A study of the potential use of membrane perturbants in enhancing the hyperthermic treatment of cancer

Abstract

Many tumour cells are more sensitive to hyperthermia than non-cancerous cells. The nature of this greater thermal sensitivity is not clear. The present study indicates that a likely cause for this increased thermal sensitivity is membrane-associated. Plasma membrane enriched fractions were obtained from two solid rat tumours: D23, a hepatoma, and Mc7, a sarcoma. Lipids from these membranes were extracted, characterized, and compared to equivalent fractions from control tissue (liver). In both cases the tumour membranes had lowered cholesterol: phospholipid ratios. There was little differenceln the phospholipid classes, but there was somecliSigfetice in the fatty acid composition of the individual phospholipids. Fluorescence polarization studies were carried out on whole membranes and indicated that the overall 'order' of the tumour membranes was decreased with respect to the controls. In addition a plasma membrane bound enzyme, the Mg2+ATPase, was found to be considerably more thermolabile in the tumour cells. The addition of the membrane pertubant tetracaine produced a greater degree of disorder in the tumour membranes compared to controls, and enhanced the thermolability of the Mg2+ATPase. These differences are further evidence that the plasma membrane is a likely site for the primary lesion in cell heat injury. Results from in vivo studies support the above mentioned in vitro work. D23 and Mc7 tumours, grown in the foot, were subject to hyperthermia and the simultaneous application of a membrane perturbant, tetracaine. The addition of the tetracaine significantly increased the efficacy of the treatment. When the D23 tumour was grown in ethanol-dependent rats there was no difference in the 'adaptive' response of the tumour, compared to the normal, plasma membranes. There was no difference in the heat sensitivity of foot tumours grown in ethanol-fed rats compared to tumours from pair fed controls.