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another in certain populations, resulting in no net mortality change?The paradox that the most widely prescribed lipid lowering agents8may increase coronary disease and decrease cancer needs to be

investigated.Crozer Cottage,Crozer-Chester Medical Center,Upland, Pennsylvania 19013, USA MARK R. GOLDSTEIN

1. Grundy SM. HMG-CoA reductase inhibitors for treatment of hypercholesterolemia.N Engl J Med 1988; 319: 24-33

2. Coleman PS, Sepp-Lorenzino L. The role of the cholesterol synthesis pathway duringtumor cell proliferation. In: Esfahani M, Swaney JB, eds. Advances in cholesterolresearch Caldwell, NJ: Telford Press, 1990: 201-70.

3. Glomset J, Gelb M, Farnsworth C. The prenylation of proteins. Curr Opin Lipidol1991; 2: 118-24.

4. Folkers K, Langsjoen P, Willis R, et al. Lovastatin decreases coenzyme Q levels inhumans. Proc Natl Acad Sci USA 1990; 87: 8931-34.

5. Bradford RH, Shear CL, Chremos AN, et al. Expanded Clinical Evaluation ofLovastatin (EXCEL) Study results, I: efficacy in modifying plasma lipoproteinsand adverse event profile in 8245 patients with moderate hypercholesterolemia.Arch Intern Med 1991; 151: 43-49.

6. Bradford RH, Shear CL, Chremos AN, et al. Expanded Clinical Evaluation ofLovastatin (EXCEL) Study: design and patient characteristics of a double-blind,placebo-controlled study in patients with moderate hypercholesterolemia. Am JCardiol 1990; 66: 44B-55B.

7. Tobert JA. The cholesterol controversy. Br Med J 1992; 304: 713.8. Wysowski DK, Kennedy DL, Gross TP. Prescribed use of cholesterol-lowering drugs

in the United States, 1978 through 1988. JAMA 1990; 263: 2185-88.

SIR,-Professor Buchwald suggests that 3-hydroxy-3-methylglutaryl (HMG) CoA reductase inhibitors might be effectivein the treatment of cancer by blocking the production of isoprenoidsin cholesterol’s synthetic pathway, which are necessary for celldivision. It should be pointed out that other lipid-loweringinterventions, such as diets low in saturated fat and bile acidsequestrants, promote the synthesis of isoprenoids by inducingde-novo cellular cholesterol synthesis until equilibirum betweencellular uptake of cholesterol from the blood and serum

concentrations can be reached.Three lines of evidence indicate that the lowering of serum

cholesterol by methods other than HMG-CoA reductase inhibitionmay promote tumour growth. First, increased cell proliferation andDNA synthesis is seen in tissues of male weanling rats fed

cholestyramine.’ Second, the reduction of serum cholesterol

through either the manipulation of dietary lipids or theadministration of cholestyramine leads to tumour promotion in a ratmammary tumour mode1,2 Third, in aggregate, trials of lipid-lowering interventions other than HMG-CoA reductase inhibitorshave shown a significant excess of cancer mortality.3 3

In one trial of a lipid-lowering diet, poor adherence to theexperimental diet was associated with increased cancer occurrence.4This finding can be understood in the context of the hypothesis thatthe induction of cellular cholesterol synthesis might act as a tumourpromoter. Those who frequently switch from a diet rich incholesterol to a cholesterol-lowering diet would be frequentlyinducing de-novo cellular cholesterol synthesis: every inductionmay serve as a separate promoting event. Whether subjects whoshow poor compliance with experimental interventions in otherlipid-lowering trials have an increased cancer risk should be

investigated. This model implies that it might be preferable to lowerserum cholesterol concentrations slowly rather than precipitously,to maintain equilibrium between cellular and serum cholesterol.The cancer experience of those currently prescribed HMG-CoA

reductase inhibitors should provide an important test of Buchwald’ ’s

hypothesis, but we should be careful not to apply it to other

lipid-lowering interventions.

Department of Biostatistics and Epidemiology,University of Tennessee,Memphis TN38163, USA STEPHEN B. KRITCHEVSKY

1. Kazanecki ME, Melhem MF, Spichty KJ, Kelly RH, Rao KN. Diet-inducedreduction in serum lipoproteins stimulates cell proliferation in weanling rats.Pharmacol Res 1989; 21: 533-47.

2. Rao KN, Melhem MF, Gabriel HF, et al. Lipid compostion and de novocholesterolgenesis in normal and neoplastic rat mammary tissues. J Natl CancerInst 1988; 80: 1248-53.

3 Kritchevsky SB, Kritchevsky D. Serum cholesterol and cancer risk: an epidemiologicperspective. Annu Rev Nutr 1992; 12: 391-416.

