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Abstract

In the assignment we will be discussing about the
application of electromagnetic field in medical environment. Electromagnetic
fields are created by differences in voltage; the higher the voltage the
stronger will be the resultant field.

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Magnetic fields are created when the electric
current flows: the greater the current, the stronger the magnetic field. An
electric field will exist even when there is no current flowing. If the current
does flow, the strength of the magnetic field will vary with power consumption,
but the electric field strength will be constant.

We will describe two possible applications of
low-intensity non-ionizing electromagnetic fields (EMF) for the treatment of
malaria and cancer, respectively.

In malaria treatment, a low-intensity extremely-low
frequency magnetic field can be used to induce vibration of hemozoin, a
super-paramagnetic polymer particle, inside malaria parasites.

This disturbance could cause free radical and
mechanical damages leading to the death of the parasite. This concept has been
tested in vitro on malaria parasites and found to be effective. This may
provide a low cost-effective treatment for malaria infection in humans. The
rationale for cancer treatment using low-intensity EMF is based on two concepts
that have been well established in the literature:

 (1)
low-intensity non-thermal EMF enhances cytotoxic free radicals via the
iron-mediated Fenton reaction; and

(2) cancer cells have higher amounts of free iron,
thus are more susceptible to the cytotoxic effects of EMF. Since normal cells
contain minimal amount of free iron, the effect would be selectively targeting
cancer cells. Thus, no adverse side effect would be expected as in traditional
chemotherapy and radiation therapy. This concept has also been tested on human
cancer cell and normal cells in vitro and proved to be feasible.

 

INTRODUCTION

Electromagnetic (EMF or EM field) is a physical
field produced by electrically charged objects. But affects the behaviour of
charged objects near the field.

Non-ionizing electromagnetic fields (EMF), from
extremely-low frequency to radiofrequency, have been showing to cause
biological effects even at low intensity. Some of these effects may be applied
for medical treatments.

One example of their effects on the physiology of
bone cells that leads to the use of these field for treatment of bone fracture
and to improve and facilitate bone healing. In this assignment we describe two
areas of research on medical applications of electromagnetic fields that we
have been engaging in, namely, treatments of malaria infection and cancer. Even
through preliminary data support the feasibility of these two applications,
mechanisms of effect are still speculative and further research is needed to
fully develop them for human treatment.

TREATMENT OF
MALARIA

Malaria affect and kills millions of people the
world, particularly in developing countries. Resistance to anti-malarial drugs
is widespread and has been a major problem in malaria treatment and
eradication. The approach for the treatment of malaria using an alternating
magnetic field. The basis of this approach is that malaria parasites generate a
super-paramagnetic particle known as hemozoin during their process of feeding.
The parasite feeds on haemoglobin in erythrocytes in the blood of the host. A
haemoglobin molecule consists of a protein-moiety globin and heme, an iron
containing porphyrin molecule. The globin portion of the haemoglobin molecule is broken down inside the
food vacuole of the parasite to amino acids which are used by the parasite for
protein synthesis and reproduction 1, 2. The heme portion,
ferriprotoporphyrin IX, is left intact, since the parasite lacks the enzyme to
break it down. Free heme is highly toxic to the malaria parasite, because it is
an inhibitor of an enzyme (Na+/K+-ATPase) that is involved in metabolic energy
production 3. Free heme can also cause a chain reaction of free
radical-induced oxidation of unsaturated fatty acids, leading to membrane
damage 4. To eliminate their toxic effects, heme molecules in the food
vacuoles of the parasite are packed by an enzymatic process into a polymer
called hemozoin. In hemozoin, the heme polymer is formed by covalent bonding of
the iron of one heme molecule with the oxygen of the carboxylate group in one
of the side chains of another heme molecule 5, 6. This molecular arrangement
makes hemozoin super-paramagnetic 7 and it behaves like a small bar magnet in
a magnetic field. It was hypothesized that exposure of the parasites to an
alternating magnetic field would shake hemozoin molecules inside the parasite.
If the energy exerted on the molecules by the magnetic field is large enough,
the rate of enzymatic formation of hemozoin would be decreased. Accumulation of
free heme in the parasite would then produce toxic effects.

 An important
advantage of using alternating magnetic fields for the treatment of malaria is
that development of resistance would be unlikely. The alternating magnetic
field would act directly on hemozoin rather than on an enzyme or other gene
product, thus producing no biological selection.

