127
hyponatraemia (Na 126 mmol/1) and functional renal failure (urea 19 mmolll, creatinine 160 (imol/1). A stool smear was positive for leucocytes, and stool samples were negative for routine culture and for parasites. Flexible proctosigmoidoscopy showed a pseudomembranous mucosa. Histopathological examination confirmed the diagnosis of pseudomembranous colitis. The patient was treated with 500 mg vancomycin daily and she rapidly improved. Some serious lower gastrointestinal tract side-effects of NSAIDs have been described: non-specific colitis,l activation of quiescent idiopathic inflammatory bowel disease,2 collagenous colitis3 ulceration of the colon,4 and acute eosinophilic colitis.5 However, pseudomembranous colitis has never been reported in association with NSAIDs. A link with antibiotics is well known.6 Pseudomembranous colitis has also been reported during gold therapyNSAIDs are widely used, especially in the elderly, and we suggest that rectosigmoidoscopy should be done when diarrhoea develops after the start of NSAID therapy. Harvier Medical Clinic, Central University Hospital, 29609 Brest Cédex, France
A. GENTRIC Y. L. PENNEC
1 Ravi S, Keat AC, Keat ECB. Colitis caused by non-steroidal anti-inflammatory drugs.
Postgrad Med J 1986; 62: 773-76. 2. Kaufmann HJ, Taubin HL. Non-steroidal anti-inflammatory drug activates quiescent inflammatory bowel disease. Ann Intern Med 1987; 107: 513-16. 3 Giardiello FM, Hansen FC, Lazenby AJ, et al. Collagenous colitis in setting of non-steroidal anti-inflammatory drugs and antibiotics. Dig Dis Sci 1990; 35: 257-60. 4. Uribe A, Hohansson C, Slezak P, et al. Ulcerations of the colon associated with naproxen and acetylsalicylic acid treatment. Gastrointest Endosc 1986; 32: 242-43. 5 Bridges AJ, Marshall JB, Diaz-Arias AA. Acute eosinophilic colitis and hypersensitivity reaction associated with naproxen therapy. Am J Med 1990; 89: 526-27. 6. Price AB, Davies DR. Pseudomembranous colitis. J Clin Pathol 1977; 30: 1-12. 7. Reinhart WH, Kappeler M, Halter F. Severe pseudomembranous and ulcerative colitis during gold therapy. Endoscopy 1983; 15: 70-72.
Peripheral neuropathy associated with fluoroquinolones have been associated with adverse system (0-9-4-4% of patients), including headache, agitation, dizziness, sleep disturbance, and seizures in those with predisposing factors.1 We report a case of peripheral neuropathy associated with fluoroquinolones therapy. A 37-year-old man with chronic vertebral osteomyelitis, caused by a methicillin-susceptible Staphylococcus aureus, received oral pefloxacin 400 mg twice daily with excellent clinical and microbiological response. Many other oral regimens had failed previously, including flucloxacillin and clindamycin. After 5 months of pefloxacin, the patient had paraesthesia in his lower legs with a stocking-glove distribution, followed by progressive right foot weakness and difficulty in walking. Common peroneal nerve conduction velocity was 43 m/s. Electromyography (EMG) revealed fibrillations and polyphasic motor unit potentials in the tibialis anterior and peroneus longus muscles. Laboratory profile was normal and he denied alcohol misuse. Biopsy of rectal mucosa was negative for amyloidosis. No epidural abscess, transverse myelitis, or other causes could be found. The patient had been cured 15 years before from Hodgkin’s disease with radiochemotherapy, including vincristine for a total dose of 18 mg. Discontinuation of pefloxacin resulted in a dramatic improvement of peripheral neuropathy within 10 days. Osteomyelitis recurred 6 months later, and treatment with ofloxacin 200 mg twice a day resulted in relapse of peripheral neuropathy within 15 days, which remitted within 7 days of stopping ofloxacin. He was treated with flucloxacillin and fusidic acid for 2 months, which was stopped for a relapse of infection, which most probably resulted from poor compliance due to gastrointestinal tolerance. Because it was the only antibiotic that had demonstrated efficacy in this patient, pefloxacin, at the same dose, was resumed cautiously. Unfomtunately, peripheral neuropathy recurred within 15 days. Ciprofloxacin 250 mg twice daily orally was given instead and could be maintained for 2 months with minimum limb paraesthesia. Thereafter, these symptoms became unbearable, necessitating withdrawal of ciprofloxacin. The common peroneal nerve
SIR,-Fluoroquinolones
effects in the central
nervous
was then 37 m/s with reduced amplitide of the digitorum brevis muscle (< 1 mV). EMG was typical of a subacute neuropathy with fibrillations and prolonged polyphasic motor unit potentials ( > 17 ms). Such alterations are indicative of a probably toxic axonal neuropathy. Patients receiving prolonged therapy with fluoroquinolones, and who had previously received neurotoxic drugs such as vinca alkaloids, should be evaluated carefully for peripheral neuropathy. Other neurotoxic agents or conditions may have the same capacity to potentiate fluoroquinolone-induced peripheral neuropathy.
