Bioreductive drugs and the selective induction of tumour hypoxia

Abstract

Summary In this work tumour hypoxia is induced by physically occluding the tumour vascular supply by clamping, or by giving mice 5 mg kg-' 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-'), RSU1069 (80 mg kg-'), mitomycin C (5 mg kg-') and SR4233 (50 mg kg-') 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.

Enhancement of bioreductive drug toxicity in murine tumours by inhibition of the activity of nitric oxide synthase

“…The timing of the drug administrations was on the basis that 15 min should be long enough for CIIOlO, and/or the active species derived from it, to reach a high tumour concentration (Binger and Workman 1990;Cole et al, 1991) before hypoxia is induced by treatment with nitro-L-arginine. This sequence has previously been found to be optimal for the use of RSU1069 with other methods of inducing tumour hypoxia (Bremner et al, 1990;Bremner, 1993).…”

“…It is thought that RSU1069 would reach its maximum tumour concentration within 15 min of administration, hence any interference with tumour blood supply thereafter would not only create hypoxia but also prevent efflux of the drug from the tumour, thereby enhancing tumour toxicity (Bremner et al, 1990). The combination of RB6145 and nitro-L-arginine was at its most potent when the drugs were given within a short time of each other.…”

“…Horsman et al (1996) have shown that tumour blood flow changes brought about by nitro-L-arginine lasted no more than an hour, whereas the changes in redox status reported by Wood et al (1994a) could last for up to 6 h. Thus, the underlying mechanism mediating these anti-tumour effects is likely to be a complex interaction between hypoxia induction and entrapment (distribution and pharmacokinetics). Such interactions have been shown to contribute to the potentiation of the activity of both RSU1069 and the alkylating agent melphalan using a variety of techniques for modifying blood flow to tumours (Chaplin and Acker 1987;Stratford et al, 1988;Bremner et al, 1990;Castellino et al, 1995).…”

Increasing the effect of photodynamic therapy on the RIF-1 murine sarcoma, using the bioreductive drugs RSU1069 and RB6145

“…Figure 6, collects data from the other studies with the RIF-1 tumour carried out in this laboratory, where RSU1069 has been used in combination with different methods for enhancing tumour hypoxia, and compares these with the results of the present study. Some retardation of tumour growth is evident in mice treated with the vasoactive drug, hydralazine (Bremner et al, 1990) and with flavone acetic acid but not with the haemaglobin left-shifter BW12C (Bremner, unpublished results). However, a large effect is observed when the tumour blood supply is occluded by mechanical clamping.…”

“…Reduce blood flow e.g. clamping (Bremner et al, 1990), 5-hydroxytryptamine (Chaplin, 1986) and hydralazine (Brown, 1987;Chaplin & Acker, 1987) 2. Increase the oxygen affinity of haemoglobin e.g.…”