BW12C: effects on tumour hypoxia, tumour thermosensitivity and relative tumour and normal tissue perfusion in C3H mice

Dj Honess,De Hu,Nm Bleehen

doi:10.1038/bjc.1991.387

Abstract

BW12C (5-[2-formyl-3-hydroxypenoxyl] pentanoic acid) is an agent which stabilises oxyhaemoglobin and thus reduces oxygen delivery to tissues. It is of interest as a possible potentiator of bioreductive agents and/or hyperthermia. The increases in radiobiological hypoxic fraction of RIF-1 and KHT tumours 30 min after 70 mg kg-1 BW12C i.v. were measured and shown to be similar; factors (+/- 2 s.e.) ranged from 3.87 (2.84-5.29) to 5.92 (1.92-18.2) despite the large variation in initial hypoxic fraction, from 0.30 (0.18-0.50) % for RIF-1 intramuscularly in the leg to 16.3 (14.7-18.1) % for subcutaneous KHT flank tumours. Thermosensitivity of intramuscular KHT leg tumours was not enhanced by 70 mg kg-1 BW12C 30 min before heating at 43 degrees C, 43.5 degrees C or 44 degrees C, assayed by regrowth delay. The effect of 70 mg kg-1 BW12C on relative tissue perfusion (RTP), assayed by 86Rb extraction, was measured from 0.5 h to 6 h after treatment. After 1 h RTP (+/- 2 s.e.) in RIF-1 tumours was reduced to 84 +/- 5.7% and 68 +/- 9.6% of control in leg and flank tumours respectively, and to 86 +/- 6.4% in leg muscle while flank skin RTP was unaltered at 109 +/- 8.6%. There were substantial increases in kidney (149 +/- 10.7%) spleen (173 +/- 22.1%) and lung (128 +/- 10.4%) at 1 h but in liver there was a decrease at 2 h to 85 +/- 8.4%. Dose response studies showed that the threshold dose for reduction of tumour RTP is between 55 and 70 mg kg-1, but perturbations in normal tissue RTP occur at lower doses, e.g. 40 mg kg-1 for spleen. BW12C had minimal effects on renal function measured by 51CrEDTA clearance. The data as a whole indicate that reduction in tumour perfusion is likely to be an important determinant in the increase in tumour hypoxia induced by BW12C.

Highlights

Viously been shown to protect both murine tumours (Adams et al, 1986 and 1989, Honess et al, 1991b) and human tumour xenografts (Cole & Robbins, 1989) from radiation, in a manner consistent with an increase in hypoxic fraction
Tumours were treated at a volume of 250-450 mm3 unless otherwise specified; i.e. for RIF-1 tumours at 10-11 days after inoculation in the leg and 14-15 days after inoculation in the flank and for KHT tumours at 7-8 days after inoculation in the leg and 10-11 days after inoculation in the flank
Radiation dose response curves for RIF-1 and KHT tumours grown in the leg or in the flank are presented in Figure 1 for animals receiving PBS or 70 mg kg-' BW12C 30 min before the start of radiation

Summary

Introduction

Viously been shown to protect both murine tumours (Adams et al, 1986 and 1989, Honess et al, 1991b) and human tumour xenografts (Cole & Robbins, 1989) from radiation, in a manner consistent with an increase in hypoxic fraction. In the Lewis lung tumour (Adams et al, 1986), KHT tumour (Adams et al, 1989) and MAWI xenograft (Cole & Robbins, 1989), all grown subcutaneously, the effect was compatible with the induction of complete hypoxia, but in RIF-1 intramuscular tumours the radioprotection was more modest (Honess et al, 1991b). In the light of these observations the aims of the present study were:

Objectives

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Results

Conclusion