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10.08.07
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Yoram Palti, MD, PhD

Alternating electric fields affect tumor cells by (a) slowing their division time from under one
hour to more than three hours. The fields also (b,c) disintegrate cells in the later stages of cell
division. (Physics Today, adapted from Kirson et al., Cancer res. 64, 3288, 2004.)
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: Generally, TTFields involve physical forces, like radiation and not chemical
interactions with specific receptors, a property that characterizes chemotherapy.

As to the mechanisms of action, they are described in the Brain Research and PNAS papers,
and additional details are available in the review of the PNAS paper in the last issue of
 . I will go over it briefly here.

There are two main mechanisms that we identified, both are related to the fact that the cancer
cells divide much more often than normal cells. The first relates to the difference in the
intracellular distribution of the 100 kHz to 200 kHz, alternating the electric fields (TTFields)
between quiescent and dividing cells. In the former, the intracellular field is uniform, while in
the latter it is highly non-uniform.

This non-uniform distribution has two effects; first, there is focusing of the field in the region
of the furrow connecting the two newly forming daughter cell. (See the figures in either one
of the above references.) This results in very high field intensity in this region.

The second effect is related to the non-uniformity of the field in itself. In a non-uniform
electric field, there are forces that act on all elements that are polar, polarizable, etc., pushing
them toward the region of higher field intensity (a process known as ³dielectrophoresis´).
This disrupts the internal cell structure and interferes with the normal division process.

The second mechanism relates to disruption of the cell division microtubule spindle that is
formed in all dividing cells. The spindle microtubules pull each one of the two newly formed
sets of chromosomes away from the cell center and, eventually, into the each daughter cell.

This chromosome dislocation is the result of a polymerization depolymerization process

carried out by macromolecules that are highly oriented (relative to the division axis) and have
an extremely large dipole moment.

When the spindle macromolecules are at a specific orientation relative to the field direction,
the forces of the field interfere with the above process, thus, to a slowing and disruption of
the division. The cells that suffered from this disruption usually die.

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: The major difference between TTFields and other cancer treatment modalities is, in
fact, that the former have practically absolute specificity to dividing cells. Thus, quiescent
cells
are left undamaged even at very high field intensities, beyond those required to affect the
dividing cells (extremely high therapeutic index).

Moreover, non-cancerous body cells, which divide at relatively high rates, those of the
hematopoietic system, are effectively spared when TTFields are used because of the relative
electric properties of muscle, bone, bone marrow, etc.

Therefore, in contrast to both radiation and chemo, TTFields are not associated with sever
side effects. It is worth mentioning here that there is a fundamental difference between
radiation and TTFields with regards to penetration.

While ionizing radiation attenuates with penetration as energy is absorbed by the different
tissues, electric fields do not follow the same phenomena. For example, if a uniform field is
generated in a homogeneous tissue (by placing plate electrodes on the two sides of the tissue
mass), the electric field intensity will be the same at all depths.

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: This means that the FDA has no concerns at all about safety, and that it is very likely
that the treatment will have significant efficacy. The consequence is that, within a relatively
short time, if all goes well, the technology may be used clinically.

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: Wearing the electrodes and device is not associated with any pain or discomfort; the
only thing the patient feels is slight warmth. The device weighs about 3kg (with batteries), so
it is a bit inconvenient to carry around. The patients wear it, on average, 18 hours a day. The
duration of treatment varies, but it is usually many months.
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: Thus far, with a total experience of more than 250 months of patient treatment, there
has not been a single severe adverse event. The only side effect that was encountered was
contact dermatitis, which responded well to steroid creams.

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: We have just finished a trial with newly diagnosed GBM (The trial described in the
PNAS paper is related to recurrent GBM.), began a clinical trial with patients having breast
cancer, and plan to begin a lung cancer trial soon. We hope to be able to expand the treatment
to all solid tumors.

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: We have very encouraging initial lab results that indicate synergism between TTFields
and chemotherapy. We plan to further investigate this, with the aim to incorporate such
treatment in the clinics.

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