Selective heat sensitivity of cancer cells. Biochemical and clinical studies

Abstract

Biochemical and clinical studies have revealed a profound and selective toxic effect of elevated temperatures on tumor cells. Whereas the oxygen uptake of Novikoff hepatoma and Ehrlich ascites carcinoma cells was considerably less at 427deg;C than at 38°C, there was little difference in respiration at these two temperatures in normal and regenerating liver. The inhibition of the respiration of Novikoff hepatoma cells was irreversible after 90 min. There was no significant effect of temperature on anaerobic glycolysis. In 22 patients with cancers of the limbs the temperature in the tumors was raised to 41.5° to 43.5°C for several hours in 25 regional perfusions with prewarmed blood. Severe complications in some patients lead to six deaths and three immediate amputations. Intensive post‐treatment care was required. Three patients failed to respond; four could not be evaluated and all others had regressions. Grossly the tumors disappeared totally in ten patients, of which three recurred. Histological evaluation of multiple biopsies demonstrated complete massive necrosis in eight cases, of which none recurred, although one died and three required amputations; of these, seven are alive and free of disease. In the cases with partial regression, the tumors all recurred and required amputation or other treatment. The most responsive tumor appeared to be melanoma. No conclusions about survivals can be drawn at present although four of seven patients with malignant melanomas treated only by heat perfusion are alive and well with functional limbs 28, 27, 11 and 7 months after treatment. Only one patient has died of metastases although two have been lost to follow‐up.

The sensitivity of a malignant cell line to hyperthermia (42°C) at low intracellular pH

“…These findings are in accord with previous work in which it was demonstrated that irreversible inhibition of respiration in SDB cells was correlated with inability of the cells to multiply in vitro and to produce tumours in the host (Dickson and Shah, 1972). A similar inhibition of respiration at 42 0C with concomitant maintenance of anaerobic glycolysis has been reported for Novikoff cells (Cavaliere et al, 1967) and for cells freshly obtained from solid tumours of the rabbit (Dickson and Muckle, 1972) and rat (Dickson and Suzangar, 1974). In the case of the latter two tumour types, the treated cells failed to take on transplantation into host animals.…”

“…As a therapeutic modality, heat has received intermittent attention since the latter years of the last century with some impressive results in the treatment of animal and human cancer (Cavaliere et al, 1967;Suit and Schwayder, 1974;Dickson and Suzangar, 1976). Before hyperthermia can warrant more widespread clinical application, more information is required on the strategy of heating tumours, and better methods of applying heat are needed, both locally to the tumour and generally to the host, than those now available.…”

“…Data currently available indicate that at 420C there is a selective destructive effect on malignant cells, both in vitro and in vivo in animal tumours (Cavaliere et at., 1967;Overgaard and Overgaard, 1972;Dickson, 1976a) and human cancers (Cavaliere et al, 1967;Dickson and Suzangar, 1976). The difference in heat sensitivity between cancer cells and normal cells decreases with increasing temperature above 42°C (Dickson, 1976a,b), so that temperatures in excess of this involve hazard to the host.…”

“…With heat-sensitive tumours, host cure is dependent upon adequate duration of heating in relation to tumour size (Dickson and Ellis, 1976). With a large tumour burden the prolonged treatment required at 42TC imposes considerable stress on the host (Cavaliere et al, 1967;Dickson, 1974), who may be elderly and in an already debilitated state from his disease. The advantages of sensitizing the cancer cells to the effects of heat are therefore apparent.…”

The Selective Inhibitory Effect of Hyperthermia on the Metabolism and Growth of Malignant Cells

“…Despite the oft-cited importance of both aerobic and anaerobic glycolysis in cancer cell metabolism (Busch 1962;Pitot 1966), and the specific positive correlation between anaerobic glycolysis and growth rate in hepatomas (Burk et al, 1967) Recent work in man has show-n that hyperthermia, achieved by regional perfusion (Cavahere et al, 1967;Stehlin, 1970) (Cavaliere et al, 1967). The use of hyperthermia for the treatment of cancer, although of undoubted effectiveness in the cases reported to date, has involved considerable hazard to the patient.…”