Scientists find novel use for old compound in cancer treatment

January 15, 2009

The compound, α-difluoromethylornithine or DFMO, targets the activity of a specific enzyme and, even in very limited doses, is effective in protecting against the malignancy in animal models. The study was published in the January 15, 2009 issue of the journal, Cancer Research (Volume 69, Issue 2).

"The drug, which was developed as a cancer therapy and later shelved because of toxicity concerns, has been around since the 1970s," said John Cleveland, Ph.D., chair of the Scripps Florida Department of Cancer Biology whose laboratory conducted the study. "But over the past five years, it has undergone a rebirth as a chemoprevention agent, first showing efficacy in animal models of human cancer and more recently in human prostate and colon cancer. Our study shows that it likely works in a large cast of tumors, even those having poor prognosis, like high-risk neuroblastoma."

Neuroblastoma is a childhood malignancy of the sympathetic nervous system (part of the nervous system that serves to accelerate the heart rate, constrict blood vessels, and raise blood pressure) that accounts for nearly eight percent of all childhood cancers and 15 percent of pediatric cancer-related deaths. Its solid tumors arise from developing nerve cells, most commonly in the adrenal gland, but also in the abdomen, neck, and chest. Neuroblastoma usually occurs in infants and young children, appearing twice as frequently during the first year of life than in the second.

Tragically, children with stage IV, high-risk neuroblastoma have a less than a 40 percent chance of long-term survival.

The best-known genetic alteration involved in neuroblastoma is the amplification of the proto-oncogene—a molecule that when overexpressed can cause cancer—called MYCN. Amplification of MYCN occurs in about 20 percent of all neuroblastoma and is associated with the high-risk form of the disease. Targeting this and related genes directly might be therapeutically tempting, the study noted, but highly problematic because the oncoproteins they produce are also required for the growth of most normal cell types.

As a result, Cleveland and colleagues focused on inhibiting ornithine decarboxylase (Odc), a protein that contributes to cancer cell growth and that is a target of the proto-oncogene MYCN. Increased levels of Odc are common in cancer, and forced Odc expression in animal models has been shown to lead to increased tumor incidence. Recent findings have shown that Odc overexpression is also an indication of poor prognosis in neuroblastoma. DFMO, the drug used by the Cleveland team, inhibits the activity of Odc.

To test the effect of DFMO on preventing neuroblastoma, the study used a transgenic mouse that faithfully models many of the hallmarks of MYCN-amplified neuroblastoma in humans.

"We were able to prevent neuroblastoma caused by MYCN, delaying the onset and incidence of this tumor type" said Cleveland. "What's even more compelling, we used low doses of the drug, and DFMO only had to be given for a moderate amount of time to prevent cancer."

While DFMO selectively impaired the proliferation of MYCN-amplified neuroblastoma, it had no appreciable effect on non-MYCN-amplified neuroblastoma cell lines, indicating that the growth of the former is "addicted" to Odc.

"Our study offers a strong suggestion to the clinical cancer community that they should keep an open mind about the Odc-polyamine pathway, and that this particular pathway might represent a novel therapeutic angle to tackle this malignancy." Cleveland said. "While there are valid safety concerns about giving DFMO to pediatric patients suffering from advanced stage MYCN-amplified neuroblastoma, it may be time to revisit the issue as our study showed that transient treatment with DFMO is sufficient to provide chemoprevention and may show benefit for this otherwise lethal malignancy."

Source: Scripps Research Institute

Explore further: Multifunctional fluorescent nanoparticles for cancer surgery show promise

Related Stories

Multifunctional fluorescent nanoparticles for cancer surgery show promise

November 14, 2017
Even with pre-operative imaging techniques, surgeons still rely on visual inspection to locate malignant tissues during surgery. New research released today at the 2017 American Association of Pharmaceutical Scientists (AAPS) ...

Researchers identify potential therapeutic target in aggressive breast cancer cells

November 15, 2017
An especially aggressive breast cancer cell can respond to hormone therapy if they express a specific protein known as estrogen receptor beta (ERβ), according to new research published on the cover of Oncotarget. The findings ...

Old World monkeys could be key to a new, powerful rheumatoid arthritis therapy

November 16, 2017
In the quest for a new and more effective treatment for rheumatoid arthritis, researchers from the Keck School of Medicine of USC looked to a primate that mostly roams the land in Asia, the Middle East and Africa. It was ...

A delicate crossing: Controller developed to open the blood-brain barrier with precision

November 15, 2017
The blood-brain barrier - the semi-permeable membrane that surrounds the brain - offers important protection for a delicate organ, but in some cases, clinicians need to get past the barrier to deliver vital drugs to treat ...

Women urged to give up alcohol before conceiving

November 14, 2017
Women who consume alcohol around the time of conception could be putting their male offspring at greater risk of obesity in later life.

'Mini liver tumors' created in a dish for the first time

November 13, 2017
Scientists have created mini biological models of human primary liver cancers, known as organoids, in the lab for the first time. In a paper published today in Nature Medicine, the tiny laboratory models of tumours were used ...

Recommended for you

Lung cancer triggers pulmonary hypertension

November 17, 2017
Shortness of breath and respiratory distress often increase the suffering of advanced-stage lung cancer patients. These symptoms can be triggered by pulmonary hypertension, as scientists at the Max Planck Institute for Heart ...

Researchers discover an Achilles heel in a lethal leukemia

November 16, 2017
Researchers have discovered how a linkage between two proteins in acute myeloid leukemia enables cancer cells to resist chemotherapy and showed that disrupting the linkage could render the cells vulnerable to treatment. St. ...

Computer program finds new uses for old drugs

November 16, 2017
Researchers at the Case Comprehensive Cancer Center at Case Western Reserve University School of Medicine have developed a computer program to find new indications for old drugs. The computer program, called DrugPredict, ...

Pharmacoscopy improves therapy for relapsed blood cancer in a first clinical trial

November 16, 2017
Researchers at CeMM and the Medical University of Vienna presented a preliminary report in The Lancet Hematology on the clinical impact of an integrated ex vivo approach called pharmacoscopy. The procedures measure single-cell ...

Wider sampling of tumor tissues may guide drug choice, improve outcomes

November 15, 2017
A new study focused on describing genetic variations within a primary tumor, differences between the primary and a metastatic branch of that tumor, and additional diversity found in tumor DNA in the blood stream could help ...

A new strategy for prevention of liver cancer development

November 14, 2017
Primary liver cancer is now the second leading cause of cancer-related death worldwide, and its incidences and mortality are increasing rapidly in the United Stated. In late stages of the malignancy, there are no effective ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.