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

Abstract

PURPOSE:

The 99mTc-labelled amine oxime 99mTc-HL91 (Prognox) 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 pO2 histograph (KIMOC 6650) with at least 5 tracks and at least 70 values, and expressing pO2 values as % < 2.5 mmHg. 99mTc-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. 14C-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 99mTc-HL91 retention in all tumours to 54%-64% of control; it also reduced the proportion of pO2 values < 2.5 mmHg in all tumours. The mean proportion of pO2 values < 2.5 mmHg correlated very well with the mean ratio of tumour to blood retention at 2 h for all tumours, both unperturbed and oxygen-enhanced (r = 0.996, p < 0.001). Retention of 14C-HL91 in SaF tumour was unchanged by nicotinamide and carbogen, confirming that 99mTc complexation of the ligand is required for hypoxia specificity.

CONCLUSION:

There is excellent correlation between 99mTc-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. 99mTc complexation of the ligand is required for hypoxia specificity. 99mTc-HL91 (Prognox) shows good potential as a clinical marker for hypoxia and warrants further development.

• Authors: D J Honess, S A Hill, D R Collingridge, B Edwards, G Brauers, N A Powell, D J Chaplin
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 42 Issue 4 Pg. 731-5 (Nov 01 1998) ISSN: 0360-3016 [Print] United States
• PMID: 9845086 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Contrast Media
• Organotechnetium Compounds
• Oximes
• Radiopharmaceuticals
• technetium Tc 99m 4,9-diaza-3,3,10,10-tetramethyldodecan-2,11-dione dioxime
• Carbon Dioxide
• Niacinamide
• carbogen
• Oxygen

Topics

• Adenocarcinoma (metabolism)
• Animals
• Carbon Dioxide (administration & dosage)
• Carcinoma (metabolism)
• Cell Hypoxia
• Colonic Neoplasms (metabolism)
• Contrast Media (pharmacokinetics)
• Humans
• Lung Neoplasms (metabolism)
• Mice
• Mice, Inbred CBA
• Mice, SCID
• Niacinamide (administration & dosage)
• Organotechnetium Compounds (pharmacokinetics)
• Oximes (pharmacokinetics)
• Oxygen (administration & dosage)
• Radiopharmaceuticals (pharmacokinetics)
• Sarcoma (metabolism)