Medical News Today News Article

Inflammation And Drugs To Control This Activity Studied = In A=20 Variety Of Tumors Sites

09 Apr = 2006

Inflammation=20 cuts both ways. When invaded by an infectious agent, for = example,=20 the body calls on the forces of inflammation to fight and = defeat the=20 intruder. But when the biochemical processes of the immune = system=20 are either misdirected or chronically turned on, = inflammation can=20 lead to adversity, including some forms of cancer. For this = reason,=20 scientists are closely studying the link between = inflammatory=20 processes and tumor formation, while others are = investigating=20 anti-inflammatory drugs as a means to prevent and treat = cancer, as=20 seen by studies presented today at the 97th Annual Meeting = of the=20 American Association for Cancer Research. =

Antihistamine=20 and Anti-inflammatory Drug Use Associated Differently for = High-Grade=20 Versus Low-Grade Gliomas: Abstract No. 486 =

Individuals=20 who used antihistamines regularly for a six-month period or = longer=20 have nearly a three-fold greater risk of developing = mid-grade brain=20 tumors, and a two-fold risk of having low-grade tumors. = Using=20 anti-inflammatory medications helped protect against = developing a=20 deadly brain tumor called glioblastoma.

The = researchers, led=20 by Michael Scheurer, Ph.D., postdoctoral fellow in Cancer = Prevention=20 and Melissa Bondy, Ph.D., professor of Epidemiology, both at = The=20 University of Texas M. D. Anderson Cancer Center in Houston, = cautioned that they are not implying that use of = antihistamines=20 causes brain tumors, but rather that these medications may = be part=20 of a complex milieu of factors that contribute to their = development.=20

Scheurer and Bondy used combined data from two = studies: the=20 Harris County Adult Glioma Study and the Bay Area Adult = Glioma=20 Study, led by Margaret Wrensch, Ph.D. at the University of=20 California, San Francisco. As part of the studies, = participants were=20 asked about their use of antihistamines and = anti-inflammatory drugs.=20

They compared antihistamine and anti-inflammatory = drug use=20 in 830 brain tumor cases and 831 controls matched for age, = gender=20 and race. The tumors were analyzed by histologic type. The = majority=20 - 339 - were high-grade glioblastomas; 117 were mid-grade, = or=20 anaplastic astrocytoma; and 154 cases were low-grade. =

The=20 scientists found that regular, long-term antihistamine use = was=20 associated with an increased risk for developing anaplastic=20 astrocytomas and low-grade brain tumors.

"To our = knowledge,=20 this report is the first time that anyone has looked at this = particular relationship - the potential effects of = antihistamines on=20 the development of brain tumors in adults," said Scheurer. = "It's=20 apparent that some type of inflammatory response is playing = some=20 role in the development of brain tumors. We don't know = exactly what=20 that role is or the specific mechanisms, but we're on the = road to=20 finding out.

"This again points to the fact that = brain=20 tumors are caused by a combination of several environmental, = endogenous and genetic factors," he said. "They are not = related to=20 one specific cause, but rather, to several that are = interplaying=20 with one another to create tumors. We're trying to figure = out what=20 those key factors and genes are and how they interact with = one=20 another."

Scheurer said several studies have = reported that=20 people with allergies or asthma have a lower risk of = developing=20 glioblastomas. One report showed that those who take = non-steroidal=20 anti-inflammatory drugs, or NSAIDs, also have a reduced risk = for=20 developing such high-grade tumors. He and Bondy focused on=20 antihistamines because people who have allergies typically = take=20 antihistamines.

"We knew that the different types of = tumors=20 have different etiologies and different genetic = characteristics and=20 we wanted to see if there were differences in risk," Bondy = said.=20 Scheurer and Bondy are also looking at certain different = variations=20 of genes in individuals and how they respond to inflammatory = processes in the brain. "We're hopefully looking at some = genes=20 related to inflammatory cytokines and we'll see how = individual=20 response to inflammatory stimuli may increase or decrease a = person's=20 risk of developing a brain tumor," Scheurer said.=20

Influence of Chronic Inflammation on Prostate=20 Carcinogenesis: A Five-Year Follow-up Study: Abstract No. = 1474=20

Researchers at Case Western Reserve University in = Cleveland=20 have evidence linking chronic inflammation in the prostate = to a=20 greater risk of developing prostate cancer. Results of = repeat=20 biopsies of prostate tissue over a five-year period from men = who had=20 abnormal serum prostate specific antigen (PSA) levels and/or = digital=20 rectal examinations (DRE) suggest that chronic inflammation = may be a=20 significant risk factor in the development of prostate = cancer.=20

