The development of non-invasive methods for the detection of cancer in-vivo is a critically important area of medical research. This proposal offers an alternative approach to nuclear medicine tumor detection by imaging radiometals which binds many protein metallothionein (MT). MT is a small intracellular protein which binds many nuclides with potentially favorable imaging or radiotherapeutic characteristics. MT is highly inducible by a variety of agents, with some tissue-specific expression. Preliminary work demonstrated enhanced uptake of Cd-109 (known to be highly bound to MT in biological systems) in a murine tumor model. The degree of uptake parallelled the degree expression of the transformed phenotype by the tumors and parent cultured cells. This proposal will first determine to what degree Cd-109 in tumors is bound to MT, by chromatography and immunoprecipitation. To determine if all tumor types are universally enriched for MT, I shall measure MT content and uptake of Cd-109 in tumors grown in mice from a wide variety of histologic types of cultured tumor cells. To determine if MT-enrichment in tumors alone is sufficient to result in the concentration in tumors of MT-binding radiometals, cultured cell lines and derivative tumors which are identical except for their degree of expression of MT will be created. The cell lines will contain plasmids with highly regulable, cloned elements that will enable regulation of the MT content in the transfected cells and derivative tumors in mice. The uptake of MT-binding nuclides will be correlated with the degree of expression of MT by these """"""""genetically-engineered"""""""" cultured cells and tumors. Next it will be determined if treatment of tumor-bearing mice by any of the numerous agents known induce genomic (endogenous) MT expression will further enhance the tumor uptake of MT-binding radiometals relative to that in normal tissues. The effect of treatment with these agents on tumor MT expression and on the uptake of MT-binding radiometals will be measured in mice bearing tumors grown from various cultured (untransfected) histologic types of tumor cells. This proposal will also involve studies where tumor-bearing mice are imaged by gamma emission scintigraphy after administration of MT-binding radiometals. The effect of many variables on the ease by which the foci of tumors can be detected by nuclear medicine imaging will be determined. This proposal offers an alternative to existing methods for Nuclear Medicine tumor imaging which may be of far- reaching importance in the diagnosis and treatment of cancer.
| Morton, K A; Jones, B J; Sohn, M H et al. (1993) Enrichment for metallothionein does not confer resistance to cisplatin in transfected NIH/3T3 cells. J Pharmacol Exp Ther 267:697-702 |
| Sohn, M H; Jones, B J; Whiting Jr, J H et al. (1993) Distribution of gallium-67 in normal and hypotransferrinemic tumor-bearing mice. J Nucl Med 34:2135-43 |
| Morton, K A; Jones, B J; Sohn, M H et al. (1992) Uptake of cadmium is diminished in transfected mouse NIH/3T3 cells enriched for metallothionein. J Biol Chem 267:2880-3 |
