67Ga-citrate incorporation and DNA synthesis in tumors

The results obtained in these studies suggest that in the tumors studied there is some form of relationship between 67Ga uptake and the rate of DNA synthesis. However, the observations in the HP melanoma, in which small tumors showed a negative correlation between 67Ga uptake and rate of DNA synthesis and larger tumors showed a positive correlation, coupled with the virtually constant uptake of 67Ga over a wide range of rates of DNA synthesis in the drug- and radiation-treated tumors, suggest that the uptake of the radionuclide is not simply related to the rate of DNA synthesis per se. Studies in embryonic mouse tissues suggested that 67Ga uptake was not related to the rate of DNA synthesis and regenerating liver does not show a greater 67Ga uptake than normal liver. Phytohemagglutinin-treated human lymphocytes show increased 67Ga uptake compared to unstimulated lymphocytes, and it has been suggested that this is related to the stimulus to divide rather than to events occurring in a specific phase of the cell cycle. This suggests that proliferating cells may exhibit membrane changes which either result in increased transport of 67Ga into the cell or permit a greater degree of binding of the radionuclide to the cell membrane than can occur in resting cells. The membrane-binding hypothesis is supported by the observations on phytohemagglutinin-stimulated lymphocytes but not by observations of the subcellular distribution of 67Ga in these tumors which confirm the suggestion that the radionuclide is concentrated in lysosomes. Thus it appears that although in tumor cells, at least, there is some correlation between 67Ga uptake and the rate of DNA synthesis and hence by implication of cell proliferation, the nature of this link remains obscure, and more detailed studies are needed to increase our understanding of the relationship