While connections between inflammation and cancer = have been=20 shown for some cancers, no one had shown a relation between = chronic=20 prostate inflammation and the development of prostate = cancer, said=20 Sanjay Gupta, Ph.D., assistant professor of urology at Case = Western=20 Reserve University in Cleveland, who led the work along with = Greg=20 MacLennan, M.D., associate professor of pathology. =

Gupta and=20 his co-workers examined the results of prostate needle = biopsies from=20 177 men between ages 47 and 83 years who were at high risk = for=20 developing cancer based on either high PSA scores or = abnormal DREs.=20 Of the 177 men, 144 or 81 percent were found to have chronic = prostate tissue inflammation.

The scientists = categorized the=20 biopsies based on pathology. They found that of the 144 = cases, 15=20 percent (22/144) had only inflammation, 15 percent (22/144) = had=20 simple atrophy, 39 percent (54/144) showed PAH/PIA = (post-atrophic=20 hyperplasia and/or proliferative inflammatory atrophy, which = indicate evidence of chronic inflammation) lesions, and = eight=20 percent, or 12/144, showed HGPIN - high-grade prostate=20 intraepithelial neoplasia, which is a precursor to prostate = cancer.=20 About 20 percent, or 29/144, had cancer (adenocarcinoma) in = the=20 initial biopsies.

The researchers analyzed 84 = subsequent=20 biopsies performed within five years in patients who had = initially=20 shown chronic prostate inflammation. In the follow up, 29 = new cancer=20 cases were diagnosed: six occurred in patients in whom = initial=20 biopsies showed only chronic inflammation, 15 in patients = with=20 initial PAH/PIA lesions, along with eight in patients with = chronic=20 inflammation and other risk factors for cancer (high-grade = prostate=20 intraepithelial neoplasia and atypical small acinar = proliferation=20 that may have been cancerous).

In contrast, the = researchers=20 found only two cases - six percent - in the 33 patients = without=20 inflammation who went on to develop cancer, both of whom had = other=20 risk factors for cancer.

"We observed a significant=20 association between serum PSA and the degree of chronic=20 inflammation," said Gupta, which was expected based on = previous=20 findings.

"The first concern is, should patients = with=20 initial biopsies showing no malignancy but showing chronic=20 inflammation be followed more closely and perhaps = re-biopsied more=20 frequently?" Gupta said.

Gupta's group plans future = studies=20 that will be similar in design, but have a larger number of=20 subjects.

COX-2 Expression in Atypia: Correlation = with=20 Breast Cancer Risk: Abstract No. 2353

Women with = atypical hyperplasia who also have high levels of the enzyme = COX-2=20 in their breast tissue were more likely to develop breast = cancer=20 than women with lower levels of the enzyme. =

According to=20 Lynn Hartmann, M.D., professor of oncology at the Mayo = Clinic=20 College of Medicine in Rochester, Minn., about one million = women a=20 year have a breast biopsy with benign findings (sometimes = called=20 benign breast disease). One form of benign breast disease, = atypical=20 hyperplasia, or atypia, is characterized by abnormal cell = growth and=20 can be precancerous. Women with this condition have a four = times=20 greater risk of developing breast cancer.

Hartmann = and her=20 co-workers wanted to find out whether or not they could use=20 molecular tools, such as COX-2 levels, to predict who among = the=20 group of women with atypia would develop breast cancer and = develop=20 ways to separate groups of women into high risk and normal = risk. The=20 COX-2, or cyclooxygenase-2, enzyme is produced by the body = when=20 there is inflammation and is also produced by precancerous = tissues.=20

They took advantage of a tissue bank from the Mayo = Clinic=20 Benign Breast Disease Cohort, which includes several = thousand women=20 who, between 1967 and 1991, had a benign breast biopsy. Of = this=20 group, 235 women had atypical hyperplasia and tissue = available for=20 the study. Cancer follow-up information was available for = all of=20 these women. Hartmann and her co-workers determined the = amount of=20 COX-2 in these samples by staining immunohistochemistry = methods.=20 Forty-one of the 235 women with atypia developed breast = cancer over=20 roughly a 15- to 20-year period.

