Lipids and the treatment of cancer

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The expression of variant forms of glycolipids on cell surfaces may offer a means of directing specific drugs to kill the tumour cells, as discussed above. In addition, several potential new treatments based on phospholipid analogues have been developed and in some cases tested in clinical trials. These compounds are intended to incorporate into target membranes, either the cell membrane or intracel-lular membranes such as the endoplasmic reticu-lum. Thus, their mode of action differs from conventional anti-cancer drugs that target DNA replication. Several types of compounds have been tested, although most are analogues of phosphati-dylcholine or of lysophosphatidylcholine, e.g. with a sugar molecule ether-linked at the sn-2 position. They are believed to act in diverse ways, all of which could be seen as targeting cells with a high rate of cell division. They may act by disrupting signal transduction and signalling pathways, e.g. inhibition of the phosphoinositide-specific phos-pholipase C with suppression of the diacylglycerol-protein kinase C pathway (Section 7.9), or inhibition of phosphocholine cytidylyltransferase leading to inhibition of phosphatidylcholine biosynthesis de novo (Section 7.1.5). These compounds have shown great promise in cellular systems, but their clinical application has been limited by problems of toxicity to the intestinal tract (whose cells are also characterized by a high rate of division). They have found some application as topical therapies (direct application, e.g. to skin lesions).

Cancer causes death through a number of mechanisms including direct invasion of critical organs. However, a common and life-threatening feature of many cancers is a marked loss of body fat, cachexia. There have been many investigations of the cause of cancer cachexia. One theory is that a circulating factor, known as cachectin, leads to inhibition of adipose tissue lipoprotein lipase and consequent failure of fat storage (so there is continuous net fat loss). Cachectin is now known to be identical to tumour necrosis factor-a, a cytokine produced by many cell types including macrophages and adipocytes. The evidence for this mechanism has largely been based on animal studies. In humans, measurements of energy intake have shown that the loss of body fat is mainly a problem of energy balance. Patients lose appetite and in many cases involving cancers of the gastrointestinal tract have difficulty eating. There have been some interesting developments in the treatment of cancer cachexia by the oral administration of relatively large amounts of n-3 PUFA (1-2 g day-1 of eicosapentaenoic acid, 20:5n-3), together with a conventional nutritional supplement. Patients who were previously losing weight have shown an increase in body weight during this treatment. It is likely that the mechanism relates to a general anti-inflammatory effect of large doses of the n-3 PUFA, mediated in part by their role as precursors of eicosanoids of the 3-series rather than the 2-series (Section 2.4). The n-3 PUFA also tend to reduce the production of pro-inflammatory cytokines including tumour necrosis factor-a and interleukin-6.

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