Tracers to monitor the response to chemotherapy: in vitro screening of four radiopharmaceuticals

L. de Geus-Oei, J. van Eerd-Vismale, C. Molthoff, F. Corstens, W. Oyen and O. Boerman

Department of Nuclear Medicine, University Medical Center, Nijmegen, The Netherlands.
Aug, 2004



It has been postulated that radiopharmaceuticals can be used to predict the therapeutic response to (chemo)therapy, which could lead to individualized treatment regimens. In this study, 18F-deoxyglucose, 99mTc-tetrofosmin, 125I-deoxyuridineribose, and 125I-methyltyrosine were tested for this purpose.The uterine sarcoma cell line MES-SA (MDR-) and its multidrug resistant variant, MES-SA/Dx5 (MDR+), were used. The MDR+ cells express high levels of P-glycoprotein, which makes them relatively resistant to various chemotherapeutic agents. Cells were cultured in the presence of escalating concentrations of doxorubicin, and the cellular uptake of the radiopharmaceuticals was determined.Decreasing 18F-deoxyglucose uptake at escalating doxorubicin concentrations reflected the chemosensitivity of the cells: 18F-deoxyglucose uptake in the MDR- cells was reduced to 40\% of the baseline level in the presence of 1 microM of doxorubicin, compared to 74\% in the MDR+ cells. The 125I-deoxyuridineribose uptake in MDR- cells was reduced to 2\% of the baseline level when cultured at a concentration of 1 microM of doxorubicin, while this was 79\% in the MDR+ cells. The same trend was observed with 125I-methyltyrosine. The enhanced doxorubicin chemosensitivity of MDR+ cells in the presence of verapamil, a modulator of P-glycoprotein, was reflected by the reduced uptake of 18F-deoxyglucose, 125I-deoxyuridineribose, and 125I-methyltyrosine. Furthermore, baseline 99mTc-tetrofosmin uptake in MDR+ cells was more than six-fold lower than in MDR- cells.In the presence of doxorubicin, the uptake of 18F-deoxyglucose, 125I-deoxyuridineribose and, to a lesser extent, 125I-methyltyrosine is more pronouncedly reduced in MDR- cells than in MDR+ cells. The reversal of doxorubicin-resistance of MDR+ cells by verapamil was also reflected by the uptake of 18F-deoxyglucose, 125I-deoxyuridineribose, and 125I-methyltyrosine. 99mTc-tetrofosmin uptake reflected P-glycoprotein expression without exposure to doxorubicin.