May 15, 2002 Berkeley - The answer to improving the effectiveness of certain cancer treatments may be in stopping the malignant cells cold.
Two researchers from the Institut Gustave-Roussy in France and the University of California, Berkeley found that freezing cancer cells in test tubes made them far more vulnerable to attack by bleomycin, a potent anti-cancer drug also known by the brand name Blenoxane.
Cryosurgery - freezing cells to destroy them - and bleomycin are approved treatments currently used separately for cancer patients. But researchers of the study, published Tuesday, May 14, in the British Journal of Cancer, say that combining the two therapies may eventually lead to a powerful new form of cancer treatment that targets malignant cells while leaving healthy tissue unharmed.
"Cryosurgery has become increasingly popular over the past decade and is being used to treat tens of thousands of cancer patients all over the world," said Boris Rubinsky, professor of bioengineering and mechanical engineering at UC Berkeley and co-author of the study.
In the procedure, cryosurgeons insert a thin probe cooled with a cryogen - often argon gas or liquid nitrogen - into a tumor, turning the malignant mass into an ice ball. Doctors see precisely where they are operating in real time and can thus avoid freezing healthy tissue through the use of ultrasound imaging, a technique pioneered by Rubinsky and former UC San Francisco physician Gary Onik in 1981.
"The neat thing is this research really could have clinical applicability in a very rapid matter," said Onik, currently the director of surgical imaging at Florida Hospital Celebration Health's Center for Surgical Advancement in Orlando, and one of the reviewers of the study. "However, it is critical that we first conduct animal model studies so that we better understand the parameters and risks involved in using cryochemotherapy treatment in humans," he said.
Coverage for cryosurgery has been approved for Medicare patients with certain types of liver and prostate cancer, and dozens of other insurers offer some form of coverage for the procedure as a primary treatment for prostate cancer.
The problem with the procedure, said Rubinsky, is that freezing cells doesn't mean they will always freeze to death. Cells near the probe at the core of the ice mass reach a frosty minus 140 degrees Celsius (minus 220 Fahrenheit) and quickly die. But survival rates increase as temperatures warm from about minus 40 degrees C (minus 40 F), often found on the outer edges of the freeze zone.
In the study, researchers froze melanoma cells in such a way as to mimic the conditions in this outer rim, both in the rate of cooling and in temperature. During freezing, the cells were treated with bleomycin in trace concentrations that ranged from 5 micromoles per liter to as low as 10 nanomoles per liter. These bleomycin concentrations are several magnitudes smaller than what is used clinically for patients. The researchers then compared those cells to a control group of cells that were not treated with bleomycin.
Cells in each group were thawed and cultured for 137 hours before researchers manually counted the resulting colonies. Cells that were frozen without the bleomycin could still produce an average of 242 colonies in six trials. In sharp contrast, cells frozen with a 500-nanomoles-per-liter concentration of bleomycin produced no colonies after four trials, indicating a complete wipeout. Even the extremely low bleomycin concentration of 10 nanomoles per liter had an effect, leaving only enough cells alive to produce an average of 13 colonies after four trials.
"The results are dramatic," said Rubinsky. "The difference in the number of clone colonies after exposure to these very low doses of bleomycin is scientifically an exciting find."
The researchers said the freezing process makes cell membranes more permeable, allowing bleomycin to kick in. Bleomycin, belongs to a class of anti-cancer drugs called antineoplastics and has been used clinically since the mid-1970s.
"Once it enters a cell, bleomycin is extremely active, breaking up the cell's DNA and interfering with its ability to divide," said Lluis M. Mir, senior researcher at the Institut Gustave-Roussy and lead author of the study. "The problem is getting the bleomycin inside the cell. Contrary to almost all anti-cancer drugs, bleomycin doesn't diffuse through the cell membrane. It must bind to specific receptors on the cell membrane to get in, and that is quite a limiting factor."
Higher doses of bleomycin are needed to compensate for the drug's difficulty in passing through the cell membrane. The same characteristics that make bleomycin inefficient as an anti-cancer agent when used alone, however, also make it useful when researchers only want to target certain cells.
"What we've found is a way to make cryosurgery more reliable," said Mir, who is also a senior scientist at the Centre National de la Recherche Scientifique (National Center for Scientific Research) in France. Neighboring, healthy cells would not get the deep freeze and would therefore have intact cell membranes that would protect them from the bleomycin.
In practice, surgeons treating prostate cancer avoid leaving malignant cells behind by "overshooting" the freezing zone slightly beyond the borders of the tumor, said Onik of Florida Hospital Celebration Health. "We know cryosurgery works very well, but very often we have to destroy more tissue than we'd like to in order to ensure that all cancer cells are dead," he said.
That creates a greater risk for damage to healthy nerves and muscles surrounding the prostate. "It becomes a tradeoff between killing off all the cancer cells and avoiding such side effects as impotence and incontinence," said Dr. Israel Barken, chairman and medical director of the Prostate Cancer Research and Education Foundation, an organization founded by cancer survivors that helped fund the research.
"The beauty of the study is the synergistic effect of pairing cryosurgery together with chemotherapy," said Barken. "By using bleomycin, there's no need to be as aggressive with the cryosurgery. By freezing the cells, you can use very low doses of bleomycin. This should drastically reduce the harmful side effects of using either treatment alone."
The study was funded by grants from the Centre National de la Recherche Scientifique and the Institut Gustave-Roussy in France, and the Prostate Cancer Research and Education Foundation in San Diego.
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