The major goal of the proposed project is to determine how p202 mediates the growth-inhibitory activities of the IFNs. We hypothesize that p202 inhibits cell growth by inhibiting E2F ac- tivity. To test our hypothesis, we propose three specific aims: (1) To examine whether constitutive overexpression of p202 arrests cells in a particular phase of the cell cycle. For this purpose, we have generated mufine AKR-2B cell lines in which the expres- sion of p202 can be selectively induced by removal of tetracy- cline. (2) To determine how p202 inhibits E2F activity. To do this, we propose to localize the p202 binding domain in E2F-1 and test whether p202 would inhibit the DNA-binding of E2F. (3) To examine the growth-regulatory activities of p202. For this purpose, we plan to localize the growth-inhibitory domain in p202. The proposed studies will contribute to our understanding of the cell growth-inhibitory activities of the IFNs.

Thesaurus Terms: cell cycle, cell growth regulation, inter- feron alpha, interferon gamma, interleukin 6, phosphoprotein DNA binding protein, cell cycle protein, growth inhibitor, transcription factor SDS polyacrylamide gel electrophoresis, animal tissue, clone cell, gel mobility shift assay, human tissue, transfection

Institution:

Fiscal Year: Department: Project Start: Project End: ICD: IRG:

Loyola University Medical Center 2160 S 1st Ave Maywood, IL 60153 1999 Radiology 08-JUL-96 30-JUN-01 National Cancer Institute CBY

)ROJECT TITLE

IN VIVO MARKER OF CELL PROLIFERATION FOR PET STUDIES OF CANCER

Grant Number: 5R01CA72896-03 PI Name: Conti, Peter S.

Abstract: Advances in morphological imaging, particularly MRI and CT, have significantly improved tumor detection, stag- ing and measurement of therapy response. Improvement in can- cer patient management through imaging is unlikely to continue at a similar rate unless anatomical studies are augmented with an assessment of tumor biology and metabolism in vivo. Progress towards this goal has been made using positron emission tomog- raphy (PET) and an in vivo radiotracer of glucose utilization, [18F] fluodeoxyglucose (FDG). However, FDG and other ra- diotracers currently used in PET oncology studies are, at best, indirect measures of cell proliferation. Investigators have employed traditional methodologies for measuring DNA syn- thesis, such as determination of biodistribution, biochemical radioassay, and autoradiography with [3H] or [14C] TdR, as

well as immunohistochemistry with bromodeoxyuridine (BUdR), in order to validate the use of [l lC] TdR with PET. Among the many issues surrounding development of an in vivo method for quantitating DNA synthesis with [11C] TdR, per- haps the most cumbersome is its rapid in vivo catabolism, which complicates interpretation of PET kinetic data. We pro- pose to specifically address this issue and hypothesize that a measurement of cell proliferation equivalent to volumetric mi- totic index (MIv), i.e., the fraction of minor volume occupied by dividing (S-phase cells) can be achieved in vivo with PET using a non-catabolized nucleoside anolog of thkymidine: 2'-fluoro-5-[11C]-methyl- 1-beat-D-arabinofuranosyluracil (FMAU). The efficacy of this radiotracaer for monitoring DNA synthesis will be examined in animal tumor models and patients in comparison with MIv, as measured with BUdR and quantitative histology. Studies using [14C] FMAU confirm the absence of significant labeled catabolites in plasma, demonstrate that tumors can be well visualized with PET, and indicate that uptake into tumor and normal organs is positively correlated with MIv. We propose to test the hy- pothesis that measurements of cell proliferaton paralleling BUdR mitotic index can be obtained in vivo with PET and [11C]FMAU.

Thesaurus Terms: biomarker, cell proliferation, neoplasm/ cancer pharmacology, prognosis, tumor progression 5 bromode- oxyuridine, DNA replication, brain neoplasm, breast neoplasm, clinical trial, disease model, drug metabolism, human therap}¢ evaluation, nonhuman therapy evaluation, prostate neoplasm, uracil nucleoside carbon, clinical research, dog, human subject, immunocytochemistry, laboratory rat, outcomes research, positron emission tomography, radionuclide

Institution: University of Southern California University Park Los Angeles, CA 90007

Fiscal Year: 1999 Department: Radiology Project Start: 21-FEB-97 Project End: 31-JAN-00 ICD: National Cancer Institute IRG: RNM

~ROJECT TITLE

IN VIVO ASSESSMENT OF TUMOR RECEPTOR LEVELS USING PET

Grant Number: 5R01CA48286-09 PI Name: Dehdashti, Farrokh

Abstract: Despite recent improvements in our understanding of the biology of breast cancer, few recent advances have been

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