STUDIES OF TC-99M-BNAO (HL-91) - A NON-NITROAROMATIC COMPOUND FOR HYPOXIC CELL DETECTION

Purpose: Solid tumours of similar type and st:age can vary widely in t heir hypoxic cell fraction. Such cells may be prognostic for aggressiv e, metastatic, and radiation-resistant disease, A (99m)technetium (Tc- 99m)-labelled non-nitroaromatic agent, butyleneamine oxime (Tc-99m-BnA O) or HL-91 (Amersham International, Inc., Amersham, UK) has been eval uated both in vitro and in vivo for its possible efficacy as a noninva sive marker for the clinical detection of hypoxic cells in solid tumou rs. Materials and Methods: Suspension cultures of Chinese hamster ovar y (CHO) cells under controlled levels of oxygen were used to measure t he oxygen dependency of Tc-99m-BnAO accumulation. V79 cells grown as m ultilayers on a semipermeable membrane served as an in vitro model for drug penetration through the extravascular space of the tumour. C3H m ice bearing KHT-C leg tumours were the in vivo models for selective dr ug accumulation as a function of time after i.v. administration of Tc- 99m-BnAO. Results: Tc-99m accumulated selectively in hypoxic vs. aerob ic cells, resulting in a 9 +/- 2-fold differential in radioactivity pe r cell at 4 h, The k(m) for this selective accumulation was 20 ppm of oxygen. The labelled drug was equally effective in penetrating the cel lular multilayer under aerobic or hypoxic conditions. in vivo measurem ents indicated favourable labelling of solid tumours containing hypoxi c cells with 1% of the total activity per g of tumour, a tumour-to-blo od ratio of 1.2, and a tumour-to-muscle ratio of 4.6 at 4 to 6 h after drug administration. In contrast to more lipophilic Tc-99m-labelled c ompounds, excretion was primarily via the urinary tract. Nitro-L-argin ine selectively increased solid tumour labelling over normal tissue. C onclusions: Tc-99m-BnAO or HL-91 is a promising agent for clinical stu dies of tumour hypoxia, although the mechanism of its selective hypoxi c cell accumulation remains unexplained. (C) 1998 Elsevier Science Inc .