PRECLINICAL EVALUATION OF THE NOVEL HYPOXIC MARKER TC-99M-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 tumo ur hypoxia whose uptake can be monitored by gamma camera imaging. The aim was to assess its retention in 3 tumours under control and enhance d oxygenation conditions. Materials and Methods: The SaF murine sarcom a, grown subcutaneously in CBA mice, and human colon carcinoma HT29 an d lung adenocarcinoma A549, grown as xenografts in SCID mice, were use d 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 expre ssing pO(2) values as % < 2.5 mmHg, Tc-99m-HL91 (0.8 or 8 MBq per mous e) was injected i.v. immediately before nicotinamide or saline, and an imals were killed 2 h after injection. Tumour, skin, muscle, and blood samples were counted and isotope retention was expressed as % injecte d dose per gram, C-14-labelled uncomplexed HL91 was used similarly (0. 2-0.4 MBq per mouse) and samples were solubilised and decolourised bef ore counting. Results: Nicotinamide and carbogen treatment reduced Tc- 99m-HL91 retention in all tumours to 54%-64% of control; it also reduc ed 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 me an ratio of tumour to blood retention at 2 b for all tumours, both unp erturbed and oxygen-enhanced (r = 0.996; p < 0.001), Retention of C-14 -HL91 in SaF tumour was unchanged by nicotinamide and carbogen, confir ming that (TC)-T-99m complexation of the ligand is required for hypoxi a specificity. Conclusion There is excellent correlation between Tc-99 m-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 ligan d 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.