conduction velocity extensor
Infectious Diseases Clinic and Microbiology Laboratory, Institut Jules Bordet, 1000 Bruxelles, Belgium
Institut Jules Bordet
M. AOUN C. JACQUY L. DEBUSSCHER D. BRON
Neurology Service, Hôpital de Tivoli
M. LEHERT
Neurology Service, Hôpital Saint-Pierre
P. NOEL
Institut Jules Bordet
P.
Haematology Service,
VAN DER
AUWERA
1. Wolfson JS, Hooper DC. Fluoroquinolone antimicrobial agents. Clin Microbiol Rev 1989; 2: 378-424. 2. Donofrio PD, Albers JW. Polyneuropathy: classification by nerve conduction studies and electromyography. Muscle Nerve 1990; 13: 889-903.
Cholesterol inhibition, cancer, and coronary heart disease SIR,-Professor Buchwald’s hypothesis (May 9, p 1154) that cholesterol inhibition can inhibit tumour growth exposes a fascinating paradox. Reductase inhibitors have been marketed for cholesterol lowering in the hope of decreasing coronary heart disease. Yet, there is evidence that they may actually increase coronary endpoints when used in the secondary prevention of coronary disease. Reductase inhibitors inhibit 3-hydroxy-3-methylglutarylcoenzyme A reductase, the rate limiting enzyme of the cholesterogenesis pathway, resulting in a decreased formation of mevalonate from its precursor 3-hydroxy-3-methylglutarylcoenzyme A. It is the inhibition of mevalonate and not cholesterol that is linked to inhibition of tumour cell replication.2 Other metabolites of mevalonate besides cholesterol that are decreased by reductase inhibitors include ubiquinone and isoprenoids. Isoprenoids are involved in the prenylation of proteins, and prenylated proteins are linked to DNA synthesis and ensuing cell division.3 Therein lies the connection with reductase inhibitors and tumour growth inhibition. Reductase inhibitors result in lower tissue levels of ubiquinone, a compound indispensable for the bioenergetics of cardiac muscle function. There is evidence that the reduction of ubiquinone results in a measurable decrease in cardiac function.4 This may be especially bothersome in those with
impaired coronary reserve. In the Expanded Clinical Evaluation of Lovastatin Study5,6 33 (0-5%) of 6582 patients in the drug treated group died compared with 3 (0-18%) of 1663 patients in the placebo group during 48 weeks. 31 of the 36 deaths were attributed to coronary disease and were predominantly individuals with known coronary disease at baseline.7 These findings suggest that reductase inhibitors could be deleterious in the secondary prevention of coronary disease, perhaps via the reduction of ubiquinone. Therefore, it is plausible that reductase inhibitors can lead to an increase in coronary endpoints in those with known coronary disease, mediated by decreases in ubiquinone, and equally plausible that they can lead to an inhibiton of the growth of tumours via decreases in isoprenoids. These possibilities raise several questions. Will reductase inhibitors prove beneficial in the primary prevention of coronary disease? Will they be efficacious in the secondary prevention of such disease in subsets of individuals with normal coronary reserve? Will reductase inhibitors help to prevent certain malignant diseases. Will lipophilic reductase inhibitors be more advantageous than hydrophilic reductase inhibitors in tumour inhibition? Will reductase inhibitors increase deaths due to one disease while decreasing deaths from
128
another in certain populations, resulting in no net mortality change? The paradox that the most widely prescribed lipid lowering agents8 may increase coronary disease and decrease cancer needs to be
investigated. Crozer Cottage, Crozer-Chester Medical Center, Upland, Pennsylvania 19013, USA
MARK R. GOLDSTEIN
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 during tumor cell proliferation. In: Esfahani M, Swaney JB, eds. Advances in cholesterol research Caldwell, NJ: Telford Press, 1990: 201-70. 3. Glomset J, Gelb M, Farnsworth C. The prenylation of proteins. Curr Opin Lipidol 1991; 2: 118-24. 4. Folkers K, Langsjoen P, Willis R, et al. Lovastatin decreases coenzyme Q levels in humans. Proc Natl Acad Sci USA 1990; 87: 8931-34. 5. Bradford RH, Shear CL, Chremos AN, et al. Expanded Clinical Evaluation of Lovastatin (EXCEL) Study results, I: efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia. 1.