Another possibility is that there may be an
additive effect, in which alternating magnetic fields would increase the
sensitivity of parasites to low concentration of anti-malarial drugs and
enhance the effectiveness of treatment.

Further research needed to be carried out to
identify the optimal magnetic field exposure conditions to disturb the growth
of the malarial parasite. Since the magnetic moment of a hemozoin molecule is
proportional to its mass, a resonant frequency probably exists that can make a
magnetic field most efficient for malaria treatment.

TREATMENT OF CANCER

Research found that acute (2 hr) exposure to a
60-Hz magnetic field caused DNA single and double strand breaks 10, DNA-protein
and DNA-DNA crosslinks 11, and increased apoptosis 12 in brain cells of
rats. The effects were medicated by free radicals, since they could be blocked
by pre-treatment with free radical scavengers 12, 13. Further studies showed
that the effects involved iron because pre-treating rats before magnetic field
exposure with the iron-chelator deferiprone eliminated the effects 13. We
proposed that magnetic fields generate free radicals via the Fenton reaction.
figure 1

Other research has also supported the notion that
electromagnetic fields in both the extremely-low frequency and radiofrequency
ranges, enhance free radical activity/formation in cells and iron could play a
role in the process 14. Iron plays a vital role in cell functions and growth, e.g., in energy
metabolism and DNA synthesis.

Special molecular mechanisms have evolved for the
transport of iron into cells. In vertebrates, an iron transport system involves
a specific interaction between the iron-binding protein transferrin in the extracellular
fluid and some cell surface transferring receptors that results in a
facilitated transport of iron across cell membrane via receptor-mediated
endocytosis 15. Due to their rapid rate of division, most cancer cells have
high rates of iron intake 16 and express a high cell surface concentration of
transferrin receptors 17 than normal cells. In general, the aggressiveness of
a tumour is positively correlated with cell surface transferrin receptor concentration
of its cells. For example, breast cancer cells have 5-15 times of transferrin
receptors on their cell surface than normal breast cells 18, and they do take
up more iron than normal breast cells 19.

Figure 1. The Fenton reaction: an iron-catalyzed conversion of hydrogen peroxide
to a more powerful and damaging hydroxyl free radical that can cause molecular
damages and cell death.

Since cellular responses to magnetic fields involve
an iron-dependent process, we hypothesize that cancer cells are more
responsible to magnetic fields than normal cells. To test this hypothesis, we
exposed Molt-4 cells, a human leukemia cell line, to a 60-Hz magnetic field in
the presence and absence of added holotransferrin (i.e., iron loaded
transferrin) in the medium. Holotransferrin, as described above, transports
iron into cells and increases iron content intracellularly. Molt-4 cells are
expected to uptake a large amount of iron when provided with holotransferrin
since they have high cell surface concentration of transferrin receptor 20,
21. An increase in intracellular iron concentration would make these cells
more susceptible to the effect of magnetic field. However, since normal
lymphocytes do not have high transferrin receptors and do not import a lot of
iron via transferrin, they would be less susceptible to the effect of magnetic
fields. The following is a description of the experimental procedures.

Molt-4 cells (American Type Culture Collection,
Rockville, MD) were grown in 100% humidity at 37oC in 5% CO2 in air, in
RPMI-1640 medium (Life Technologies, Gaithersberg, MD) with 10% fetal bovine
serum (Hyclone, Logan, UT). At 24 hrs. after splitting into two by adding
culture medium, 0.1 ml aliquots were put into microfuge tubes. Half of these
samples were incubated with the addition of human holotransferrin (1 mg/ml,
Sigma Chemical Co, St. Louis, MO) for 1 hr. Samples from
holotransferrin-treated and non-treated cultures were then each further divided
into two sets. One of the sets was exposed to a 0.25 mT 60 Hz sinusoidal
magnetic field for 2 hrs. in an incubator at 37°C.

The other was incubated at 37°C without magnetic
field exposure. Therefore, there were four treatment conditions:
holotransferrin/ magnetic field, holotransferrin/no magnetic field; no
holotransferrin/magnetic field, and no holotransferrin/no magnetic field.
Exposure to 60-Hz magnetic field was done in a Helmholtz coil exposure system
consisting of two 16 cm diameter coils (250 turns/coil) encased in Perspex.
Current input to the coils was adjusted using a variac. The flux density (0.25
mT) within the coils was determined by an Enertech Emdex II magnetic field
meter. Similarly, 50 ?l of human whole blood obtained from a finger prick was
mixed with 1 ml of RPMI-1640 and divided into 0.1 ml samples. These samples
were subjected to the same procedures of holotransferrin treatment and magnetic
field exposure as described above. Cell counts were made from each cell sample
immediately before and after exposure (2 hrs.) and at 22 hrs. after exposure.
After thoroughly suspending cells, 20 ?l of cells were mixed well with 20 ?l of
10 ?g per ml of acridine orange and 10 ?l of this was loaded in a hemocytometer
chamber. Acridine orange is a DNA intercalating dye and stains DNA and RNA
only. This allowed us to count leukocytes in whole blood without isolating them
from the blood. Duplicate cell counts were made from each sample.

