Fate of gallium in vivo and its significance in tumour diagnosis and therapy respectively with gallium-67 and cold gallium

Abstract

Of the 105 elements known today, gallium is the only one which lends itself to both non-invasive diagnosis and therapy of tumours. Almost the first report on the clinical application of gallium dates as far back as 1931 [1], the observation by Edwards and Hayes [2] in 1969 that gallium-67 concentrates in several soft tumours aroused great interest in this radionuclide and today it has become the most widely used radiopharmaceutical in the imaging of a wide variety of tumours [3]. Two years later Hart ▪ ▪ and co-workers [4, 5] reported the potential usefulness of cold gallium nitrate for treatment of solid tumours in both rodents and humans. Although the literature reports less work on the antitumour activity of cold gallium as compared to that on the diagnostic properties of gallium-67, it has been felt that if the aqueous solution chemistry of both gallium-67 and cold gallium is well studied, gallium has a promising future in the early diagnosis and treatment of cancer [6]. Many studies have been reported to show that transferrin in vivo plays an important role in the transport of gallium from the site of its administration to the tumour [6]. There is little agreement on the role of ion storage protein, ferritin, on the biological behaviour of gallium and on its tumour affinity [7]. We have studied chromatographically and electrophoretically the relative stability of gallium complexes with citrate ion, transferrin, and ferritin. The stability of the complexes follows the order gallium-ferritin complex ⪢ citratogallate gallium- transferrin complex. All three complexes are anionic. Based on these results, and on those on the distribution of gallium-67 and of cold gallium in healthy and tumour-bearing subjects (Fig. 1), we proposed a mechanism (Fig. 2) of the uptake of gallium from different formulations. It is found that only free or loosely bound gallium easily binds to transferrin which transports it to the tumour site, where a transferrin receptor in the tumour cell membrane sequesters transferrin and allows free gallium to diffuse into the cell to be bound firmly to ferritin, found in high concentration in malignant tissue cells [9]. We could succeed in making gallium-67 uptake tumour-specific and have also obtained encouraging results to the experimental mammary tumours (TGS) by administration of weakly bound cold gallium.