Arch Intern Med 1991; 151: 43-49. 6. Bradford RH, Shear CL, Chremos AN, et al. Expanded Clinical Evaluation of Lovastatin (EXCEL) Study: design and patient characteristics of a double-blind, placebo-controlled study in patients with moderate hypercholesterolemia. Am J Cardiol 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-3methylglutaryl (HMG) CoA reductase inhibitors might be effective in the treatment of cancer by blocking the production of isoprenoids in cholesterol’s synthetic pathway, which are necessary for cell division. It should be pointed out that other lipid-lowering interventions, such as diets low in saturated fat and bile acid sequestrants, promote the synthesis of isoprenoids by inducing de-novo cellular cholesterol synthesis until equilibirum between cellular 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 inhibition may promote tumour growth. First, increased cell proliferation and DNA 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 the administration of cholestyramine leads to tumour promotion in a rat mammary tumour mode1,2 Third, in aggregate, trials of lipidlowering interventions other than HMG-CoA reductase inhibitors have shown a significant excess of cancer mortality.33 In one trial of a lipid-lowering diet, poor adherence to the experimental diet was associated with increased cancer occurrence.4 This finding can be understood in the context of the hypothesis that the induction of cellular cholesterol synthesis might act as a tumour promoter. Those who frequently switch from a diet rich in cholesterol to a cholesterol-lowering diet would be frequently inducing de-novo cellular cholesterol synthesis: every induction may serve as a separate promoting event. Whether subjects who show poor compliance with experimental interventions in other lipid-lowering trials have an increased cancer risk should be investigated. This model implies that it might be preferable to lower serum 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, STEPHEN B. KRITCHEVSKY Memphis TN38163, USA ME, Melhem MF, Spichty KJ, Kelly RH, Rao KN. Diet-induced reduction 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 novo cholesterolgenesis in normal and neoplastic rat mammary tissues. J Natl Cancer Inst 1988; 80: 1248-53. 3 Kritchevsky SB, Kritchevsky D. Serum cholesterol and cancer risk: an epidemiologic perspective. 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.
Buchwald’s hypothesis suggesting that cholesterol availability can achieve tumour inhibition is restricting difficult to reconcile with the results of numerous clinical trials, as highlighted by Muldoon and co-workers’ meta-analysis,l which demonstrated a significant increase (rather than a decrease) in cancer mortality with cholesterol-lowering drugs. However, it may be that the important factor that determines the cancer risk of treatment 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 of cholesterol on cell growth, or to the inhibition of farnesyl pyrophosphate synthesis, the substance that anchors ras proteins to the cell membrane.3 The importance of these two mechanisms is unknown. The potential anticancer effect of a treatment that lowers intracellular cholesterol might be outweighed by an increase in intracellular farnesyl residues. Treatments that lower plasma cholesterol independently of HMG-CoA reductase (eg, bile acid resins, nicotinic acid, dietary therapy) could have tumour promoting effects by secondarily increasing HMG-CoA reductase activity, increasing famesyl residues, and potentiating ras oncogene activation. This adaptive mechanism, along with upregulation of LDL receptors, can also prevent a decrease in intracellular cholesterol. These mechanisms might explain why cholesterollowering agents do not reduce cancer mortality. It is known from experimental studies that lowering plasma cholesterol by dietary restriction leads to a compensatory increase in HMG-CoA reductase activity in the liver.4 Conversely, rats fed a high cholesterol diet reduce their HMG-CoA reductase activity, and, importantly, farnesyl pyrophosphate synthetase mRNA and enzyme activity are also reduced, suggesting that dietary cholesterol restriction may increase intracellular farnesyl residues.s Cholestyramine is also known to increase the expression of hepatic HMG-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 that fibrates do not inhibit HMG-CoA reductase at therapeutic doses.’ Buchwald states that decreasing cholesterol availability, or falling intracellular cholesterol synthesis, will inhibit tumour growth. I suggest that although lowering intracellular cholesterol and farnesyl pyrophosphate specifically by HMG-CoA reductase inhibition may be important in preventing tumour growth, there is little evidence from clinical trials that reducing plasma cholesterol by other means is cancer protective.
