. 30, no. 9, pp. 1281-1291. https://doi.org/10.1007/s00259-003-1143-z

Imaging of dihydrofolate reductase fusion gene expression in xenografts of human liver metastases of colorectal cancer in living rats. / Mayer-Kuckuk, Philipp; Doubrovin, Mikhail; Gusani, Niraj J.; Gade, Terence; Balatoni, Julius; Akhurst, Tim; Finn, Ronald; Fong, Yuman; Koutcher, Jason A.; Larson, Steven; Blasberg, Ronald; Tjuvajev, Juri Gelovani; Bertino, Joseph R.; Banerjee, Debabrata.

In: European Journal of Nuclear Medicine and Molecular Imaging, Vol. 30, No. 9, 01.09.2003, p. 1281-1291.

Research output: Contribution to journalArticle

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AU - Gade, Terence

AU - Balatoni, Julius

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AU - Finn, Ronald

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AU - Koutcher, Jason A.

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AU - Blasberg, Ronald

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N2 - Radionuclide imaging has been demonstrated to be feasible to monitor transgene expression in vivo. We hypothesized that a potential application of this technique is to non-invasively detect in deep tissue, such as cancer cells metastatic to the liver, a specific molecular response following systemic drug treatment. Utilizing human colon adenocarcinoma cells derived from a patient's liver lesion we first developed a nude rat xenograft model for colorectal cancer metastatic to the liver. Expression of a dihydrofolate reductase-herpes simplex virus 1 thymidine kinase fusion (DHFR-HSV1 TK) transgene in the hepatic tumors was monitored in individual animals using the tracer [ 124I]2′-fluoro-2′-deoxy-5-iodouracil-β -D-arabinofuranoside (FIAU) and a small animal micro positron emission tomograph (microPET), while groups of rats were imaged using the tracer [ 131I]FIAU and a clinical gamma camera. Growth of the human metastatic colorectal cancer cells in the rat liver was detected using magnetic resonance imaging and confirmed by surgical inspection. Single as well as multiple lesions of different sizes and sites were observed in the liver of the animals. Next, using a subset of rats bearing hepatic tumors, which were retrovirally bulk transduced to express the DHFR-HSV1 TK transgene, we imaged the fusion protein expression in the hepatic tumor of living rats using the tracer [124I]FIAU and a micro-PET. The observed deep tissue signals were highly specific for the tumors expressing the DHFR-HSV1 TK fusion protein compared with parental untransduced tumors and other tissues as determined by gamma counting of tissue samples. A subsequent study used the tracer [ 131I]FIAU and a gamma camera to monitor two groups of transduced hepatic tumor-bearing rats. Prior to imaging, one group was treated with trimetrexate to exploit DHFR-mediated upregulation of the fusion gene product. Imaging in the living animal as well as subsequent gamma counting of tissue samples showed increased signal and tracer accumulation, respectively, as compared to the group not treated with the antifolate. It is concluded that the two examined nucleotide imaging methods are feasible techniques for monitoring of DHFR-HSV TK fusion protein expression in hepatic colorectal tumor tissue in living animals.

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