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 A sudden drop in outdoor temperature increases the risk of respiratory infections
11.01.2017 | University of Gothenburg

nachricht Urbanization to convert 300,000 km2 of prime croplands
27.12.2016 | Mercator Research Institute on Global Commons and Climate Change (MCC) gGmbH

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: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

Im Focus: Bacterial Pac Man molecule snaps at sugar

Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.

The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

Water - as the underlying driver of the Earth’s carbon cycle

17.01.2017 | Earth Sciences

Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

17.01.2017 | Materials Sciences

Smart homes will “LISTEN” to your voice

17.01.2017 | Architecture and Construction

VideoLinks
B2B-VideoLinks
More VideoLinks >>>