Multidrug resistance remains the primary cause of treatment failure in cancer patients. Among the multiple cellular mechanisms underlying the resistant phenotype, the enhanced efflux of anticancer drugs mediated by members of the ATP-binding cassette family of transporters such as P-glycoprotein (Pgp) and the reduced apoptosis due to dysregulation of the process are the most common causes of drug resistance. Here we report the results of our studies on the possibility to detect in vivo and non-invasively malignant tumors that will become resistant to subsequent therapy using single-photon emission tomography and 99mTc-Sestamibi, a tumor-seeking agent currently used in clinical practice. This tracer is a lipophilic cation that accumulates in mitochondria in response to plasma membrane e mitochondrial membrane potentials. In addition, the tracer is subjected to Pgp-mediated outward transport thus mimicking the kinetic behaviour of anticancer drugs in resistant cells. Our studies showed that both the uptake and efflux mechanisms of 99mTc-Sestamibi can be helpful for the non-invasive assessment of drug resistance in cancer. While an enhanced tracer clearance is an index of Pgp-function, an altered pattern of tracer uptake is associated with an impaired apoptosis due to Bcl-2/Bcl-xL overexpression or unopposed action. In conclusion, molecular imaging of drug resistance is suitable and may provide biological information that can improve the efficacy of individual-tailored therapeutic strategies.

Molecular Imaging of drug resistance in cancer.

DEL VECCHIO, SILVANA;Fonti R;SALVATORE, MARCO
2009

Abstract

Multidrug resistance remains the primary cause of treatment failure in cancer patients. Among the multiple cellular mechanisms underlying the resistant phenotype, the enhanced efflux of anticancer drugs mediated by members of the ATP-binding cassette family of transporters such as P-glycoprotein (Pgp) and the reduced apoptosis due to dysregulation of the process are the most common causes of drug resistance. Here we report the results of our studies on the possibility to detect in vivo and non-invasively malignant tumors that will become resistant to subsequent therapy using single-photon emission tomography and 99mTc-Sestamibi, a tumor-seeking agent currently used in clinical practice. This tracer is a lipophilic cation that accumulates in mitochondria in response to plasma membrane e mitochondrial membrane potentials. In addition, the tracer is subjected to Pgp-mediated outward transport thus mimicking the kinetic behaviour of anticancer drugs in resistant cells. Our studies showed that both the uptake and efflux mechanisms of 99mTc-Sestamibi can be helpful for the non-invasive assessment of drug resistance in cancer. While an enhanced tracer clearance is an index of Pgp-function, an altered pattern of tracer uptake is associated with an impaired apoptosis due to Bcl-2/Bcl-xL overexpression or unopposed action. In conclusion, molecular imaging of drug resistance is suitable and may provide biological information that can improve the efficacy of individual-tailored therapeutic strategies.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/361735
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