SIR,-Professor
Department of Clinical Medicine, Trinity College Dublin, St James Hospital, Dublin 8, Eire
MICHAEL GOGGINS
SB, Matthews KA. Lowering cholesterol concentrations and quantitative review of primary prevention trials. BMJ 1990; 301:
1. Muldoon MF, Manuck
mortality:
a
309-14. 2. Maltese WA, Defindini R, Green RA, Sheridan KM, Donley DK. Suppression of murine neuroblastoma growth in vivo by mevinolin, a competitive inhibitor of 3-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 and humans. Science 1989; 245: 379-85. 4. Mazur A, Remesy C, Gueux E, Levrat MA, Demigne C. Effects of diets rich in fermentable 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-3methylglutaryl-CoA reductase activity by dietary cholesterol is not due to altered mRNA levels. J Biol Chem 1991; 266: 14 854-57. 6. Dory L, Bhattacharyya A, Strong J, Chappuis C. Hapatic low density lipoprotein receptors, HMG CoA reductase, and plasma lipids and apoproteins in high- and low-resonding rhesus monkeys: effect of cholestyramine treatment. J Lipid Res 1990; 31: 279-87. 7. Elmberger PG, Kalen A, Lund E, et al. Effects of pravastatin and cholestyramine on products of the mevalonate pathway in familial hypercholesterolemia. J Lipid Res 1991; 32: 935-40. 8. Tikkanen MJ. Fibric acid derivatives. Curr Opin Lipidol 1992; 3: 29-33.
1. Kazanecki
CORRECTION Randomised comparison of oral ofloxacin alone with combination of
parenteral antibiotics in neutropenic febrile patients. -Our apologies to Dr Imtiaz Malik and colleagues for an error in the patients and methods section of this paper (May 2, p 1092}-the dose of ofloxacin used (correctly given in the summary) was 400 mg twice daily.
hyponatraemia (Na 126 mmol/1) and functional renal failure (urea 19 mmolll, creatinine 160 (imol/1). A stool smear was positive for leucocytes, and stool samples were negative for routine culture and for parasites. Flexible proctosigmoidoscopy showed a pseudomembranous mucosa. Histopathological examination confirmed the diagnosis of pseudomembranous colitis. The patient was treated with 500 mg vancomycin daily and she rapidly improved. Some serious lower gastrointestinal tract side-effects of NSAIDs have been described: non-specific colitis,l activation of quiescent idiopathic inflammatory bowel disease,2 collagenous colitis3 ulceration of the colon,4 and acute eosinophilic colitis.5 However, pseudomembranous colitis has never been reported in association with NSAIDs. A link with antibiotics is well known.6 Pseudomembranous colitis has also been reported during gold therapyNSAIDs are widely used, especially in the elderly, and we suggest that rectosigmoidoscopy should be done when diarrhoea develops after the start of NSAID therapy. Harvier Medical Clinic, Central University Hospital, 29609 Brest Cédex, France
A. GENTRIC Y. L. PENNEC
1 Ravi S, Keat AC, Keat ECB. Colitis caused by non-steroidal anti-inflammatory drugs.
Postgrad Med J 1986; 62: 773-76. 2. Kaufmann HJ, Taubin HL. Non-steroidal anti-inflammatory drug activates quiescent inflammatory bowel disease. Ann Intern Med 1987; 107: 513-16. 3 Giardiello FM, Hansen FC, Lazenby AJ, et al. Collagenous colitis in setting of non-steroidal anti-inflammatory drugs and antibiotics. Dig Dis Sci 1990; 35: 257-60. 4. Uribe A, Hohansson C, Slezak P, et al. Ulcerations of the colon associated with naproxen and acetylsalicylic acid treatment. Gastrointest Endosc 1986; 32: 242-43. 5 Bridges AJ, Marshall JB, Diaz-Arias AA. Acute eosinophilic colitis and hypersensitivity reaction associated with naproxen therapy. Am J Med 1990; 89: 526-27. 6. Price AB, Davies DR. Pseudomembranous colitis. J Clin Pathol 1977; 30: 1-12. 7. Reinhart WH, Kappeler M, Halter F. Severe pseudomembranous and ulcerative colitis during gold therapy. Endoscopy 1983; 15: 70-72.
