Lipophilic cations are capable of passive diffusion into the cytoplasm and mitochondria of cells in response to a large negative plasma- and mitochondrial- membrane potentials. 99mTc-2-methoxyisobutylisonitrile (MIBI) was taken up into both normal and malignant cells being driven by metabolic demand and membrane potential (1) (2) 99mTc-MIBI was originally developed as a myocardial perfusion imaging agent and subsequently as tumor imaging agent. The uptake of 99mTc-MIBI is also used as a biomarker for cellular metabolism in malignant tumors.
One of the mechanisms of cells to escape the cytotoxic effects of chemotherapeutic agents, such as Adriamycin, Vinca alkaloids, epipodophyllotoxins, actinomycin D, and taxol, is to limit their presence inside the cells by a multidrug resistance (MDR-1) gene protein. The MDR-1 gene encodes a transmembrane P-glycoprotein (Pgp) as a multidrug transporter that is capable of actively pumping a variety of agents out of the cells (3). Overexpression of Pgp in tumor cells leads to resistance to anticancer drugs (4). MIBI is a transport substrate of Pgp in a variety of tumor cells (5). Another mechanism of tumor cells to escape anticancer treatments is to acquire a defective apoptotic program. Apoptosis is a highly regulated, multistep process involving the mitochondria. Bcl-2 is an integral protein on the outer mitochondrial membrane, nuclear membrane, and endoplasmic reticulum. Cancer cells have been found to have a high level of Bcl-2, which is anti-apoptotic. Overproduction of the Bcl-2 protein also prevents cell death induced by nearly all cytotoxic anticancer drugs and radiation (6, 7). MIBI is being used as a myocardial perfusion imaging agent in clinical use to assess the risk of future cardiac events. It is also used as a tumor-imaging agent in breast, lung, thyroid, and brain cancers.