Induction of Tumour Hypoxia Post-irradiation: A Method for Increasing the Sensitizing Efficiency of Misonidazole and RSU 1069in Vivo

Abstract

It is known that hydralazine can decrease blood flow to experimental murine tumours. A consequence of this, in the KHT sarcoma, is the induction of close to 100 per cent radiobiological hypoxia, which lasts for nearly 2 h following i.v. injection of 5 mg/kg hydralazine to the mouse. This phenomenon is exploitable in order to increase the apparent sensitizing efficiency of the nitroheterocyclic radiosensitizers, misonidazole and RSU 1069, and is demonstrated using the treatment schedule: sensitizer----60 min----X-rays----1 min----hydralazine. Such a strategy will first take advantage of the radiosensitizing properties of the nitroimidazole, then after irradiation the hydralazine should allow expression of the differential toxicity towards hypoxic cells known to occur with misonidazole and RSU 1069. Misonidazole gives an enhancement ratio (ER) of 1.3 at 100 mg/kg, rising to 2.0 at 1000 mg/kg. Where hydralazine is given after irradiation, no additional cell kill is observed with 1000 mg/kg. In contrast, at lower doses of misonidazole, hydralazine induces a substantial increase in cell killing such that the ER obtained with 100 mg/kg is the same as that achieved with 1000 mg/kg misonidazole when used alone with radiation. Similarly, 20 mg/kg RSU 1069 with radiation followed by hydralazine is equivalent to the radiosensitizing effect of 80 mg/kg RSU 1069 without hydralazine. In addition, doses of RSU 1069 that normally give no radiosensitization (5 or 10 mg/kg) produce substantial increases in cell killing when combined with hydralazine.

The potential for prazosin and calcitonin gene-related peptide (CGRP) in causing hypoxia in tumours

“…coma The most effective vasodilator reported to cause hypoxia in experimental tumours appears to be hydralazine which acts directly on smooth muscle Voorhees & Babbs, 1982;Brown, 1987;Chaplin & Acker, 1987;Horsman et al, 1989;Stratford et al, 1989). The effect results either from diversion of blood away from the tumour to the normal tissues termed the 'steal phenomenon' or from the reduction in systemic blood pressure, leading to vascular collapse (Chaplin et al, 1987;Trotter et al, 1989).…”

“…Selective reduction in tumour blood flow and the consequent increase in hypoxia could have several advantages in cancer treatment, for example in combination with drugs which are selectively toxic to hypoxic cells (Brown, 1987;Chaplin & Acker, 1987;Stratford et al, 1989;Bremner et al, 1990). It might also be an advantage in treatment by hyperthermia, resulting in higher tumour temperatures and more uniform heating together with increased tumour sensitivity resulting from decreased nutrient delivery and reduced pH (Gerweck et al, 1979;Horsman et al, 1989).…”

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

“…RB6145 or nitro-L-arginine alone killed no more than 20% of cells when used alone. However, when excision was within 2-4 h of the combined drug treatment, there was a fourfold increase in cell killing, and this became much greater when the time between treatment and excision was increased to 12 and 24 h. To gain some understanding of survival to be governed by the residual radiation-resistant hypoxic cells (Stratford et al, 1989). The symbols in Figure 6B show the temporal dependence of the toxicity of RB6145 after irradiation.…”

“…Clearly, when excision was at 2-4 h after treatment, there was a three-to fourfold increase in cell killing of the residual radiation-resistant hypoxic cells in the tumour. As the time to excision was increased to 12 and 24 h, there was further cell killing and, on theoretical grounds, this 20-fold increase over that seen with radiation alone was the maximum achievable if all the hypoxic cells were sterilized (Stratford et al, 1989). A similarity between Figure 6A and B is the increase in cell killing that occurred in the 4-to 12-h period, and this may be a reflection of the time that was necessary for RB6145 to fully exert its cytotoxic action towards the hypoxic cells.…”

“…Such reductions can lower the oxygen status of tumours and thereby cause radiation resistance (Kruuv et al, 1967;Stratford et al, 1989). This so-called 'stealing effect' has been exploited to increase the anti-tumour efficiency of various bioreductive drugs (Chaplin, 1986(Chaplin, , 1989.…”