Electric fields have potential as a cancer treatment
Low-intensity alternating fields can hinder or destroy
dividing cells and slow the growth of brain tumors in cancer patients.
August 2007, page 19
Healthy cells have regulating mechanisms that generally
limit how rapidly they can divide. Skin cells, for example, normally divide about once every 30
days, but they can divide faster in response to a wound that needs healing. Cancer, however, is characterized
by cell division that has gone out of control. In cancer cells, the mechanisms that regulate division
break down, and the cells spend less time in the quiescent state and more time dividing.
Many chemotherapy drugs work by interfering
with the cell-division cycle. The drugs reach healthy cells and cancer cells alike, but they do
most of their damage to the cancer cells. Unfortunately, some types of healthy cells divide as rapidly
as cancer cells and are badly damaged as well. Such cells are found in bone marrow, the lining of the
digestive tract, and hair follicles, so chemotherapy patients often lose their hair and are susceptible
to infection. The damage to healthy cells limits the drug dose that a patient can tolerate and therefore
limits the treatment's effectiveness.
Yoram Palti, of the Technion–Israel
Institute of Technology in Haifa, and his colleagues have demonstrated another way to disrupt
cell division: alternating electric fields with intensities of just 1–2 V/cm. The fields
they use, with frequencies in the hundreds of kilohertz, were previously thought to do nothing
significant to living cells other than heating them. But Palti and colleagues have conducted a
small clinical trial showing that the fields have an effect in slowing the growth of tumors.1
In studies of tumor cells in vitro, Palti
and colleagues observed two distinct effects, both of which depend on the direction of cell division
with respect to the applied field.2 First, they found that cells in the electric field
take longer than usual to divide, as shown in figure 1a. Second, they found that dividing cells sometimes
disintegrate just before the division process is complete, as shown in figure 1, panels b and c.
They offer an explanation for each effect.
The researchers suggest
that cell division is slowed because the electric field hinders the formation and function of the
mitotic spindle, the structure that guides the newly replicated chromosomes as they separate
into the two daughter cells. The mitotic spindle is made up of microtubules, formed by the polymerization
of dimers of the protein tubulin. (Microtubules and other cellular structures are illustrated
in PHYSICS TODAY, September 2006, page 80.) The tubulin dimers and polymers have large dipole moments,
so they are affected by the electric field. But most other biochemical processes also involve polar
molecules and structures, and small oscillating electric forces don't appear to have much of an
effect on them. The difference, says Palti, is that when the tubulin dimers assemble into the mitotic
spindle, they all line up in the same direction. If that direction happens to be orthogonal to the
direction of the electric field, the microtubules are less likely to function normally.
The proposed mechanism
for the destruction of dividing cells stems from the distribution of the electric field in each
cell. The cell membrane, a lipid bilayer, acts as a capacitor with high impedance at the frequencies
used, so the electric field doesn't readily penetrate the cell membrane. In a quiescent cell, the
electric field inside the cell (shown in figure 2a) is much smaller than the field outside the cell
and is largely uniform. But in the late stages of cell division, a higher-field region forms at the
bottleneck point, or furrow, between the two newly forming cells, as shown in figure 2b. The nonuniform
electric field generates a so-called dielectrophoretic force that draws polarizable molecules
and structures in the direction of the higher-field region. The researchers calculate that the
force, which can be as large as 60 pN, is enough to cause the organelles to pile up at the furrow within
a few minutes.
Just how that pileup destroys
the cell is still largely a matter of speculation, but Palti and his colleagues have a few ideas.
"The organelles are attached to a cytoskeleton," Palti says. "They're not just floating around
in the cytoplasm," so maybe the dielectrophoretic force rips them from that connective structure
and kills the cell. Also, the pinching-off mechanism, by which the furrow closes and one cell becomes
two, is a sensitive process that could be disrupted by the presence of molecules and organelles
that are supposed to be elsewhere in the cell.
Palti's 100-kHz fields
are not the only form of electrical stimulation that can hinder cell division. Luca Cucullo, Damir
Janigro, and their colleagues at the Cleveland Clinic have found that low-intensity alternating
current with a much lower frequency—about 50 Hz—can keep some types of cells from dividing.3
They don't yet know exactly how the process works, but their experiments suggest that the mechanism
involves a particular protein that forms pores in the cell membrane to transport potassium ions
into the cell. Cells whose division was halted by electric current contained more than the usual
amount of the protein. And when the stimulated cells were exposed to cesium or barium, which block
the potassium-transport pores, they divided at the same rate as unstimulated cells.
Clinical trial
Palti and colleagues had extensively
studied the effects of the electric fields on tumor cells in vitro and in laboratory mice and rats
when in 2003 they began their first clinical trial on human patients. They used their electric fields
to treat glioblastoma multiforme (GBM), a type of brain tumor with a very low survival rate. When
the tumor is treated by surgery, radiation, or chemotherapy, it nearly always progresses, or starts
to grow again. The tumor usually kills the patient, often by the buildup of intracranial pressure
that results from the tumor's sheer size.
The researchers recruited
10 patients for their trial. All had recurrent GBM, meaning that their tumors had been treated by
other methods and had begun to grow again. The patients were fitted with electrodes, as shown in
figure 3, that applied a 200-kHz electric field to their brains. At one-second intervals, the field
orientation switched between front to back and side to side, so that the field would have the greatest
effect on tumor cells dividing in all directions. Patients wore the electrodes 18 hours per day
for up to 18 months.
Healthy cells in an adult
brain don't divide, so there was little danger that the electric field would damage the normal tissue
surrounding the tumor. In fact, because of the way applied fields are distributed in the body, the
researchers are confident that when they apply their treatment to tumors in other parts of the body,
the fields will do little damage to the bone marrow or the digestive tract. The field strength that
could be used was limited not by toxicity to healthy tissues but by thermal effects in the skin: The
field intensity was automatically lowered if the skin was heated enough to be in danger of thermal
damage. The patients didn't lose their hair, but they had to keep their heads shaved in order for
the electrodes to make good contact.
Because their small trial
had no control group, the researchers compared their device's performance with historical data
from other studies of GBM patients. Palti's trial found a median time to progression of 26 weeks
and a median survival time of 62 weeks, whereas studies of recurrent GBM treated by other means found
a time to progression of about 10 weeks and a survival time of about 30 weeks. Two years after their
treatment began, 3 of the 10 patients in Palti's trial were still alive, and two were progression
free.
To better evaluate their
treatment's effectiveness, Palti and colleagues are currently working on a controlled study
in which patients are randomly assigned to receive either the electric-field treatment or a chemotherapy
regimen. They are also looking into combining the electric-field treatment with low-dose chemotherapy.
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