Effects of hypoxia on the uptake of tritiated thymidine, L-leucine, L-methionine and FDG in cultured cancer cells.
We previously demonstrated in vitro that FDG uptake into viable cancer cells increases in the presence of hypoxic versus normoxic conditions. Since position-emitter labeled thymidine and amino acids are being used for PET, we evaluated uptake into tumor cells of several tracers (thymidine, L-leucine, L-methionine and FDG) in the presence of either normoxic or hypoxic atmospheres in vitro.


METHODS
Uptake of tritiated thymidine, L-leucine, L-methionine and FDG into two human tumor cell lines (HTB 63 melanoma and HTB 77 IP3 ovarian carcinoma) was determined after a 4-hr exposure to each of three different oxygen atmospheres (0, 1.5 and 20% O2) in vitro.


RESULTS
Under moderately hypoxic conditions (1.5% O2), thymidine uptake decreased significantly from the 20% O2 baseline for both melanoma and ovarian carcinoma cell lines (33% and 15%, respectively) and with anoxia, thymidine uptake declined from baseline by 43% and 21%, respectively. Leucine uptake decreased substantially in the melanoma cells, by 23% when exposed to 1.5% O2 and 36% in the presence of 0% O2, but only modestly or not at all in the IP3 cells. After 1.5% or 0% O2 exposure, methionine uptake was not significantly different from 20% O2 levels in either cell line. In contrast, FDG uptake in both cell lines increased significantly (23% and 38%, respectively) over normoxic (20% O2) conditions when cells were exposed to moderate hypoxia. FDG uptake also increased over basel conditions after anoxia, by 11% and 30% for melanoma and ovarian carcinoma cells, respectively.


CONCLUSIONS
Hypoxia decreases cellular uptake of thymidine and increases FDG uptake in two different malignant human cell lines. Leucine uptake decreases with hypoxia in the melanoma cell line but not markedly in the IP3 cell line, while hypoxia does not alter methionine uptake in either cell line significantly. Hypoxia has varying effects on metabolic tracers used for PET. The use of paired hypoxia-sensitive PET tracers has potential for noninvasively characterizing tissue oxygenation levels.
Clavo
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AC
Department of Internal Medicine, University of Michigan, Ann Arbor 48109-0028, USA.
Wahl
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D015687:Cell Hypoxia; D003847:Deoxyglucose / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D066298:In Vitro Techniques; D007930:Leucine / Q000493:pharmacokinetics*; D008545:Melanoma / Q000378:metabolism; D008715:Methionine / Q000493:pharmacokinetics*; D010051:Ovarian Neoplasms / Q000378:metabolism; D010100:Oxygen / Q000502:physiology*; D013936:Thymidine / Q000493:pharmacokinetics*; D013997:Time Factors; D014055:Tomography, Emission-Computed; D014316:Tritium; D014407:Tumor Cells, Cultured / Q000378:metabolism*
D019788:Fluorodeoxyglucose F18; D014316:Tritium; D003847:Deoxyglucose; D008715:Methionine; D007930:Leucine; D010100:Oxygen; D013936:Thymidine