Preclinical evaluation of the novel hypoxic marker 99mTc-HL91 (Prognox) in murine and xenograft systems in vivo

Purpose: The Tc-99m-labelled amine oxime Tc-99m-HL91 (Prognox(TM)) is under investigation as a potential noninvasive clinical marker of tumour hypoxia whose uptake can be monitored by gamma camera imaging. The aim was to assess its retention in 3 tumours under control and enhanced oxygenation conditions. Materials and Methods: The SaF murine sarcoma, grown subcutaneously in CBA mice, and human colon carcinoma HT29 and lung adenocarcinoma A549, grown as xenografts in SCID mice, were used at 6-8 mm diameter. Oxygenation status was enhanced by giving 500 mg/kg nicotinamide i.p. and breathing carbogen until the point of assay. Oxygenation/hypoxia was measured using the Eppendorf pO(2) histograph (KIMOC 6650) with at least 5 tracks and at least 70 values, and expressing pO(2) values as % < 2.5 mmHg, Tc-99m-HL91 (0.8 or 8 MBq per mouse) was injected i.v. immediately before nicotinamide or saline, and animals were killed 2 h after injection. Tumour, skin, muscle, and blood samples were counted and isotope retention was expressed as % injected dose per gram, C-14-labelled uncomplexed HL91 was used similarly (0.2-0.4 MBq per mouse) and samples were solubilised and decolourised before counting. Results: Nicotinamide and carbogen treatment reduced Tc-99m-HL91 retention in all tumours to 54%-64% of control; it also reduced the proportion of pO(2) values < 2.5 mmHg in all tumours, The mean proportion of pO(2) values < 2.5 mmHg correlated very well with the mean ratio of tumour to blood retention at 2 b for all tumours, both unperturbed and oxygen-enhanced (r = 0.996; p < 0.001), Retention of C-14-HL91 in SaF tumour was unchanged by nicotinamide and carbogen, confirming that (TC)-T-99m complexation of the ligand is required for hypoxia specificity. Conclusion There is excellent correlation between Tc-99m-HL91 retention and hypoxia, as measured by the Eppendorf histograph, over the range of 50%-90% of values < 2.5 mmHg in 3 different tumour models, including 2 human xenografts, Tc-99m complexation of the ligand is required for hypoxia specificity. Tc-99m-HL91 (Prognox(TM)) shows good potential as a clinical marker for hypoxia and warrants further development. (C) 1998 Elsevier Science Inc.