Anti-Inflammatory Drug Promising in Control of Colonic Tumorigenesis

Anti-Inflammatory Drug Promising in Control of Colonic Tumorigenesis

by David W. Sharp

WHAT'S HOT IN MEDICINE...

Rank	Paper	Citations This Period Jul- Aug 01	Rank Last Period May- Jun 01
1	P.M. Ridker, et al., "Long-term effects of pravastatin on plasma concentration of C-reactive protein," Circulation, 100(3):230-5, 20 July 1999. [Brigham & Women's Hosp., Boston, MA; Harvard U. Sch. Med., Boston; Children's Hosp., Boston] *218AV	27	†
2	S. Yusuf, et al., "Effects of angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients," New Eng. J. Med., 342(3):145-53, 20 January 2000. [Hamilton Gen. Hosp., Ont., Canada] *275ZT	26	1
3	P.M. Ridker, et al., "C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women," New Engl. J. Med., 342(12):836-43, 23 March 2000. [Brigham & Women's Hosp., Boston, MA; Harvard U. Sch. Med., Boston; Children's Hosp., Boston] *296FU	26	†
4	R. Maini, et al., "Infliximab (chimeric anti-tumour necrosis factor a monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial," The Lancet, 354(9194):1932-9, 4 December 1999. [11 institutions worldwide] *261XA	24	†
5	B. Pitt, et al., "The effect of spironolactone on morbidity and mortality in patients with severe heart failure," New Engl. J. Med., 341(10):709-17, 2 September 1999. [6 institutions worldwide] *231DB	23	2
6	H.B. Rubins, et al., "Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol," New Engl. J. Med., 341(6):410-8, 5 August 1999. [11 U.S. institutions] *223UN	23	3
7	D.M. Harrington, et al., "Effects of estrogen replacement on the progression of coronary-artery atherosclerosis," New Engl. J. Med., 343(8):522-9, 24 August 2000. [6 U.S. institutions] *346QM	23	†
8	G. Steinbach, et al., "The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis," New Engl. J. Med., 342(26):1946-52, 29 June 2000. [U. Texas, M.D. Anderson Cancer Ctr., Houston; ICRF, St. Marks Hosp., London, U.K.; NCI, Bethesda, MD; G.D. Searle & Co., Skokie, IL] *328TZ	22	†
9	B. Ettinger, et al., "Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene. Results from a 3-year randomized clinical trial," JAMA-J. Amer. Med. Assoc., 282(7):637-45, 18 August 1999. [11 institutions worldwide] *226QY	20	†
10	M. Cavazzano-Calvo, "Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease," Science, 288(5466):669-72, 28 April 2000. [Hop. Necker, Paris, France; Inst. Pasteur, Paris, France] *308RR	20	4
SOURCE: ISI’s Hot Papers Database. the Legend.

hen researchers talk of disease "models" they are usually referring to laboratory animals. However, quite a lot is known about the sequence of events in human colon cancer, and there is a condition called familial adenomatous polyposis in which the numbers of adenomatous polyps (precancerous) is so huge and the risk of cancer so great, at almost 100%, that the disease makes a good model for studying cancer prevention. It has been known for 20 years that a class of drugs known as nonsteroidal anti-inflammatory agents (NSAIDs) could reduce the incidence of chemically induced tumors of the colon in rats, and there have been hints that one of these agents (sulindac) might cause colorectal adenomas to regress in patients with inherited adenomatous polyposis.

Unfortunately, as is well known from experience in patients taking NSAIDs for other reasons, these drugs can damage the stomach, so long-term application to cancer prevention might be problematic. Enter a different sort of NSAID, the selective type-2 cyclooxygenase inhibitor, developed to overcome the side-effects of conventional NSAIDs associated with inhibition of the type-1 enzyme. It appears that the colorectal protective effects of NSAIDs are also associated with the blocking of type 2, so the randomized trial reported by a team led by Dr. Gideon Steinbach from the University of Texas M.D. Anderson Cancer Center, Houston (#8), was a logical next step.

Steinbach’s group counted colorectal polyps in 77 patients with familial adenomatous polyposis who had been randomly assigned to one of two doses of the selective type-2 cyclooxygenase inhibitor celecoxib or to placebo. At the baseline endoscopy the patients, who came from the Houston center and from St. Mark’s in London, U.K., a hospital specializing in colorectal disease, had the colon site of interest stained with Indian ink. Six months later that site could be specifically re-examined.

Patients given 400 mg twice daily achieved an average, and statistically significant, 28% reduction in polyps. The changes for the other groups were 11.9% (not significant) for the 100 mg twice daily group and 4.5% for those on placebo. There was wide individual scatter, and in all three groups some patients had more colorectal polyps than they had had to start with.

Celecoxib (Celebrex;Searle/Pharmacia) has now been approved by the U.S. Food and Drug Administration as an adjuvant treatment for familial adenomatous polyposis. Steinbach’s group, again with U.S. National Cancer Institute support, is looking in similar fashion at prevention in hereditary non-polyposis colon cancer. In the two conditions different genes place patients at high risk of colon cancer.

In the reported trial (#8) the drug was found to be safe but a later paper published in JAMA (see D. Mukherjee et al., JAMA, 286[8]:954-9, 2001) raised a "cautionary flag" in respect of the cardiovascular system. However, the manufacturer remains confident in the safety of this drug and finds the JAMA study’s conclusions "flawed and unsound."

For many years when people spoke of preventing cancer the focus was assumed to be on avoidance of known risk factors such as tobacco smoke, radiation, and certain chemicals in the workplace or environment. Now medical scientists are starting to take chemoprevention seriously. The citation recognition of paper #8 is therefore encouraging even though chemoprevention in the more common, sporadic colon cancers is some way off.

Mr. David W. Sharp, M.A. (Cambridge), was deputy editor of The Lancet, London, U.K., from 1976 to May, 2001; he is currently a contributing editor to that journal.