4. Pearce ML, Dayton S. Incidence of cancer in men on a diet high in polyunsaturated fat.Lancet 1971; i: 464-67.

SIR,-Professor Buchwald’s hypothesis suggesting that

restricting cholesterol availability can achieve tumour inhibition isdifficult to reconcile with the results of numerous clinical trials, ashighlighted by Muldoon and co-workers’ meta-analysis,l whichdemonstrated a significant increase (rather than a decrease) incancer mortality with cholesterol-lowering drugs. However, it maybe that the important factor that determines the cancer risk oftreatment is the mechanism of cholesterol reduction.The inhibitory effect of HMG-CoA reductase inhibitors on

tumour growth in animals2 may relate to the direct effects ofcholesterol on cell growth, or to the inhibition of farnesylpyrophosphate synthesis, the substance that anchors ras proteins tothe cell membrane.3 The importance of these two mechanisms isunknown. The potential anticancer effect of a treatment that lowersintracellular cholesterol might be outweighed by an increase inintracellular farnesyl residues. Treatments that lower plasmacholesterol independently of HMG-CoA reductase (eg, bile acidresins, nicotinic acid, dietary therapy) could have tumour

promoting effects by secondarily increasing HMG-CoA reductaseactivity, increasing famesyl residues, and potentiating ras oncogeneactivation. This adaptive mechanism, along with upregulation ofLDL receptors, can also prevent a decrease in intracellularcholesterol. These mechanisms might explain why cholesterol-lowering agents do not reduce cancer mortality. It is known fromexperimental studies that lowering plasma cholesterol by dietaryrestriction leads to a compensatory increase in HMG-CoAreductase activity in the liver.4 Conversely, rats fed a highcholesterol diet reduce their HMG-CoA reductase activity, and,importantly, farnesyl pyrophosphate synthetase mRNA andenzyme activity are also reduced, suggesting that dietary cholesterolrestriction may increase intracellular farnesyl residues.s

Cholestyramine is also known to increase the expression of hepaticHMG-CoA reductase.6 It also raises serum concentrations of

products of the mevalonate pathway in patients with familial

hypercholesterolaemia.7 Finally, the latest evidence suggests thatfibrates do not inhibit HMG-CoA reductase at therapeutic doses.’Buchwald states that decreasing cholesterol availability, or falling

intracellular cholesterol synthesis, will inhibit tumour growth. Isuggest that although lowering intracellular cholesterol and farnesylpyrophosphate specifically by HMG-CoA reductase inhibitionmay be important in preventing tumour growth, there is littleevidence from clinical trials that reducing plasma cholesterol byother means is cancer protective.

Department of Clinical Medicine,Trinity College Dublin,St James Hospital, Dublin 8, Eire MICHAEL GOGGINS

1. Muldoon MF, Manuck SB, Matthews KA. Lowering cholesterol concentrations andmortality: a quantitative review of primary prevention trials. BMJ 1990; 301:309-14.

2. Maltese WA, Defindini R, Green RA, Sheridan KM, Donley DK. Suppression ofmurine neuroblastoma growth in vivo by mevinolin, a competitive inhibitor of3-hydroxy-3-methylglutaryl-coenzyme A reductase. J Clin Invest 1985; 76:

1748-54.3. Schafer WR, Kim R, Steme R, Thomer J, Kim SH, Rine J. Genetic and

pharmacological suppression of oncogenic mutations in RAS genes of yeast andhumans. Science 1989; 245: 379-85.

4. Mazur A, Remesy C, Gueux E, Levrat MA, Demigne C. Effects of diets rich infermentable carbohydrates on plasma lipoprotein levels and on lipoprotein

catabolism in rats. J Nutr 1990; 120: 1037-45.5. Ness GC, Keller RK, Pendleton LC. Feedback regulation of hepatic 3-hydroxy-3-

methylglutaryl-CoA reductase activity by dietary cholesterol is not due to alteredmRNA levels. J Biol Chem 1991; 266: 14 854-57.

6. Dory L, Bhattacharyya A, Strong J, Chappuis C. Hapatic low density lipoproteinreceptors, HMG CoA reductase, and plasma lipids and apoproteins in high- andlow-resonding rhesus monkeys: effect of cholestyramine treatment. J Lipid Res1990; 31: 279-87.

7. Elmberger PG, Kalen A, Lund E, et al. Effects of pravastatin and cholestyramine onproducts of the mevalonate pathway in familial hypercholesterolemia. J Lipid Res1991; 32: 935-40.

8. Tikkanen MJ. Fibric acid derivatives. Curr Opin Lipidol 1992; 3: 29-33.

CORRECTION

Randomised comparison of oral ofloxacin alone with combination ofparenteral antibiotics in neutropenic febrile patients. -Our apologies toDr Imtiaz Malik and colleagues for an error in the patients and methodssection of this paper (May 2, p 1092}-the dose of ofloxacin used (correctlygiven in the summary) was 400 mg twice daily.