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Pulses of electricity shorter than a millionth of a second can cause complete remission of melanomas on the skin of mice, researchers at the Frank Reidy Research Center for Bioelectrics report in a paper scheduled to be published online Wednesday in Biochemical and Biophysical Research Communications.

Previous experiments at the Reidy Center, which is operated by Old Dominion University and Eastern Virginia Medical School, had shown that nanosecond-range pulses of relatively high field strength could reduce tumor size and mass by cell "suicide." The latest results extend these earlier studies showing that the process-with field strengths ranging as high as 40,000volts/cm-can cause skin tumors to self-destruct.

Following this treatment, tumor cell nuclei shrink by 50 percent within minutes and the tumor blood supply is disrupted for weeks. The paper also suggests that tumors inside the body may respond to a similar treatment delivered by catheter electrodes.

Richard Nuccitelli, a biophysicist on the Old Dominion faculty and a researcher at the Reidy Center, believes the results are an important step toward human cancer treatments that involve no drugs and produce no lasting side effects. The paper notes that the pulsed electric field also seems capable of curing skin cancers without causing the scarring left by surgical incisions.

"We see these results as very important," said Nuccitelli, first author of the paper. "We want to continue the research to learn more about how the pulses work."

Another of the paper's authors, Karl H. Schoenbach, is director of the Reidy Center and a leading expert in the new field of intracellular electromanipulation. A professor and eminent scholar of electrical and computer engineering, Schoenbach also is Batten Endowed Chair in Bioelectrics Engineering at Old Dominion.
Earlier papers from Schoenbach's research group have described pulsed electric field experiments that destroyed cancer cells through apoptosis-an orderly self-destruct mechanism. Two of his collaborators in the earlier research, Stephen J. Beebe, EVMS professor of physiological sciences and pediatrics, and Juergen F. Kolb, ODU assistant professor of electrical and computer engineering, are also authors of the latest paper. R. James Swanson, ODU professor of biological sciences, is another author of the paper, as are two ODU graduate students, Xinhua Chen and Wentia Ford.

The nanosecond-range electric field pulses produce remarkable effects compared to longer pulses because of the field's penetration of the outer cellular membrane. Membranes typically resist penetration by electric fields, but the ultrashort pulses, lasting only 300 nanoseconds or 0.3 millionths of a second each, essentially sneak through before the outer membrane can mount a defense. Once inside the cell, the electric field is able to act upon the nucleus and other intercellular organelles.

Soon after the pulsed electric field penetrates tumor cells, the nuclei shrink-possibly because of DNA damage-and blood supply to the melanoma is cut off, according to the researchers. In a study that lasted more than a year involving the treatment of 300 tumors on 120 mice, the researchers consistently were able to shrink melanomas by 90 percent within two weeks of initial treatment. Pulse applications to the tumors varied in length and staging, but generally comprised a series of pulses with a total duration much shorter than the blink of an eye. The researchers report that after two weeks, melanomas began to regenerate, requiring a second treatment before complete remission was accomplished.

Because of the short duration, the pulses cause no significant heating of the tumor; researchers also observed no lasting damage to healthy cells surrounding the tumor.

Schoenbach predicts that cell electromanipulation "will end up in your doctor's office" with applications not only for tumor treatment, but also for gene therapy, wound healing, removal of warts, treatment of fungal infections and other cosmetic uses. "The effects that have been observed so far are only the tip of the iceberg," he said.

Largely because of the work of Schoenbach and Beebe, Old Dominion administers a multi-university consortium for bioelectrics researchers representing the Harvard/MIT Division of Health Sciences and Technology, University of Texas Health Sciences Center, Washington University, the University of Wisconsin, as well as the Reidy Center. Old Dominion also is involved in international bioelectrics collaboration, having established a consortium for bioelectrics with Kumamoto University in Japan and Universitat Karlsruhe in Germany.

Not long after the startup of the Reidy Center three years ago, Schoenbach recruited Nuccitelli, who served on the faculty of the University of California, Davis, for 23 years before retiring in 2000 to begin his own biotech company.

Nuccitelli's experience with a mouse/melanoma research model led Schoenbach to suggest the experiment that resulted in the paper published today. "In the very first experiment 15 months ago, the tumor shrunk dramatically," Nuccitelli said. "I was, to say the least, excited. But we also wanted to be 100 percent sure. We followed up on 300 tumors, and every single tumor responded. We have established a high degree of accuracy for the findings and documented them with four different imaging techniques."

Electrical pulses were delivered to some tumors via needles, but the researchers found it difficult to obtain uniform field coverage of the tumors. Another of the paper's authors, Uwe Pliquett, a German engineer who was a visiting scholar at Old Dominion last year, designed tiny parallel plates that delivered the pulsed electric field to melanomas pinched between the two plates. This technique provided a uniform field and produced better results.

Researchers at the Reidy Center are planning experiments to determine if a mouse can survive a melanoma and still be healthy four to six months after treatment, as well as further research to explain how it is that nanosecond pulsed electric fields impact both diseased and healthy cells. Nuccitelli said experiments on higher mammals may be required before the researchers turn to human subjects.

The work reported in today's paper was supported by grants from the Air Force Office of Scientific Research, American Cancer Society, Old Dominion University Education Foundation, BioElectroMed Corp

This article was posted on: March 13, 2006

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