April 16, 2012
New Compound Stops Brain Tumors from Spreading
(Ivanhoe Newswire)-- A new compound has shown evidence of stopping the spread of tumors while also improving brain cancer treatment in animals, researchers explore how this could this work for humans.
Traditional treatment of invasive brain tumors consists of a combination of chemotherapy and radiation, with this treatment few patients survive longer than two years after diagnosis.
The reason for this is because the effectiveness of the treatment is limited by the tumor's aggressive invasion of healthy brain tissue, which restricts chemotherapy access to the cancer cells and complicates surgical removal of the tumor.
Recently researchers from the Georgia Institute of Technology and Emory University have designed a new treatment approach that appears to stop the spread of cancer cells into normal brain tissue in animal models. The researchers treated animals possessing an invasive tumor with a vesicle carrying a molecule called imipramine blue, followed by conventional chemotherapy. The tumors stopped spreading to the healthy tissue and the animals survived longer than animals treated with chemotherapy alone.
"Our results show that imipramine blue stops tumor invasion into healthy tissue and enhances the efficacy of chemotherapy, which suggests that chemotherapy may be more effective when the target is stationary," Ravi Bellamkonda, a professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, was quoted as saying. "These results reveal a new strategy for treating brain cancer that could improve clinical outcomes."
Jack Arbiser, a professor in the Emory University Department of Dermatology; designed the imipramine blue compound, which is an organic triphenylmethane dye. After in vitro experiments showed that imipramine blue effectively inhibited movement of several cancer cell lines, the researchers tested the compound in an animal model of aggressive cancer that exhibited attributes similar to a human brain tumor called glioblastoma.
"There were many reasons why we chose to use the RT2 astrocytoma rat model for these experiments," Brat was quoted as saying. "The tumor exhibited properties of aggressive growth, invasiveness, angiogenesis and necrosis that are similar to human glioblastoma; the model utilized an intact immune system, which is seen in the human disease; and the model enabled increased visualization by MRI because it was a rat model, rather than a mouse."
Imipramine blue is hydrophobic and doxorubicin is cytotoxic, so the researchers encapsulated each compound in an artificially-prepared vesicle called a liposome so that the drugs would reach the brain. The liposomal drug delivery vehicle also prevented the drugs from being released into tissue until they passed through leaky blood vessel walls, which are only present where a tumor is growing.
Amazingly, all of the animals that received the sequential treatment of imipramine blue followed by doxorubicin chemotherapy survived for 200 days -- more than 6 months -- with no observable tumor mass. Of the animals treated with doxorubicin chemotherapy alone, 33 percent were alive after 200 days with a median survival time of 44 days. Animals that received capsules filled with saline or imipramine blue — but no chemotherapy -- did not survive more than 19 days.
"Our results show that the increased effectiveness of the chemotherapy treatment is not because of a synergistic toxicity between imipramine blue and doxorubicin. Imipramine blue is not making the doxorubicin more toxic, it's simply stopping the movement of the cancer cells and containing the cancer so that the chemotherapy can do a better job," Bellamkonda, Carol Ann and David D. Flanagan Chair in Biomedical Engineering and a Georgia Cancer Coalition Distinguished Cancer Scholar, was quoted as saying
What researchers found was that MRI results showed a reduction and compaction of the tumor in animals treated with imipramine blue followed by doxorubicin chemotherapy, while animals treated with chemotherapy alone presented with abnormal tissue and glioma cells. MRI also indicated that the blood-brain barrier breach often seen during tumor growth was present in the animals treated with chemotherapy alone, but not the group treated with chemotherapy and imipramine blue.
According to the research team, imipramine blue appears to improve the outcome of brain cancer treatment by altering the regulation of actin, a protein found in all eukaryotic cells. Actin mediates a variety of essential biological functions, including the production of reactive oxygen species. Most cancer cells exhibit overproduction of reactive oxygen species, which are thought to stimulate cancer cells to invade healthy tissue. The dye's reorganization of the actin cytoskeleton is thought to inhibit production of enzymes that produce reactive oxygen species.
"While we need to conduct future studies to determine if the effect of imipramine blue is the same for different types of cancer diagnosed at different stages, this initial study shows the possibility that imipramine blue may be useful as soon as any tumor is diagnosed, before anti-cancer treatment begins, to create a more treatable tumor and enhance clinical outcome," Bellamkonda said.
SOURCE: Science Translational Medicine, March 28, 2012