Use of myocardial imaging agents for tumour diagnosis - a success story?

The search for new radiopharmaceuticals for tumour diagnosis usually procee ds on the basis of rational concepts drawing on the latest advances in mole cular biology. Using this approach, radioactive peptide hormones, antibodie s and oligonucleotides have been developed that are used increasingly in nu clear medicine for diagnostic and therapeutic purposes. This article, howev er, focusses on a group of radiopharmaceuticals whose use in tumour diagnos is was not the outcome of a methodical development programme but rather the result of a chance discovery. These radiopharmaceuticals, thallium-201 and technetium-99m labelled 2-methoxyisobutylisonitrile (MIBI), tetrofosmin an d furifosmin, were first developed through extensive research efforts for c ardiac imaging, but during their worldwide application for myocardial scint igraphy they were accidentally found to accumulate in tumours. Intensive st udies were then begun on cell cultures in an attempt to discover the cause of their uptake into rumours. The aim was to compare the effectiveness of t he radiopharmaceuticals for tumour diagnosis in a range of indications and to investigate the various mechanisms by which they are taken up into rumou rs. While the more favourable radiophysical properties of Tc-99m-MIBI rende r it superior to Tl-201 for many diagnostic purposes, neither Tc-99m-tetrof osmin nor Tc-99m-furifosmin has yet proved suitable for clinical routine ex aminations, although the former has found limited application. In the case of Tc-99m complexes, the breakthrough came with the experimental finding th at these substances are substrates of P-glycoprotein, a product of the huma n multidrug resistance gene (MDR1). The concentration of Tc-99m complexes i n tumour cells is a function of a passive, membrane potential-dependent inf lux into and a P-glycoprotein-controlled efflux out of the tumour cell. Pre liminary studies suggest that in vivo detection of MDR may even be possible . There is also evidence that the P-glycoprotein-mediated transport system can be blocked competitively. However, it will be some time before a system can be developed for detection of MDR on a routine basis.