Effect of p53 activation on cell growth, thymidine kinase-1 activity, and 3'-deoxy-3'fluorothymidine uptake.
The use of thymidine (TdR) and thymidine analogs such as 3'-deoxy-3'-fluorothymidine (FLT) as positron emission tomography (PET)-based tracers of tumor proliferation rate is based on the hypothesis that measurement of uptake of these nucleosides, a function primarily of thymidine kinase-1 (TK(1)) activity, provides an accurate measure of cell proliferation in tumors. Tumor growth is influenced by many factors including the oxygen concentration within tumors and whether tumor cells have been exposed to cytotoxic therapies. The p53 gene plays an important role in regulating growth under both of these conditions. The goal of this study was to investigate the influence of p53 activation on cell growth, TK(1) activity, and FLT uptake. To accomplish this, TK(1) activity, S phase fraction, and the uptake of FLT were determined in plateau-phase and exponentially growing cultures of an isogenic pair of human tumor cell lines in which p53 expression was normal or inactivated by human papilloma virus type 16 E6 expression. Ionizing radiation exposure was used to stimulate p53 activity and to induce alterations in cell cycle progression. We found that exposure of cells to ionizing radiation induced dose-dependent changes in cell cycle progression in both cell lines. The relationship between S phase percentage, TK(1) activity, and FLT uptake were essentially unchanged in the p53-normal cell line. In contrast, TK(1) activity and FLT uptake remained high in the p53-deficient variant even when S phase percentage was low due to a p53-dependent G2 arrest. We conclude that a functional p53 response is required to maintain the normal relationship between TK1 activity and S phase percentage following radiation exposure.
Schwartz
Jeffrey L
JL
Department of Radiation Oncology, University of Washington Medical Center, Box 356069, Seattle, WA 98195-6069, USA. jschwart@u.washington.edu
Tamura
Yasuko
Y
Jordan
Robert
R
Grierson
John R
JR
Krohn
Kenneth A
KA
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology*; D002455:Cell Division / Q000528:radiation effects; D045744:Cell Line, Tumor / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D015224:Dideoxynucleosides / Q000493:pharmacokinetics*; D004307:Dose-Response Relationship, Radiation; D004789:Enzyme Activation; D005720:Gamma Rays; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D013937:Thymidine Kinase / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D015224:Dideoxynucleosides; D016159:Tumor Suppressor Protein p53; D013937:Thymidine Kinase; C092717:thymidine kinase 1; C002854:alovudine