New strides being made in chemoprevention

10/26/05

Baltimore, Md. -- There are a number of things people are told to do to prevent cancer – eat well, exercise, don't smoke. However, despite these obvious preventive measures, many individuals will develop the disease.

Researchers have been trying to develop methods to identify why certain individuals are more susceptible to cancer and from these insights, determine the molecular causes of the disease. Based on these results, scientists are now seeking to pinpoint compounds that can reduce the incidence or recurrence of cancer, a field of study known as chemoprevention. Several studies presented today at the American Association for Cancer Research's 4th annual Frontiers in Cancer Prevention Research meeting in Baltimore are focusing on new directions in this promising new field.

"We have made great strides in recent years in identifying the risk factors for pre-cancer as well as cancer by studying large groups of individuals who have and do not have cancer," according to David S. Alberts, M.D., Regents' Professor of medicine, pharmacology, nutritional science, and public health at the University of Arizona College of Medicine and director of the Arizona Cancer Center. "Chemoprevention is a promising field that may help us develop new drugs to combat this deadly disease before patients begin suffering from its symptoms."

Use of Thiazolidinediones and Lung Cancer Survival in Type 2 Diabetes Patients (Abstract 3711)

Patients with type-2 diabetes, treated with a class of drugs called thiazolidinediones (TZDs), had a significantly reduced risk of death from lung cancer compared to non-users, according to a retrospective study of patients from the South Central VA Health Care Network, also known as the Integrated Service Network (VISN 16).

Specifically, the study found that patients with both diabetes and lung cancer, treated with TZDs, had a 33 percent reduced risk of mortality compared to non-users. Patients using TZDs to control diabetes versus patients who were not using any medication to control the disease experienced a 23 percent reduced risk of mortality. Diabetics who used insulin to control their disease were at a 70 percent increased risk of mortality from lung cancer compared to lung cancer patients not using insulin to control diabetes. TZDs are part of a class of drugs called peroxisome proliferators-activated receptor gamma (PPARã) ligands. Since PPARã ligands induce cell death, scientists have theorized that they also may suppress growth of lung-cancer tumors.

The study population comprised 128,571 males who were forty years of age or older with a diagnosis of diabetes mellitus, 3,600 of whom were diagnosed with lung cancer. Data on the diagnosis of lung cancer, use of TZDs, other oral anti-diabetic agents, insulin and other variables were also obtained from the VISN database. Survival analysis methods were used to assess the association between TZD use and lung cancer survival. Hazard ratios were adjusted for confounders, including age, race, body mass index, use of insulin, and other oral anti-diabetic agents.

"We were encouraged that the use of TZDs in diabetic patients was associated with a significant reduction in risk of death from lung cancer," said Luke Ratnasinghe, of the National Center for Toxicological Research, FDA and lead author of the study. Also participating in the study were scientists from Central Arkansas Veterans Healthcare System and the University of Arkansas for Medical Sciences.

"Based on these results, more research is needed to see whether the use of this class of drugs may be beneficial in reducing rates of death in lung cancer patients in the clinic," added Dr. Ratnasinghe.

Potent Protection against Aflatoxin-induced Tumorigenesis through Induction of Nrf2-Regulated Pathways by the Synthetic Triterpenoid, CDDO-Imidazole (Abstract 2497)

A synthetic version of oleanolic acid, found in olive leaf extracts, significantly reduced the growth of liver tumors in laboratory animals, according to researchers from Johns Hopkins University and Dartmouth Medical School.

In their study, the use of small amounts of the artificially produced leaf extract, a triterpenoid analog called CDDO-Im, yielded a greater than 85 percent reduction in the volume of liver tumors. Larger doses produced a 99 percent reduction.

"Even at low-doses, CDDO-Im induces cell protecting genes, inhibits DNA damage by aflatoxin and dramatically blocks development of liver tumors," according to Melinda Yates of Johns Hopkins University and lead author of the study.

As described in their study, laboratory rats were given CDDO-Im three days per week for three weeks, with doses ranging from from 1 to 100 ìmol/kg body weight. Beginning one week after the start of CDDO-Im, they were given daily doses over a two-week period of aflatoxin B1, a known cancer-causing agent produced by molds in stored agricultural crops.

Aside from the significant reduction in liver tumor formation, the scientists also confirmed that CDDO-Im activated Nrf2, a gene that acts as a master regulator of the majority of antioxidant pathways and detoxifying enzymes for environmental pollutants.

"The unparalleled potency of CDDO-Im in rats highlights the chemopreventive promise of targeting Nrf2 pathways with triterpenoids, and provides a new direction for drug development," said Dr. Yates.

"The triterpenoid CDDO-Im appears to be at least 100-fold more potent in this model than other drugs targeting Nrf2 that are currently in clinical development."

NSAIDs and COXIBs: The Burden of Proof (Abstract 3480)

The effectiveness of non-aspirin non-steroidal anti-inflammatory drugs (NA-NSAIDs), the related cyclooxygenase-2 selective inhibitors (COXIBs), and aspirin against colorectal cancer has been confirmed and established by an enormous body of data. More than 35 epidemiologic studies have consistently associated routine aspirin or NA-NSAID use with a 40 to 50 percent reduced risk of benign colorectal (CR) tumors, CR cancer and CR cancer-related mortality, regardless of age, gender, family history, nationality, health care setting or study design.

Researchers from the National Cancer Institute (NCI) believe that four strategies have evolved that may allow researchers to build upon the chemopreventive benefits of aspirin and NA-NSAIDs and/or reduce their risk: modify the recommended regimen to separate effectiveness from safety concerns; provide gastrointestinal protection through use of proton pump inhibitors; conduct trials with similar drugs that have greater specificity for anti-cancer effects (e.g., COX-2 inhibitors or NA-NSAID derivatives); and identify combinations of chemopreventive agents that will synergize the effectiveness of aspirin or another NA-NSAID.

Through recent long-term chemoprevention trials with rofecoxib and celecoxib, researchers discovered a previously unrecognized cardiovascular toxicity, of relatively low frequency but significant magnitude, associated with the drugs. These reports have not only diminished interest in the use of NA-NSAIDs and COXIBs in cancer chemoprevention, but have also caused some researchers to question the notion of chemoprevention more broadly.

"The questions raised by recent developments with the use of COXIBs are similar to those faced by prior researchers studying cancer chemoprevention with tamoxifen or fenasteride," according to Ernest Hawk of the NCI and lead author of the study. "Establishing an acceptable balance between risks and benefits is critical in all areas of medicine, but medical oncology has rarely been dissuaded by an initial suboptimal therapeutic index. The risks posed by NA-NSAIDs and COXIBs should be seen as a stimulus for research to improve the balance of benefits versus risks, rather than a mandate to abandon one of the most consistent and powerful classes of chemopreventive agents known."

Indeed, before making any such decisions, researchers need to evaluate the data on the potential chemopreventive benefits of COXIBs in these studies. If studies show remarkable effectiveness in all or a subset of patients, they may yet prove to be useful despite their shortcomings. If COXIBs are not shown to work, researchers need to continue to study why in light of their substantial preliminary promise.

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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