Radiolabelled fluoromisonidazole as an imaging agent for tumor hypoxia.
Fluoromisonidazole labeled with H-3 or F-18 has been tested as a quantitative probe for hypoxic cells in vitro and in rodent and spontaneous dog tumors in vivo. In V-79, EMT-6(UW), RIF-1, and canine osteosarcoma cells in vitro, the binding of 50 microM [H-3]Fluoromisonidazole was 50% inhibited by 1000-2000 ppm O2, relative to binding under anoxic conditions. After a 3 hr incubation with labeled drug, the anoxic/oxic binding ratios ranged from 12 to 27 for the four cell types. Retention of [H-3]fluoromisonidazole 4 hr after injection was greater in large KHT tumors (400-600 mm3) with an estimated hypoxic fraction greater than 30%, than in smaller tumors (50-200 mm3) with an estimated hypoxic fraction of 7-12%. RIF-1 tumors, with an estimated hypoxic fraction of 1.5%, retained the least label, with tumor: blood ratios ranging from 1.7 to 1.9. Spontaneous dog osteosarcomas were imaged with a time of flight positron emission tomograph for up to 5 hr following injection of [F-18] fluoromisonidazole. Analysis of regions of interest in images allowed creation of dynamic tissue time activity curves and calculation of tissue uptake in cpm/gram. These values were compared to radioactivity in plasma. In all cases, retention in some tumor regions exceeded that in plasma and in normal tissue, such as muscle or brain, by 3 to 5 hr post injection. Uptake of fluoromisonidazole in tumors was heterogeneous, with ratios of maximum to minimum uptake as high as 4 in different regions of interest in the same tumor. Tumor:plasma values ranged from 0.28 to 2.02. The oxygen dependency of fluoromisonidazole retention was similar in a variety of cell types and was 50% inhibited by O2 levels in the transition between full radiobiological hypoxia and partial sensitization. The quantitative regional imaging of [F-18] fluoromisonidazole in spontaneous canine tumors at varying times post-injection lays the basis for imaging and modeling of oxygen-dependent drug retention in different regions of human neoplasms.
Rasey
J S
JS
Department of Radiation Oncology, University of Washington School of Medicine, Seattle 98195.
Koh
W J
WJ
Grierson
J R
JR
Grunbaum
Z
Z
Krohn
K A
KA
D000230:Adenocarcinoma / Q000000981:diagnostic imaging; D000818:Animals; D001859:Bone Neoplasms / Q000000981:diagnostic imaging; D015687:Cell Hypoxia; D002478:Cells, Cultured; D003287:Contrast Media; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D005347:Fibroblasts; D008325:Mammary Neoplasms, Experimental / Q000000981:diagnostic imaging; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000032:analysis / Q000097:blood; D012516:Osteosarcoma / Q000000981:diagnostic imaging; D011836:Radiation Tolerance; D011877:Radionuclide Imaging; D012513:Sarcoma, Experimental / Q000000981:diagnostic imaging
D003287:Contrast Media; D008920:Misonidazole