Peripheral neuropathy associated with fluoroquinolones have been associated with adverse system (0-9-4-4% of patients), including headache, agitation, dizziness, sleep disturbance, and seizures in those with predisposing factors.1 We report a case of peripheral neuropathy associated with fluoroquinolones therapy. A 37-year-old man with chronic vertebral osteomyelitis, caused by a methicillin-susceptible Staphylococcus aureus, received oral pefloxacin 400 mg twice daily with excellent clinical and microbiological response. Many other oral regimens had failed previously, including flucloxacillin and clindamycin. After 5 months of pefloxacin, the patient had paraesthesia in his lower legs with a stocking-glove distribution, followed by progressive right foot weakness and difficulty in walking. Common peroneal nerve conduction velocity was 43 m/s. Electromyography (EMG) revealed fibrillations and polyphasic motor unit potentials in the tibialis anterior and peroneus longus muscles. Laboratory profile was normal and he denied alcohol misuse. Biopsy of rectal mucosa was negative for amyloidosis. No epidural abscess, transverse myelitis, or other causes could be found. The patient had been cured 15 years before from Hodgkin’s disease with radiochemotherapy, including vincristine for a total dose of 18 mg. Discontinuation of pefloxacin resulted in a dramatic improvement of peripheral neuropathy within 10 days. Osteomyelitis recurred 6 months later, and treatment with ofloxacin 200 mg twice a day resulted in relapse of peripheral neuropathy within 15 days, which remitted within 7 days of stopping ofloxacin. He was treated with flucloxacillin and fusidic acid for 2 months, which was stopped for a relapse of infection, which most probably resulted from poor compliance due to gastrointestinal tolerance. Because it was the only antibiotic that had demonstrated efficacy in this patient, pefloxacin, at the same dose, was resumed cautiously. Unfomtunately, peripheral neuropathy recurred within 15 days. Ciprofloxacin 250 mg twice daily orally was given instead and could be maintained for 2 months with minimum limb paraesthesia. Thereafter, these symptoms became unbearable, necessitating withdrawal of ciprofloxacin. The common peroneal nerve
SIR,-Fluoroquinolones
effects in the central
nervous
was then 37 m/s with reduced amplitide of the digitorum brevis muscle (< 1 mV). EMG was typical of a subacute neuropathy with fibrillations and prolonged polyphasic motor unit potentials ( > 17 ms). Such alterations are indicative of a probably toxic axonal neuropathy. Patients receiving prolonged therapy with fluoroquinolones, and who had previously received neurotoxic drugs such as vinca alkaloids, should be evaluated carefully for peripheral neuropathy. Other neurotoxic agents or conditions may have the same capacity to potentiate fluoroquinolone-induced peripheral neuropathy.
conduction velocity extensor
Infectious Diseases Clinic and Microbiology Laboratory, Institut Jules Bordet, 1000 Bruxelles, Belgium
Institut Jules Bordet
M. AOUN C. JACQUY L. DEBUSSCHER D. BRON
Neurology Service, Hôpital de Tivoli
M. LEHERT
Neurology Service, Hôpital Saint-Pierre
P. NOEL
Institut Jules Bordet
P.
Haematology Service,
VAN DER
AUWERA
1. Wolfson JS, Hooper DC. Fluoroquinolone antimicrobial agents. Clin Microbiol Rev 1989; 2: 378-424. 2. Donofrio PD, Albers JW. Polyneuropathy: classification by nerve conduction studies and electromyography. Muscle Nerve 1990; 13: 889-903.
