Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Fluorescent probes may permit monitoring of chemotherapy effectiveness

15.07.2009
Going out like a brilliant flame is one way to get attention. If physicians could watch tumor cells committing a form of programmed suicide called apoptosis, a desired effect of workhorse cancer treatments such as chemotherapy and radiotherapy, they could more quickly pick the most effective treatment. Now scientists at the Stanford University School of Medicine have found a way to do just that, by lighting up cells as they die.

Apoptosis is a carefully orchestrated sequence of intracellular events that leads to the cell's death. "The cell takes itself apart in a finite series of steps," said Matthew Bogyo, PhD, associate professor of pathology and of microbiology and immunology, and a member of the Stanford Cancer Center.

Bogyo is senior author of a study to be published online July 13 in Nature Medicine in which he and his Stanford colleagues demonstrated in mice that it is possible to noninvasively image the degree of apoptosis occurring in living animals' tumors, and thereby to gauge the effectiveness of apoptosis-inducing treatments. Several steps still remain before it can be determined whether this diagnostic method is safe for use in humans.

Apoptosis occurs all the time in healthy bodies. Cells have this suicide system in place to deal with viral infections, or just to complete their normal life cycle. Cells lining the gut, for example, or immune cells in the spleen and thymus are meant to live only a couple of days. "You lose three-quarters of a million cells per second in your body due to apoptosis," noted Guy Salvesen, PhD, director of the program on apoptosis and cell-death management at the Burnham Institute for Medical Research, in La Jolla, Calif.

But apoptosis is also a check against unwanted cell division, as occurs during tumor growth, said Salvesen, who collaborates with Bogyo on various research projects but did not participate in this study. "Cancer cells have to learn to do two things," Salvesen said. "First, they've got to learn to start dividing rapidly. But once they do that, they become very vulnerable to apoptosis. So they've got to learn to switch off this death mechanism. Chemotherapy and radiotherapy aim to turn it back on."

One way of determining whether they're succeeded is by monitoring key early players in apoptosis called caspases, a family of usually quiescent enzymes found inside every mammalian cell. Activated by various biochemical cues from within or outside of the cell, caspases commence a cascade of molecular steps that steer the cell to a clean, quiet, orderly death.

"Caspases have to be very tightly controlled, since they are regulating cell death. If they get turned on, the cell dies," said Bogyo. His team created probes by affixing fluorescent "tags" to small molecules that were engineered to bind — and stay bound — almost exclusively to caspases, and only when the caspases are in an active state. The resulting probes are excited by certain wavelengths of light that travel through skin without being absorbed. The probes respond by giving off their own light, which can be imaged by a special detector.

"Our probe can't bind to inactive caspases," Bogyo said. "It can go into cells, but it doesn't get stuck — it just circulates back out. So the only cells that fluoresce are the ones approaching death."

In an early test of the probe, Bogyo and his colleagues gave mice a drug called dexamethosone, which preferentially induces apoptosis in certain immature immune cells residing primarily in the thymus. After systemically injecting a solution containing the probes, the investigators observed fluorescence in the thymus, as predicted. They confirmed by chemical methods that the fluorescent probes were indeed binding to caspases.

Next, the team performed experiments with a new, experimental monoclonal antibody that activates caspases, by a mechanism different from that of dexamethasone, and initiates apoptosis particularly in rapidly dividing cells such as those in tumors. In one such test, the researchers administered this antibody to mice onto which human tumors had been engrafted. After injecting these live mice at various time points with the fluorescent probes, Bogyo and his colleagues again saw the many tumor cells undergoing apoptosis light up, but not the healthy surrounding tissues.

The potential for practical payoffs is significant, Bogyo said. Radiotherapy and many chemotherapeutic selectively damage DNA in rapidly replicating cells, dramatically boosting the amount of apoptotic death happening in tumors. Some experimental models indicate that inducing apoptosis is the main way these treatments kill cancer cells.

"Different individuals respond differently to a given treatment. The quicker you can make a decision about whether a drug is working or not, the better," Bogyo said. Moreover, he said, new-generation drugs, some of them now in clinical trials, are designed specifically to turn on caspases.

Because caspase activation is a very early event in apoptosis, monitoring it could speed clinicians' ability to determine whether, how and when these new drugs work, said Bogyo. He has started a company, Akrotome, to speed the fluorescent probes' development and commercialization. Stanford has licensed this technology to Akrotome for a 4 percent ownership stake.

"The entire cancer chemotherapy field is very, very excited about probes like this," said the Burnham Institute's Salvesen, who has no financial ties to the current study or to Akrotome. The approach also holds promise for tracking unwanted apoptotic damage to tissues in disorders such as macular degeneration or traumas such as post-ischemic reperfusion injury.

The National Institutes of Health funded the study. Co-authors were graduate student Laura Edgington and former graduate student Alicia Berger, PhD, and postdoctoral researchers Galia Blum, PhD; Victoria Albrow, PhD; and Margot Paulick, PhD, all of the Bogyo lab. (Berger is now with the Boston Consulting Group.) Another contributor was postdoctoral scholar Neil Lineberry, PhD.

The Stanford University School of Medicine consistently ranks among the nation's top 10 medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://mednews.stanford.edu. The medical school is part of Stanford Medicine, which includes Stanford Hospital & Clinics and Lucile Packard Children's Hospital. For information about all three, please visit http://stanfordmedicine.org/about/news.html.

Bruce Goldman | EurekAlert!
Further information:
http://www.stanford.edu

More articles from Studies and Analyses:

nachricht Win-win strategies for climate and food security
02.10.2017 | International Institute for Applied Systems Analysis (IIASA)

nachricht The personality factor: How to foster the sharing of research data
06.09.2017 | ZBW – Leibniz-Informationszentrum Wirtschaft

All articles from Studies and Analyses >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Neutron star merger directly observed for the first time

University of Maryland researchers contribute to historic detection of gravitational waves and light created by event

On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

Im Focus: Shrinking the proton again!

Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.

It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

Climate Engineering Conference 2017 Opens in Berlin

10.10.2017 | Event News

 
Latest News

Researchers release the brakes on the immune system

18.10.2017 | Health and Medicine

Separating methane and CO2 will become more efficient

18.10.2017 | Life Sciences

Ocean atmosphere rife with microbes

17.10.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>