Mechanisms for localization of radiopharmaceuticals in neoplasms.

Localization of a radiopharmaceutical agent in a "tumor" is best conceptualized in terms of the altered regional physiology attendant to the presence of the "tumor". Such localization should be expected to occur in association with other disease states characterized by similar altered regional physiology. Neoplasms, areas of inflammation, and certain phases of infarct development are characterized by increased permeability of their capillary beds to macromolecules. This is largely due to neovascularization and the large intercapillary pores associated with new growth of capillary beds in these circumstances. Often, total perfusion to such lesions is increased in comparison to surrounding normal tissue. Thus, in all three clinical conditions, the entry of macro-molecules into the interstitial fluid space from the intravascular space is increased above that seen in normal tissue. Moreover, with neoplasms and inflammatory processes, there may be a delay in new lymphatic vessel growth adding to the residence time of the macromolecules in the interstitial fluid space. In all three conditions, the increased macrophage activity associated with tissue necrosis may result in ingestion of the labeled macromolecule by the macrophage. Pinocytosis may result in ingestion of the labeled macromolecule by other cells in the lesion, or there may be specific receptor sites on the cell membrane for the macromolecule, which may lead to fixation of the labeled macromolecule on the cell surface and possible intracellular translocation of the label itself. Radiolabeled macromolecules such as albumin, fibrinogen, or gamma globulins, and radionuclides that bind to macromolecules such as radiogallium, radioindium, and other radioelements, exhibit localizing behavior in tumors, inflammatory lesions, and during certain stages of infarcts. In the case of radiogallium and radioindium, the binding macromolecule is transferrin, and it is known that some cells have specific receptor sites for transferrin-bound iron on the cell membrane. It is possible that certain cells within these lesions have cell membrane receptor sites for radiogallium- and radioindium-labeled transferrin, and the cell erroneously accepts these radioelements from the transferrin in lieu of iron in attempting to engage in heme enzyme synthesis. Another mechanism that may be operative in the localization of agents in neoplasms, infarcts, and inflammatory lesions may be the altered cell permeability found in many cells of such lesions. It is known that many agents, such as supravital dyes, are excluded from entering normal cells by the selective permeability of normal cell membranes. When cell membrane permeability is altered, such as can be seen in traumatized, dying, or dead cells, the normally excluded agent may penetrate the abnormal cell membrane and bind, and consequently accumulate in intracellular constituents.