Cholesterol inhibition, cancer, and coronary heart disease SIR,-Professor Buchwald’s hypothesis (May 9, p 1154) that cholesterol inhibition can inhibit tumour growth exposes a fascinating paradox. Reductase inhibitors have been marketed for cholesterol lowering in the hope of decreasing coronary heart disease. Yet, there is evidence that they may actually increase coronary endpoints when used in the secondary prevention of coronary disease. Reductase inhibitors inhibit 3-hydroxy-3-methylglutarylcoenzyme A reductase, the rate limiting enzyme of the cholesterogenesis pathway, resulting in a decreased formation of mevalonate from its precursor 3-hydroxy-3-methylglutarylcoenzyme A. It is the inhibition of mevalonate and not cholesterol that is linked to inhibition of tumour cell replication.2 Other metabolites of mevalonate besides cholesterol that are decreased by reductase inhibitors include ubiquinone and isoprenoids. Isoprenoids are involved in the prenylation of proteins, and prenylated proteins are linked to DNA synthesis and ensuing cell division.3 Therein lies the connection with reductase inhibitors and tumour growth inhibition. Reductase inhibitors result in lower tissue levels of ubiquinone, a compound indispensable for the bioenergetics of cardiac muscle function. There is evidence that the reduction of ubiquinone results in a measurable decrease in cardiac function.4 This may be especially bothersome in those with
impaired coronary reserve. In the Expanded Clinical Evaluation of Lovastatin Study5,6 33 (0-5%) of 6582 patients in the drug treated group died compared with 3 (0-18%) of 1663 patients in the placebo group during 48 weeks. 31 of the 36 deaths were attributed to coronary disease and were predominantly individuals with known coronary disease at baseline.7 These findings suggest that reductase inhibitors could be deleterious in the secondary prevention of coronary disease, perhaps via the reduction of ubiquinone. Therefore, it is plausible that reductase inhibitors can lead to an increase in coronary endpoints in those with known coronary disease, mediated by decreases in ubiquinone, and equally plausible that they can lead to an inhibiton of the growth of tumours via decreases in isoprenoids. These possibilities raise several questions. Will reductase inhibitors prove beneficial in the primary prevention of coronary disease? Will they be efficacious in the secondary prevention of such disease in subsets of individuals with normal coronary reserve? Will reductase inhibitors help to prevent certain malignant diseases. Will lipophilic reductase inhibitors be more advantageous than hydrophilic reductase inhibitors in tumour inhibition? Will reductase inhibitors increase deaths due to one disease while decreasing deaths from
128
another in certain populations, resulting in no net mortality change? The paradox that the most widely prescribed lipid lowering agents8 may increase coronary disease and decrease cancer needs to be
investigated. Crozer Cottage, Crozer-Chester Medical Center, Upland, Pennsylvania 19013, USA
MARK R. GOLDSTEIN
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 during tumor cell proliferation. In: Esfahani M, Swaney JB, eds. Advances in cholesterol research Caldwell, NJ: Telford Press, 1990: 201-70. 3. Glomset J, Gelb M, Farnsworth C. The prenylation of proteins. Curr Opin Lipidol 1991; 2: 118-24. 4. Folkers K, Langsjoen P, Willis R, et al. Lovastatin decreases coenzyme Q levels in humans. Proc Natl Acad Sci USA 1990; 87: 8931-34. 5. Bradford RH, Shear CL, Chremos AN, et al. Expanded Clinical Evaluation of Lovastatin (EXCEL) Study results, I: efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia. 1.
Arch Intern Med 1991; 151: 43-49. 6. Bradford RH, Shear CL, Chremos AN, et al. Expanded Clinical Evaluation of Lovastatin (EXCEL) Study: design and patient characteristics of a double-blind, placebo-controlled study in patients with moderate hypercholesterolemia. Am J Cardiol 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-3methylglutaryl (HMG) CoA reductase inhibitors might be effective in the treatment of cancer by blocking the production of isoprenoids in cholesterol’s synthetic pathway, which are necessary for cell division. It should be pointed out that other lipid-lowering interventions, such as diets low in saturated fat and bile acid sequestrants, promote the synthesis of isoprenoids by inducing de-novo cellular cholesterol synthesis until equilibirum between cellular 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 inhibition may promote tumour growth. First, increased cell proliferation and DNA 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 the administration of cholestyramine leads to tumour promotion in a rat mammary tumour mode1,2 Third, in aggregate, trials of lipidlowering interventions other than HMG-CoA reductase inhibitors have shown a significant excess of cancer mortality.33 In one trial of a lipid-lowering diet, poor adherence to the experimental diet was associated with increased cancer occurrence.4 This finding can be understood in the context of the hypothesis that the induction of cellular cholesterol synthesis might act as a tumour promoter. Those who frequently switch from a diet rich in cholesterol to a cholesterol-lowering diet would be frequently inducing de-novo cellular cholesterol synthesis: every induction may serve as a separate promoting event. Whether subjects who show poor compliance with experimental interventions in other lipid-lowering trials have an increased cancer risk should be investigated. This model implies that it might be preferable to lower serum 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, STEPHEN B. KRITCHEVSKY Memphis TN38163, USA ME, Melhem MF, Spichty KJ, Kelly RH, Rao KN. Diet-induced reduction 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 novo cholesterolgenesis in normal and neoplastic rat mammary tissues. J Natl Cancer Inst 1988; 80: 1248-53. 3 Kritchevsky SB, Kritchevsky D. Serum cholesterol and cancer risk: an epidemiologic perspective. 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.