The research team = found a=20 significantly higher level of COX-2 in atypias of those = women who=20 went on to develop breast cancer than they did in control = subjects.=20 "Intense COX-2 expression," Hartmann said, "is associated = with a=20 significantly greater likelihood of a subsequent breast = cancer in=20 women with atypia. Specifically, for women with strong = staining,=20 their risk of breast cancer at 20 years was 31 percent, = versus 14=20 percent for those with negative or weak staining." =

She noted=20 that increased COX-2 expression has also been seen in an = early form=20 of breast cancer called ductal carcinoma in situ, or DCIS. = Hartmann=20 said that COX-2 represents a potential target for = chemoprevention.=20 Her team plans to expand the test group and will continue to = profile=20 women with atypia who did and who did not develop breast = cancer in=20 an attempt to identify early predictors of risk.=20

Reduction in the Risk of Human Breast Cancer by = COX-2=20 Inhibitors: Abstract No. 2352

Results of a = five-year=20 study have shown for the first time a significant reduction = in risk=20 associated with selective COX-2 inhibitors in human breast = cancer.=20

Randall Harris, M.D., Ph.D., professor and director = of the=20 Center of Molecular Epidemiology in the College of Medicine = and=20 School of Public Health at The Ohio State University Medical = Center=20 in Columbus and his co-workers looked at the use of = selective COX-2=20 inhibitors such as Vioxx and Celebrex between 1999 and 2004 = and the=20 incidence of breast cancer. They compared 323 breast cancer = cases to=20 649 healthy controls and found a risk reduction of about 71 = percent=20 with the use of selective COX-2 blockers.

Harris was = not=20 surprised. "This was not a surprising result showing = selective COX-2=20 inhibitors would have a significant effect in reducing the = incidence=20 of breast cancer," he said.

A number of studies have = shown=20 that people who regularly take non-steroidal = anti-inflammatory drugs=20 (NSAIDs), such as aspirin and ibuprofen to treat conditions = like=20 arthritis, have lower rates of colorectal polyps, colorectal = cancer,=20 breast cancer and many other cancers. NSAIDs exert = anti-inflammatory=20 effects by blocking COX, or cyclooxygenase enzymes, which = are=20 produced by the body when there is inflammation and are also = produced by precancerous tissues.

"The combined = results of=20 20 human studies of aspirin and ibuprofen reflect an = approximate 30=20 percent reduction in the risk for breast cancer, and animal = studies=20 have shown a profound effect by COX-2 blockers against a = variety of=20 cancers," he said.

Harris said that these results = have=20 implications for chemoprevention of breast cancer and other = cancers.=20 This particular study is a sub-study of four types of = cancer,=20 including prostate, lung and colon cancer. The researchers = will=20 release data at the meeting showing results consistent with = the=20 breast cancer findings.

"There's a lot of interest = in the=20 use of these compounds in therapy and prevention," Harris = noted. "It=20 will be important for investigators to look at these = compounds in=20 prospective and retrospective studies to see if these = results are=20 consistent." "We're concerned about potential side effects = of these=20 agents, and before making specific recommendations for their = use,=20 further studies are needed to determine if low dosages that = cause no=20 harm have consistent preventive effects against cancer," = Harris=20 said.

COX-2 inhibitors may also have effects in = preventing=20 other diseases, and his laboratory would like to explore = their=20 effects against cardiovascular and neurodegenerative = diseases such=20 as Alzheimer's disease. He hopes to continue to look at = COX-2=20 blockers at sub-therapeutic doses in chemoprevention. =

"We=20 need to look at a broader spectrum of conditions related to = the=20 inflammatory cascade and modulating the cascade with these = and other=20 compounds."

Variants in the alpha-Methylacyl-CoA = Racemase=20 Gene and the Association with Advanced Distal Colorectal = Adenomas in=20 the Prostate, Lung, Colorectal and Ovarian Screening Trial: = Abstract=20 No. LB-344

Researchers have shown that a particular = version=20 of a gene that enhances ibuprofen's anti-inflammatory = effects also=20 makes it more effective in preventing the development of = potentially=20 precancerous polyps in the colon.

Sarah Daugherty, = research=20 fellow at the National Cancer Institute and doctoral = candidate at=20 Johns Hopkins Bloomberg School of Public Health and her = colleagues=20 looked at seven variants of the gene for = alpha-methylacyl-CoA=20 racemase, or AMACR. This protein metabolizes branched chain = fatty=20 acids, cholesterol metabolites and enhances the activity of=20 ibuprofen.