Cell count of a sample at a certain time point was
converted as a ratio of the count of that sample at time zero (i.e., start of
exposure). Four experiments each were run with Molt-4 cells and leukocytes and
average responses of the experiments were calculated and plotted. Data were
then compared by the Mann-Whitney U test and a difference at p< .05 was considered statistically significant. Cell counts of Molt-4 cells after various times after magnetic field exposure were compared with those of similarly treated normal human leukocytes. Results of the experiment are presented in Figures 2 and 3. Data on Molt-4 cells are presented in Fig. 2. At the end of two hours of exposure, magnetic fields in the presence of holotransferrin significantly decreased the cell count (p< .014, compared to control (non-exposed) cells with holotransferrin). Magnetic field alone and holotransferrin alone also showed a slight but significant decrease in cell counts at hour 2. At 22 hrs. (hour-24) after exposure, cell counts of control, 'control + transferrin' and magnetic field alone had significantly increased (hour-24 versus hour-2, p< 0.014 for all three groups). There was no significant difference among these groups at hour-24. However, cell counts of the 'magnetic field + holotransferrin' treated cells remained low at that time. Figure 2. Effects of magnetic field exposure and incubation with holotransferrin on Molt-4 human leukemia cells. Magnetic field exposure started at time zero and lasted for two hours. Each curve represents data from four experiments. C = sham exposed control, MF = magnetic field, HT = holotransferrin. Data of leukocytes are shown in Fig. 3. At hour-2, there was no significant difference in cell counts among the four treatment groups. Cell counts were significantly decreased at hour-24 (compared to hour-2). This drop-in cell count over time is normal for leukocytes in culture. However, the only difference at hour-24 was found between the 'magnetic field + holotransferrin' and 'control' group (p< .029). There was no significant difference between 'control + holotransferrin' vs 'control' and 'magnetic field alone' vs 'control'. Figure 3. Effects of magnetic field exposure and incubation with holotransferrin on normal human leukocytes. Magnetic field exposure started at time zero and lasted for two hours. Each curve represents data from four experiments. C = sham exposed control, MF = magnetic field, HT = holotransferrin. Data from this experiment indicate that a 60-Hz magnetic field, in the presence of holotransferrin, has a selective toxic effect on human cancer cells, whereas its effect on normal cells is minimal. This supports our hypothesis that cancer cells are more susceptible to magnetic fields after subjected to a treatment that enhances intracellular iron. CONCLUSION The finding that cells count of Molt-4 cells remained stable at 22 hrs. after magnetic field exposure and holotransferrin treatment suggests that the effect of magnetic field is long lasting. The initial decrease in cell count was probably due to cell death because of DNA and other types of  cellular damages triggered by the magnetic field. After that, the remaining cells became stable and stopped proliferating. Free radicals are known to cause cell cycle arrest 22, 23. A recent study also reports a delay in cell cycling in cells exposed to a 50-Hz magnetic field 24. Thus, our data indicate that magnetic fields have selective cytotoxic effect on cancer cells, especially under conditions of high iron availability. This can also be applied to in vivo situation. Since transferrin in the circulation is only 30% saturated with iron, it is very easy to increase the availability of iron to cancer cells by simply feeding an animal with a ferrous salt. This will make cancer cells more susceptible to subsequent magnetic field exposure. Oral administration of an iron salt followed by magnetic field exposure can be used for treatment of cancer. Enhanced free radical activity in cells was observed not with 60-Hz magnetic field, similar effects have been reported with EMF of different frequencies. Thus, EMF of various frequencies could conceivably be used for cancer treatment 25-33. Thus, EMF may be useful for the treatment of cancer, since cancer cells use high amount of iron and are more susceptible to magnetic fields. Depending on the amount of damage, cell death (apoptosis and necrosis) or cell cycle arrest (e.g., due to DNA strand breaks 34, 35) can occur. In both cases, the progress of the tumor is retarded. 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