Buchwald’s hypothesis suggesting that cholesterol availability can achieve tumour inhibition is restricting difficult to reconcile with the results of numerous clinical trials, as highlighted by Muldoon and co-workers’ meta-analysis,l which demonstrated a significant increase (rather than a decrease) in cancer mortality with cholesterol-lowering drugs. However, it may be that the important factor that determines the cancer risk of treatment 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 of cholesterol on cell growth, or to the inhibition of farnesyl pyrophosphate synthesis, the substance that anchors ras proteins to the cell membrane.3 The importance of these two mechanisms is unknown. The potential anticancer effect of a treatment that lowers intracellular cholesterol might be outweighed by an increase in intracellular farnesyl residues. Treatments that lower plasma cholesterol independently of HMG-CoA reductase (eg, bile acid resins, nicotinic acid, dietary therapy) could have tumour promoting effects by secondarily increasing HMG-CoA reductase activity, increasing famesyl residues, and potentiating ras oncogene activation. This adaptive mechanism, along with upregulation of LDL receptors, can also prevent a decrease in intracellular cholesterol. These mechanisms might explain why cholesterollowering agents do not reduce cancer mortality. It is known from experimental studies that lowering plasma cholesterol by dietary restriction leads to a compensatory increase in HMG-CoA reductase activity in the liver.4 Conversely, rats fed a high cholesterol diet reduce their HMG-CoA reductase activity, and, importantly, farnesyl pyrophosphate synthetase mRNA and enzyme activity are also reduced, suggesting that dietary cholesterol restriction may increase intracellular farnesyl residues.s Cholestyramine is also known to increase the expression of hepatic HMG-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 that fibrates do not inhibit HMG-CoA reductase at therapeutic doses.’ Buchwald states that decreasing cholesterol availability, or falling intracellular cholesterol synthesis, will inhibit tumour growth. I suggest that although lowering intracellular cholesterol and farnesyl pyrophosphate specifically by HMG-CoA reductase inhibition may be important in preventing tumour growth, there is little evidence from clinical trials that reducing plasma cholesterol by other means is cancer protective.
SIR,-Professor
Department of Clinical Medicine, Trinity College Dublin, St James Hospital, Dublin 8, Eire
MICHAEL GOGGINS
SB, Matthews KA. Lowering cholesterol concentrations and quantitative review of primary prevention trials. BMJ 1990; 301:
1. Muldoon MF, Manuck
mortality:
a
309-14. 2. Maltese WA, Defindini R, Green RA, Sheridan KM, Donley DK. Suppression of murine neuroblastoma growth in vivo by mevinolin, a competitive inhibitor of 3-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 and humans. Science 1989; 245: 379-85. 4. Mazur A, Remesy C, Gueux E, Levrat MA, Demigne C. Effects of diets rich in fermentable 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-3methylglutaryl-CoA reductase activity by dietary cholesterol is not due to altered mRNA levels. J Biol Chem 1991; 266: 14 854-57. 6. Dory L, Bhattacharyya A, Strong J, Chappuis C. Hapatic low density lipoprotein receptors, HMG CoA reductase, and plasma lipids and apoproteins in high- and low-resonding rhesus monkeys: effect of cholestyramine treatment. J Lipid Res 1990; 31: 279-87. 7. Elmberger PG, Kalen A, Lund E, et al. Effects of pravastatin and cholestyramine on products of the mevalonate pathway in familial hypercholesterolemia. J Lipid Res 1991; 32: 935-40. 8. Tikkanen MJ. Fibric acid derivatives. Curr Opin Lipidol 1992; 3: 29-33.
1. Kazanecki
CORRECTION Randomised comparison of oral ofloxacin alone with combination of
parenteral antibiotics in neutropenic febrile patients. -Our apologies to Dr Imtiaz Malik and colleagues for an error in the patients and methods section of this paper (May 2, p 1092}-the dose of ofloxacin used (correctly given in the summary) was 400 mg twice daily.