The AMACR protein is overexpressed in = some=20 cancers such as prostate, colon and precancerous colorectal=20 adenomas, or polyps, though it is expressed very little in = normal=20 tissues. According to Daugherty, no one had examined the = association=20 between AMACR variants and colorectal adenomas or cancer.=20

The research team identified 725 white men and women = between=20 ages 55 and 74 who had participated in the multicenter, = National=20 Cancer Institute-supported Prostate, Lung, Colorectal and = Ovarian=20 (PLCO) Cancer Screening Trial and who had a sigmoidoscopy = that=20 showed a suspicious polyp in the distal colon that was = confirmed by=20 a follow-up exam. These participants were compared to 729 = control=20 subjects who had a sigmoidoscopy showing no polyps. All = subjects=20 completed questionnaires that asked about ibuprofen use and = each=20 provided a blood sample.

The scientists looked at = the seven=20 gene variants among the two groups. They found that four of = seven=20 variants were associated with an increased risk for advanced = distal=20 colorectal adenomas. The frequency of these variants was = higher=20 among those with polyps than among controls.

The = researchers=20 also compared ibuprofen use among the two groups. Studies = have shown=20 that non-steroidal anti-inflammatory drugs such as ibuprofen = can=20 reduce the risk of adenomas and colorectal cancer. =

"We found=20 that regular use of ibuprofen had a slight protective effect = in the=20 development of advanced distal colorectal adenomas - a 20 = percent=20 reduction in risk, which was not statistically significant," = Daugherty said.

When they looked further at the = association=20 between ibuprofen use and colorectal adenomas, they found = that a=20 subgroup of individuals who had two copies of one variant = showed a=20 statistically significant reduction of nearly 70 percent in = the risk=20 for developing adenomas. Among the other individuals who did = not=20 have this genotype, regular use of ibuprofen had little = effect on=20 risk of colorectal adenomas.

"Our data are the first = to show=20 a link between these genotypes and effectiveness of = ibuprofen in=20 protecting against adenomas," Daugherty said. She noted that = previous research in animals has shown that AMACR modifies a = component of ibuprofen that enhances its chemopreventive = effects.=20

"This is the first study to corroborate the = biological data=20 at a statistical level in humans," she said.

Her = team's=20 results need to be verified in other populations, she said. = "While=20 our results are statistically suggestive that there is an=20 association between these variations in the gene and = colorectal=20 adenomas, there needs to be biological follow-up so we know = the=20 functional relevance of these markers."

Daugherty = said that=20 before AMACR can be used for any potential clinical = application,=20 more study is needed to verify the findings and determine=20 relationships to ibuprofen dose, duration and timing. =

###=20

The mission of the American Association for Cancer = Research=20 is to prevent and cure cancer. Founded in 1907, AACR is the = world's=20 oldest and largest professional organization dedicated to = advancing=20 cancer research. The membership includes more than 24,000 = basic,=20 translational, and clinical researchers; health care = professionals;=20 and cancer survivors and advocates in the United States and = more=20 than 60 other countries. AACR marshals the full spectrum of=20 expertise from the cancer community to accelerate progress = in the=20 prevention, diagnosis and treatment of cancer through = high-quality=20 scientific and educational programs. It funds innovative,=20 meritorious research grants. The AACR Annual Meeting = attracts over=20 16,000 participants who share the latest discoveries and=20 developments in the field. Special Conferences throughout = the year=20 present novel data across a wide variety of topics in cancer = research, treatment, and patient care. AACR publishes five = major=20 peer-reviewed journals: Cancer Research; Clinical Cancer = Research;=20 Molecular Cancer Therapeutics; Molecular Cancer Research; = and Cancer=20 Epidemiology, Biomarkers & Prevention. Its most recent=20 publication, CR, is a magazine for cancer survivors, patient = advocates, their families, physicians, and scientists. It = provides a=20 forum for sharing essential, evidence-based information and=20 perspectives on progress in cancer research, survivorship, = and=20 advocacy.

Warren Froelich
froelich@aacr.org
American = Association for=20 Cancer Research

Article URL:=20 = http://www.medicalnewstoday.com/medicalnews.php?newsid=3D41027

=20

Save time! Get the latest = medical news=20 headlines for your specialist area, in a weekly newsletter = e-mail.=20 See http://www.medic= alnewstoday.com/newsletters.php=20 for details.

Send your press releases to =