Medical Pike
Arthritis Drugs Inhibit Breast Tumors, Ohio Study Reports
Prostate Tests Expected
August 16, 2000. COLUMBUS, Ohio - A COX-2 inhibitor drug called Celebrex and to lesser extent the over-the-counter NSAID ibuprofen, both commonly used to treat the symptoms
of arthritis, reduce the
number and the size of cancerous breast tumors in animals.
Celebrex and other NSAIDs have positive activity against colon cancer polyps, previous studies have shown. Celebrex may also have some activity against lung tunors. Tests for prostate and other cancers are expected to follow.
NSAIDs do not have "direct cytotoxic effect," according to studies in dogs. They are thought to slow and diminish new tumor growth by disrupting formation of new tumor blood supplies (angiogenesis).
The latest study in rats examined the effectiveness of Celebrex (chemical name
celecoxib) in fighting breast cancer. When
compared with a control group, rats who were fed celecoxib had
a 68 percent decrease in tumor incidence and an 81 percent decrease
in average tumor size.
The researchers describe the effects of Celebrex as "striking." Ibuprofen, they add, "also produced significant effects, but of lesser magnitude."
While the drug's anti-tumor effects have yet to be tested
in humans in a clinical trial, researchers at Ohio State University
say celecoxib shows great promise as a tool that someday may
help treat and even prevent breast cancer. Celecoxib belongs
to the family of nonsteroidal anti-inflammatory drugs (NSAIDs),
which include the pain-reducers aspirin and ibuprofen.
The research appears in a recent issue of the journal Cancer
Research.
"Across the board, regular intake of NSAIDs lowers the
risk
of breast cancer," said Randall Harris, co-author of the
study and a professor of epidemiology at Ohio State. "NSAIDs
inhibit an enzyme that is produced by a gene that is normally
silent in breast tissue. Too much of this enzyme in breast tissue
leads to the initiation and promotion of breast cancer."
The culprit enzyme, cyclooxygenase-2 (COX-2), is normally
triggered only during the body's response to foreign invaders,
such as viruses and bacteria. But for reasons unknown to researchers,
there is a proliferation of COX-2 in the breast tissue of patients
with breast cancer, Harris said. This abundance causes a "prostaglandin
cascade" - a flow of biochemicals that fights invaders.
Prostaglandins are hormone-like compounds in the body that initiate
the body's immune response.
NSAIDs turn off the prostaglandin cascade, Harris said. "There
is something about COX-2 and the ensuing cascade that encourages
carcinogenesis, and celecoxib seems to turn it around."
Harris and his colleagues separated 120 female rats into three
treatment groups. Forty received 1,500 mg of celecoxib for every
kilogram of food in their diet; 40 received an equivalent amount
of ibuprofen per kilogram of their diet; and 40 served as the
control group, receiving only a powdered diet. The drug dosages
given to rats in this study were comparable to the average daily
therapeutic dose of either drug for a human - about 100 to 200
mg.
After seven days on the respective diets, each rat was injected
with DMBA, a carcinogen which causes breast tumors. The diets
were continued for 105 more days.
At 28 days after the DMBA injection, the researchers examined
the rats for tumors. "It takes at least four to five weeks
for the tumors to become large enough to detect by palpation,"
Harris said. At the end of the experiment, all animals were
sacrificed and the tumors extracted and measured.
The researchers found that 13 of the 40 rats given celecoxib
had developed malignant tumors, while 24 of the 40 rats in the
ibuprofen group developed cancerous tumors. Each of the 40 rats
in the control group had developed malignant tumors; many animals
in this group had also developed multiple tumors.
Researchers detected the majority of tumors in the celecoxib
group much later than they did in the control group (95 vs. 58
days). In the ibuprofen group, most of the tumors were detected
at 86 or more days after DMBA injection.
Harris also noted that the rats that had received celecoxib
experienced no toxic side effects sometimes associated with NSAIDs,
such as weight loss, ulcers or bleeding.
"Ten to 20 percent of women aged 50 and older use NSAIDs
on a regular basis," Harris said. "Not only are these
drugs potentially important for breast cancer prevention and
control, they may also have significant value in the prevention
and therapy of other cancers, too, such as cancers of the colon,
lung and prostate."
This research was supported in part by Searle Research and
Development, St. Louis, the manufacturer of celecoxib, and in
part by Ohio State. (the Center of Molecular Epidemiology and
Environmental Health, the Comprehensive Cancer Center, the School
of Public Health and the Department of Surgery.)
Harris conducted the research with Galal Alshafie, a graduate
student in the School of Public Health at Ohio State; Hussein
Abou-Issa, an associate professor of surgery at Ohio State; and
Karen Seibert, director of COX-2 research at Searle Monsanto
Research and Development.
Links
Harris RE, Alshafie GA, Abou-Issa H, Seibert K.
Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2
inhibitor.
Cancer Res. 2000 Apr 15;60(8):2101-3.
Reddy BS, et al.
Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib,
administered during different stages of carcinogenesis.
Cancer Res. 2000 Jan 15;60(2):293-7.
Masferrer JL, et al.
Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors.
Cancer Res. 2000 Mar 1;60(5):1306-11.
Genetic alterations in human prostate cancer: a review of
current literature.
Ozen M, Pathak S
Department of Cancer Biology, University of Texas M. D. Anderson Cancer Center,
Houston 77030, USA.
Alshafie GA, Harris RE, et al. Comparative chemopreventive activity of ibuprofen and N-(4-hydroxyphenyl)
retinamide against the development and growth of rat mammary
adenocarcinomas.
Anticancer Res. 1999 Jul-Aug;19(4B):3031-6.
Cautions
Duffy CP, et al.
Enhancement of chemotherapeutic drug toxicity to human tumour cells in vitro by
a subset of non-steroidal anti-inflammatory drugs (NSAIDs).
Eur J Cancer. 1998 Jul;34(8):1250-9.
Perazella MA, Eras J.
Are selective COX-2 inhibitors nephrotoxic?
Am J Kidney Dis. 2000 May;35(5):937-40.
Carrillo-Jimenez R, Nurnberger M.
Celecoxib-induced acute pancreatitis and hepatitis: a case report.
Arch Intern Med. 2000 Feb 28;160(4):553-4.
Bennett WM, Porter GA.
Nephrotoxicity of common drugs used by urologists.
Urol Clin North Am. 1990 Feb;17(1):145-56. Review.
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