HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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

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 [(124)I]2'-fluoro-2'-deoxy-5-iodouracil-beta- d-arabinofuranoside (FIAU) and a small animal micro positron emission tomograph (microPET), while groups of rats were imaged using the tracer [(131)I]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 [(124)I]FIAU and a microPET. 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 [(131)I]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.
AuthorsPhilipp 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
JournalEuropean journal of nuclear medicine and molecular imaging (Eur J Nucl Med Mol Imaging) Vol. 30 Issue 9 Pg. 1281-91 (Sep 2003) ISSN: 1619-7070 [Print] Germany
PMID12664136 (Publication Type: Comparative Study, Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Folic Acid Antagonists
  • Iodine Radioisotopes
  • Radiopharmaceuticals
  • Recombinant Fusion Proteins
  • Viral Proteins
  • Arabinofuranosyluracil
  • fialuridine
  • Tetrahydrofolate Dehydrogenase
  • thymidine kinase, Canid herpesvirus 1
  • Thymidine Kinase
Topics
  • Animals
  • Animals, Genetically Modified (metabolism)
  • Arabinofuranosyluracil (analogs & derivatives, pharmacokinetics)
  • Cell Line, Tumor
  • Colorectal Neoplasms (diagnostic imaging, genetics, metabolism)
  • Feasibility Studies
  • Folic Acid Antagonists (therapeutic use)
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Iodine Radioisotopes (pharmacokinetics)
  • Liver Neoplasms (diagnostic imaging, drug therapy, metabolism, secondary)
  • Male
  • Neoplasm Transplantation
  • Organ Specificity
  • Radionuclide Imaging
  • Radiopharmaceuticals (pharmacokinetics)
  • Rats
  • Rats, Nude
  • Recombinant Fusion Proteins (antagonists & inhibitors, metabolism)
  • Tetrahydrofolate Dehydrogenase (drug effects, genetics, metabolism)
  • Thymidine Kinase (genetics, metabolism)
  • Tissue Distribution
  • Transplantation, Heterologous
  • Viral Proteins (genetics, metabolism)
  • Whole-Body Counting

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: