Abstract
In this work tumour hypoxia is induced by physically occluding the tumour vascular supply by clamping, or by giving mice 5 mg kg-1 hydralazine. These methods have previously been shown to increase the radiobiological hypoxic fraction in tumours close to 100%. Their effectiveness in potentiating the bioreductive toxicity of: misonidazole (800 mg kg-1), RSU1069 (80 mg kg-1), mitomycin C (5 mg kg-1) and SR4233 (50 mg kg-1) is assessed in the RIF-1 and KHT tumours using regrowth delay as an assay. Clamping alone for 120 min gives little or no response, but when RSU1069 is administered 15 min before clamping, large growth delays result. RIF-1 tumours clamped for 90 or 120 min with RSU1069 give cure rates of 12.5% and 37.5% respectively. Less effect with clamping is seen for the other bioreductive agents. The effect of hydralazine with RSU1069 although significant in the RIF-1 tumour, is modest compared to that for clamping. Small enhancements of toxicity are seen with hydralazine in combination with misonidazole in the RIF-1 tumour and mitomycin C in both tumours. The varying effectiveness of these treatments is attributed to several factors which include the level and duration of hypoxia, concentration and contact time of the bioreductive drugs, the microenvironment of the tumour and the nature of the reductive metabolic pathways available in the different tumour cell types.
Highlights
The results indicate that the RIF-1 tumour is more responsive than the KHT tumour in mice given 80 mg kg-' RSU 1069 followed by clamping
This study has examined the hypothesis that induction of hypoxia in tumours should potentiate anti-tumour effects of drugs which are preferentially toxic to cells under hypoxic conditions
Clamping and hydralazine induce close to 100% radiobiological hypoxia in murine tumours for different periods of time
Summary
Mice and tumoursEight to twelve week-old category IV C3H/He mice, obtained from NIMR, Mill Hill, London in 1984 and subsequently bred in-house were used for all experiments. The KHT and RIF-I sarcoma tumour lines were provided by Dr P. Tumours were derived by subcutaneous injection of 2-5 x 105 viable cells, obtained by trypsin/DNAase digestion, into the mid-dorsal pelvic region of the back. 6-10 per group, were treated when tumours reached a geometric mean diameter of 4.5-5.5 mm (calculated from three orthogonal diameters measured with graduated vernier calipers). After treatment the tumours were measured 3 x weekly. The end-point was the time to reach 4 x initial tumour volume after which the animals were humanely killed. A 'cure' was defined as occurring when the tumour regressed completely and there was no sign of local recurrence at 150 days. No significant difference was seen between male and female mice in response to any of the treatments
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