Zhang X, Melo T, Ballinger J R, Rauth A M
Division of Experimental Therapeutics, Ontario Cancer Institute, Toronto, Canada.
Int J Radiat Oncol Biol Phys. 1998 Nov 1;42(4):737-40. doi: 10.1016/s0360-3016(98)00301-0.
Solid tumours of similar type and stage can vary widely in their hypoxic cell fraction. Such cells may be prognostic for aggressive, metastatic, and radiation-resistant disease. A 99mtechnetium (99mTc)-labelled non-nitroaromatic agent, butyleneamine oxime (99mTc-BnAO) or HL-91 (Amersham International, Inc., Amersham, UK) has been evaluated both in vitro and in vivo for its possible efficacy as a noninvasive marker for the clinical detection of hypoxic cells in solid tumours.
Suspension cultures of Chinese hamster ovary (CHO) cells under controlled levels of oxygen were used to measure the oxygen dependency of 99mTc-BnAO accumulation. V79 cells grown as multilayers on a semipermeable membrane served as an in vitro model for drug penetration through the extravascular space of the tumour. C3H mice bearing KHT-C leg tumours were the in vivo models for selective drug accumulation as a function of time after i.v. administration of 99mTc-BnAO.
99mTc accumulated selectively in hypoxic vs. aerobic cells, resulting in a 9 +/- 2-fold differential in radioactivity per 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 cellular multilayer under aerobic or hypoxic conditions. In vivo measurements indicated favourable labelling of solid tumours containing hypoxic cells with 1% of the total activity per g of tumour, a tumour-to-blood 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 99mTc- labelled compounds, excretion was primarily via the urinary tract. Nitro-L-arginine selectively increased solid tumour labelling over normal tissue.
99mTc-BnAO or HL-91 is a promising agent for clinical studies of tumour hypoxia, although the mechanism of its selective hypoxic cell accumulation remains unexplained.
