Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.
The best cancer drugs in the world are not much good if they cannot get to tumor cells. That problem has been challenging physicians and researchers for years because the physical structure of many tumors can prevent anticancer agents from reaching their neoplastic targets.
A paper released online in Nature Medicine on May 19, 2003, describes a new technique for assessing the permeability of tumors, and a promising, novel way of improving tumors' accessibility to chemotherapeutic drugs.
The report is titled "Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation." Its authors are at Massachusetts General Hospital in Boston.
"We've known for a long time that many cancer drugs work very well on cells," observed the article's senior author, tumor biologist Rakesh Jain. "As we have improved the understanding of tumor physiology," he continued, "we have found that a significant portion of a tumor is made up of an extracellular matrix that acts as a barrier - keeping drugs away from tumor cells."
This matrix is largely made up of the connective tissue collagen. To determine its structure and content in different tumor types, and to assess its effect on a tumor's permeability, the co-authors used a new imaging technique called "second-harmonic generation" (SHG). That is a noninvasive method for measuring an optical signal emitted by certain molecular structures. They showed that SHG can distinguish among types of connective tissue molecules and specifically image the structure and density of collagen fibers.
By imaging tumors that had been implanted in mice, the team was able to produce high-definition 3-dimensional images that reveal the amount and form of collagen. Studying three types of tumors known to have different relative collagen contents, they showed that SHG could accurately measure collagen levels that correlated with measurements of tumor permeability. The result suggests that SHG could allow analysis of the structure and content of a tumor's collagen to help with treatment planning.
To test whether SHG could measure collagen modification, the co-authors first applied the enzyme collagenase, which breaks down collagen, directly to mouse tumors. Images taken after collagen application showed significant changes in the SHG images. However, because collagen is an important part of the body's overall structure, collagenase would not be a useful treatment adjunct as its effect could spread far beyond the tumor itself.
In their search for an agent to selectively break down tumor-matrix collagen, the researchers turned to a hormone called relaxin. Normally produced in pregnant females, relaxin eases labor by increasing production of enzymes that aid dilation of the cervix and other birth processes. Clinical trials of other potential uses of relaxin have found only minor side effects in humans.
To deliver relaxin into the bloodstream of mice with implanted human tumors, the researchers used intravenous pumps. They then monitored SHG to image the tumors over a 12-day period. They also imaged a control group of rodents that did not receive relaxin. While the amount of collagen in the relaxin-treated tumors was similar to that seen in the controls at the end of the study period, in the relaxin-treated mice the collagen fibers had broken down and were measurably shorter and more permeable, so less of an obstacle to penetration.
Jain and his co-authors already started animal studies to gauge whether relaxin can improve actual response to chemotherapy drugs. "If these results are positive," he concluded, "the fact that relaxin is so safe means we can move relatively quickly into human clinical trials."
In Type II Diabetics, Enzyme Stops Liver From Producing Glucose When It's Present In Food
Scientists have turned up a strangely named molecule that may be a useful drug target for Type II diabetes - the form of the disease that tends to affect the elderly and overweight. Their report in Science dated June 6, 2003, bears the title "TRB3: A tribbles homolog that inhibits Akt/PKB activation by insulin in liver." Its co-authors are at the Salk Institute for Biological Studies in La Jolla, Calif.
Insulin helps muscle cells absorb glucose from the blood and regulates blood glucose levels via a series of reactions known collectively as insulin signaling. People with Type II diabetes produce insulin, but they either don't produce enough or their bodies are resistant to it. Part of the insulin signal involves the Akt enzyme, which stops the liver from producing glucose when this sugar is available from food.
The co-authors searched for proteins that directly interacted with Akt, and came up with the TRB3 protein, which blocks Akt. Mouse studies indicated that TRB3 inhibits Akt and thus promotes glucose production by the liver under fasting conditions. A drug that suppressed TRB3 in individuals who eat normally might thus offer treatment for Type II diabetes, the authors proposed.
Dopamine Receptor Mitigates Levodopa's Side Effects In Parkinson's Disease Therapy
The drug of choice for treating the symptoms of Parkinson's disease (PD) is the brain neuron dopamine. Levodopa (l-dopa), which supplies the PD brain and body with dopamine. It works well up to a point, beyond which its symptomatic relief dwindles.
But even at its prime, l-dopa inflicts severe side effects. These initially induce PD motor symptoms, but in most patients they eventually induce debilitating and drug-resistant involuntary movements called dyskinesia. Levodopa may be due to an excess of dopamine. One treatment approach has been to raise brain dopamine levels.
In a primate animal model of PD, treatment with l-dopa specifically increased expression of the D3 dopamine receptor. The l-dopa therapy in combination with compounds that bind to the D3 receptor were able to eliminate dyskinesia without losing the beneficial effects of l-dopa. These findings are reported in Nature Medicine for June 2003, under the title "Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function." Its authors are at INSERM, the French National Institute of Health and Medicine Research in Paris.