Tracers to Monitor the Response to Chemotherapy: In Vitro Screening of Four Radiopharmaceuticals

Abstract

Objectives: 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. Methods: 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. Results: 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 mM of doxorubicin, compared to 74% in the MDR+ cells. The ¹²⁵Ideoxyuridineribose uptake in MDR– cells was reduced to 2% of the baseline level when cultured at a concentration of 1 mM 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. Conclusion: 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.