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Applicability of ^99mTc-HL91, a Putative Hypoxic Tracer, to Detection of Tumor Hypoxia

Division of Tracer Kinetics, Biomedical Research Center, Osaka University Medical School, Osaka, Japan

Correspondence: For correspondence or reprints contact: Tsunehiko Nishimura, MD, PhD, Division of Tracer Kinetics, Osaka University Medical School, 2-2 Yamadaoka, Suita Osaka 565-0871 Japan.

ABSTRACT

To elucidate the applicability of ^99mTc-HL91 (HL91) a putative hypoxic tracer, to the imaging of hypoxia in tumors, a biodistribution study of the tracer was performed. The intratumoral distribution of HL91 was compared with that of ¹⁴C-deoxyglucose (DG) and the expression of glucose transporter 1 (GLUT1) in an implanted tumor. Methods: Biodistribution of HL91 after intravenous injection into Wistar rats with rat mammary tumor (Walker-256) was studied by determining blood and tissue levels of radioactivity from 15 min to 6 h after injection. Dual ex vivo autoradiography was performed on sections of the tumor using HL91 (74 MBq) and DG (185 kBq). The same sections were immunohistologically analyzed with anti-GLUT1 antibody. Tumor tissue was histologically divided into areas of viable cancer cells, necrosis and granulation tissue. The viable cancer cell area was further divided into normoxic and hypoxic areas. Uptake of both tracers in each area was measured quantitatively. The intensity of GLUT1 staining (relative optical density [ROD]) in each area was evaluated by densitometry. Results: The uptake of HL91 in the tumor reached a maximal value (0.897 ± 0.118% ID [injected dose], mean ± SD, n = 5) at 120 min after intravenous injection of HL91, then gradually decreased. The tumor-to-muscle ratio continued to increase until 360 min (4.34 at 120 min, 7.01 at 240 min and 10.4 at 360 min). HL91 accumulated to significantly higher levels in the hypoxic area than those in the other tissues (P < 0.0001). Uptake of DG and expression of GLUT1 were significantly higher in the hypoxic area than in the normoxic area (P < 0.0001). In the viable cancer cell area, uptake of HL91 and expression of GLUT1 were strongly correlated (r = 0.624–0.868, mean r = 0.743, P < 0.0001), and DG uptake was moderately correlated with GLUT1 expression (r = 0.328–0.669, mean r = 0.505, P < 0.0001). Conclusion: These results indicate that HL91 can be used to detect tumor hypoxia.

Key Words: ^99mTc • HL91 • ¹⁴C-deoxyglucose • glucose transporter 1 • tumor hypoxia

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