Summary An attempt has been made to reverse cachexia and to selectively deprive the tumour of metabolic substrates for energy production by feeding a ketogenic regime, since ketone bodies are considered important in maintaining homeostasis during starvation. As a model we have used a transplantable mouse adenocarcinoma of the colon (MAC 16) which produces extensive weight loss without a reduction in food intake. When mice bearing the MAC16 tumour were fed on diets in which up to 80% of the energy was supplied as medium chain triglycerides (MCT) with or without arginine 3-hydroxybutyrate host weight loss was reduced in proportion to the fat content of the diet, and there was also a reduction in the percentage contribution of the tumour to the final body weight. The increase in carcass weight in tumour-bearing mice fed high levels of MCT was attributable to an increase in both the fat and the non-fat carcass mass. Blood levels of free fatty acids (FFA) were significantly reduced by MCT addition. The levels of both acetoacetate and 3-hydroxybutyrate were elevated in mice fed the high fat diets, and tumour-bearing mice fed the normal diet did not show increased plasma levels of ketone bodies over the non-tumour-bearing group despite the loss of carcass lipids. Both blood glucose and plasma insulin levels were reduced in mice bearing the MAC16 tumour and this was not significantly altered by feeding the high fat diets. The elevation in ketone bodies may account for the retention of both the fat and the non-fat carcass mass. This is the first example of an attempt to reverse cachexia by a diet based on metabolic differences between tumour and host tissues, which aims to selectively feed the host at the expense of the tumour.

Summary The presence of succinyl-coenzyme A: acetoacetate CoA-transferase (3-oxo acid-CoA transferase), an initiator of ketone body utilization in non-hepatic tissue was examined in a number of animal and human tumours of peripheral tissues. While enzyme levels in heart, kidney, lymphocytes and bladder were high, the tumours contained low or non-detectable levels of transferase activity, comparable with that of normal liver. The activities of acetoacetyl-CoA thiolase paralleled that of the transferase, except for the high activity in liver, and in all cases the tumour content of the enzyme was lower than that of the brain. The activity of 3-hydroxybutyrate dehydrogenase was similar in both normal and tumour tissue. The results indicate that tumours of non-hepatic tissues may be unable to metabolize ketone-bodies and suggest a therapeutic strategy for selective starvation of the tumour by dietary modification.

Summary A comparison has been made between the ability of long-chain triglycerides (LCT) and mediumchain triglycerides (MCT) to prevent weight loss induced by the cachexia-inducing colon adenocarcinoma (MAC16) and to reduce tumour size. There was no difference in calorie consumption or nitrogen intake between the various groups. When compared with a normal control high carbohydrate, low fat diet, animals fed MCT showed a reduced weight loss and a marked reduction in tumour size. In contrast neither weight loss nor tumour size differed significantly from the controls in animals fed the LCT diet. An elevated plasma level of 3-hydroxybuturate was found only in the animals fed the MCT diets. Administration of LCT caused an increase in the plasma level of FFA, which was not observed in the MCT group. These results suggest that diets containing MCT would provide the best ketogenic regime to reverse the weight loss in cancer cachexia with a concomitant reduction in tumour size.Weight loss is a common feature of many neoplastic diseases (De Wys, 1986) and appears to be independent of the tumour burden and often precedes clinical diagnosis. The end result of the continuing decline in nutritional status is the clinical syndrome of cancer cachexia. Patients with weight loss have a poorer response to chemotherapy and a shorter survival time than those without weight loss (De Wys et al., 1980).We have utilized the MAC 16 adenocarcinoma of the mouse colon as an experimental model of human cachexia, where weight loss arises from the metabolic effects of the tumour on the host (Bibby et al., 1987). Animals bearing the MAC16 tumour show weight loss at small tumour burdens (less than 1% of the host weight) and without a reduction in either food or water intake. Weight loss is characterized by a progressive loss of both body fat and muscle dry weight, which increases in direct proportion to the tumour burden (Beck & Tisdale, 1987). Although there is extensive mobilization of body fat reserves ketosis does not occur (Bibby et al., 1987). Ketonuria has also been shown not to occur in cancer patients . Since ketone bodies are believed to play an important role in the regulation of lean body mass during starvation we and others (Tisdale, 1982;Magee et al., 1979;Williamson & Matthaei, 1981) have suggested that a high fat/low carbohydrate ketogenic diet should also preserve lean body mass during cancer cachexia, and would not be expected to be utilized by a poorly vascularized tumour, which would depend primarily on glucose as an energy source. In addition 3-hydroxybutyrate has recently been shown to inhibit the lipolytic and proteolytic factors produced by the MAC16 tumour and which may be responsible for the cachexia (Beck & Tisdale, 1987). Such an approach has been vindicated since mice bearing the MAC16 tumour fed a diet in which up to 80% of the energy was supplied as medium-chain triglycerides (MCT) show a reduction in both the extent of weight loss and tumour weight . A ketogenic diet containing 70% MCT and supplemented with D-3-...

The MAC 16 is a chemically induced transplantable adenocarcinoma of the colon which produces extensive weight loss in tumour-bearing mice without a reduction in overall food intake (Bibby et al., 1986). Weight loss appears to be directly related to the size of the tumour and is apparent at small tumour masses (less than 1% of the host body weight). We have considered this tumour to be an appropriate model of human cachexia where weight loss originates from a metabolic effect of the tumour.During the phase of host weight loss in mice bearing the MAC 16 tumour extensive mobilization of adipose tissue occurs with a corresponding rise in the plasma level of free fatty acids (FFA), although there is not a marked ketosis as might be expected in simple starvation (Tisdale et al., 1985). The tumour also has a marked hypoglycaemic effect on the host. We have reduced the host weight loss produced by the MAC 16 tumour by feeding a diet with increasing proportions of energy derived from medium chain triglycerides. In addition this dietary regime produced marked reductions in tumour size, suggesting the inability of the tumour to utilize fat as an energy source .This study compares the rate of substrate utilization and oxidative metabolism of MAC 16Correspondence: M.J. Tisdale.

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