Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Potential viral therapy weapon for difficult cancers is safe and effective in study

24.04.2008
Study led by Cincinnati Children's proposes further development to advance treatment

Combining a herpes virus genetically altered to express a drug-enhancing enzyme with a chemotherapy drug effectively and safely reduced the size of highly malignant human sarcoma grafted into mice. This new finding may add to the growing arsenal of so called oncolytic viruses under development as novel cancer treatments, especially for difficult, inoperable tumors, according to a research led by Cincinnati Children’s Hospital Medical Center and published April 24 in Molecular Therapy.

“Our study shows the chemotherapy drug cyclophosphamide (CPA) enhances the anti-tumor effectiveness of the oncolytic virus rRp450 in mice carrying aggressive human sarcoma, resulting in significant tumor shrinkage,” said Timothy P. Cripe, M.D., Ph.D., a physician and researcher at Cincinnati Children’s and the study’s corresponding author. “Just as important is the fact that the combination of rRp450 and CPA appears to be well tolerated, because non-cancer bearing mice treated with the therapy survive long term. It will take some time to continue developing this approach before its potential to be tested in clinical trials, but our results are encouraging and warrant further study.”

New treatment options are desperately needed for sarcomas, which occur in soft and connective tissues like bone, cartilage, muscle and blood vessels. In most sarcomas that metastasize – or spread to other parts of the body – less than 30 percent of the patients are curable, Dr. Cripe said. Chemotherapy combined with surgery and radiation has advanced the treatment of these cancers, but these therapies have limitations. In childhood sarcomas that respond well to chemotherapy but metastasize, less than half of the children who undergo intense, high-dose therapies survive five years from diagnosis. Another challenge is adult sarcomas, which are generally resistant to chemotherapy and radiation.

Dr. Cripe’s research team injected sarcoma tumors in mice with rRp450, in which a normally occurring gene was deleted and replaced with a gene that encodes an enzyme to activate chemotherapy drugs called oxazophosphorines, including cyclophosphamide (CPA). Previous studies have reported the rRp450 virus kills cancer cells by causing their cell membranes to erupt, and that the virus helps the anti-tumor effects of CPA. In the current study, rRp450/CPA treatment significantly shrunk a form of human rhabdomyosarcoma, a relatively rare and aggressive tumor that wraps around muscles and soft tissues, usually in younger children. When the grafted tumors reached 200-500mm in size, seven mice were treated twice over eight days with a combination of rRp450/CPA, with rRp450 administered by direct tumor injection 24 hours prior to CPA. The researchers noted significant tumor shrinkage with one animal perishing 20 days following initial injection, two more within 30 days, two within 40 days and the last two mice surviving nearly 50 days post treatment.

The investigators also confirmed the anti-tumor effect of rRp450 treatment alone in mouse models of human cancers rhabdomyosarcoma and neuroblastoma, where they observed significant tumor shrinkage in 13 of 13 injected tumors. Treatment with CPA alone in these models showed limited anti-tumor effectiveness. In a control group of tumor-carrying mice treated with a placebo, all died within 10 days of injection.

Also noteworthy in this study is documentation of the treatment’s potential safety, specifically toxicity to nerve tissues. Most research of oncolytic herpes simplex viruses (oHSVs) has so far been limited to those engineered by deleting both copies of the neurovirulence gene that prompts wild-type HSV-1 virus to spread and invade the nervous system. Deleting both copies disarms most of the virus’ disease-spreading properties while retaining its ability to damage targeted cancer cells. The rRp450 virus is different because it retains both copies of the virulence gene but is attenuated by deletion of a different gene. Earlier preclinical studies showed that deleting just the single gene increases rRp450’s ability to degrade cancer cells, but until the current study little had been known about whether a virus with a single-gene mutation would retain neural toxicity to the recipient.

Dr. Cripe and his colleagues addressed the neural toxicity question in part by injecting normal human liver, skin and nerve sheath cells grown in the laboratory with the rRp450 virus and with the normal wild-type HSV-1 virus. Over a 72-hour period, researchers noted a robust replication of the wild-type HSV-1 in these cells, but in cells injected with rRp450, the replication rate was inhibited 10,000 fold with no signs of productive virus infection.

Researchers also tested wild-type HSV-1 in mice by intravenous and intracerebral (brain) injection, comparing those results to mice injected initially with rRp450 and with CPA 24 hours later. Mice getting the wild-type virus suffered from high infection rates, abnormal gait and in some cases death. In contrast, mice receiving a combination of rRp450/CPA tolerated the treatment well with no significant clinical effects on their blood counts or chemistries. The researchers did note that tissue samples tested during the study retained some viral genetic material, notably DNA fragments, although there were no signs of active disease. Because mice received combined rRp450/CPA only once during the toxicity part of the study, safety tests based on repeated dosing are still needed, and would be necessary to support a multi-dose clinical trial, the researchers said.

“Based on these findings and other preclinical studies, we expect oncolytic viral therapy will be one additional treatment modality available in the future for oncologists,” Dr. Cripe said. “The challenge over the next decade will be determining which viruses work best for which cancers, at what doses, schedules, routes of administration, and in what combinations with other treatments.”

Nick Miller | EurekAlert!
Further information:
http://www.cincinnatichildrens.org/

Further reports about: Anti-Tumor CPA Cripe HSV-1 Injection Tissue chemotherapy oncolytic rRp450 rRp450/CPA sarcoma toxicity

More articles from Life Sciences:

nachricht Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University

All articles from Life Sciences >>>

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 >>>