Molecular Imaging of cancer cell response to chemotherapeutic drugs emphasized on P-glycoprotein function

The occurrence of cellular drug resistance to cytotoxic drugs at the clinical level called multidrug resistance (MDR) has been studied by many research groups. Drug resistance is a major problem in chemotherapy for cancer. One of the most important reasons for this resistance is the over-expression of the multiple drug resistance (mdr) gene before and after induction of chemotherapy. It is frequently associated to an overexpression of drug transporters proteins, 170 kDa P-glycoprotein (P-gp), the MDR1 gene product and 190 kDa multidrug resistance-associated protein (MRP), the MRP1 gene product. Along with the drugs, many surrogate markers of Pgp function in vivo, such as 99mTc-labelled lipophilic cationic radiopharmaceuticals, can be pumped out of cells with MDR overexpression. The mechanism of uptake of 99mTc-MIBI by tumor cells is related to the cell membrane potential, although its passage through the membrane involves passive diffusion. Moreover, since the recognition of 99mTc-MIBI as a transport substrate for P-glycoprotein, this modality has attracted great interest for the prediction of chemotherapy resistance. The 99mTc-MIBI interacts with a common transport domain on Pgp shared by other substrates. The decrease intracellular level of the substrates is the result of enhanced efflux by these membrane transporters. It has been suggested that cellular accumulation of cationic agents is inversely proportional to the level of Pgp expression. Enhancement of 99mTc-MIBI content in tumor cells is observed after exposure to MDR modulators or chemosensitisers which modulate Pgp function and increase intracellular concentrations of chemotherapeutic drugs in tumor cells. Bioflavonoids are demonstrated to be effective in protection of various normal cell types from oxidative injury. Bioflavonoid as the strong antioxidants renews an interest for cancer treatment since they induce apoptosis of various cancer cell types, but not in normal cells, via induction of the mitochondrial dysfunction in both in vitro and in vivo. Bioflavonoids, therefore, might be the beginning of a new generation of antitumour drugs, particularly for overcoming MDR phenomena.