Selective modification of sterol composition of hepatomas: new opportunities for chemotherapy.
The absence of feedback regulation of cholesterol biosynthesis in hepatomas suggests the possibility of substitution of cholesterol with its biosynthetic precursors (7-dehydrocholesterol or lanosterol) selectively in hepatomas without the accumulation of these precursors in liver and other normal tissues, by a combination of a high cholesterol diet and specific inhibitors of cholesterol biosynthesis (AY-9944 for accumulation of 7-dehydrocholesterol and ketoconazole for accumulation of lanosterol). We suggest: (1) using a selective accumulation of 7-dehydrocholesterol in hepatoma plasma membranes to increase the sensitivity of hepatoma cells to polyene antibiotics (amphotericin B, nystatin), because polyene antibiotics have higher affinity to 7-dehydrocholesterol compared to cholesterol; (2) using a selective accumulation of lanosterol in hepatoma cells to increase the sensitivity of hepatoma cells to different antitumor agents, because lanosterol is much less effective in supporting vital cell functions (including barrier properties of natural membranes) compared to cholesterol.
Monell Chemical Senses Center, Philadelphia, PA 19104-3308, USA.
A M
AM
Feigin
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D005246:Feedback; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D008954:Models, Biological; D013261:Sterols / Q000737:chemistry / Q000378:metabolism*
D013261:Sterols; D002784:Cholesterol