Although cynicism and disillusionment with the failed
“war against cancer” are widespread, I remain very optimistic that we
will triumph over this seemingly invincible killer. Given the disappointing
results and many drawbacks of cytotoxic therapies, it seems clear that
our best hope for a decisive victory against cancer lies in immuno-augmentive
therapies – those that enhance the body’s innate immune response to
As a research immunologist, I have spent 18 years studying
immuno-modulating substances – natural compounds derived from mushrooms,
herbs, fungi, and bacteria, as well as synthetic drugs like Interleukin-2
and interferon. Approximately six years ago, I stumbled across a natural
substance that was so promising, so profoundly superior to everything
else I had ever evaluated, that I abandoned all other projects, including
NIH-funded research, in order to focus entirely on this substance.
The product, MGN-3 (an arabinoxylane compound), is a
polysaccharide composed of the hemicellose-§ extract of rice bran, modified
by enzymes from Shiitake mushrooms. As we have detailed in 7 previously
published studies, involving a total of 72 human subjects, the
efficacy of MGN-3 equals or surpasses the very best immune-modulating
drugs available but, in stark contrast to these, exhibits a complete
lack of toxicity. (Copies of complete research papers and data on MGN-3
can be obtained from Lane Labs at 201-236-9090.)
Much of the data regarding MGN-3 has been previously
published in technical journals and presented at international research
conferences, but the information remains largely unknown to oncologists
and other health professionals dealing directly with the cancer patient.
The aim of this article is to bring this research to the attention of
the practicing clinician, to summarize what is known about the actions
of MGN-3, and explore its present role in the treatment of cancer patients.
Anti-viral activity: In addition to very encouraging
results using MGN-3 in the treatment of malignancies, other research
suggests a promising role for MGN-3 as a therapy for HIV, Hepatitis
C, and other viral infections. MGN-3 has antiviral activity and also
enhances the body’s immune response against virally-infected cells.
In vitro research shows that MGN-3 inhibits replication of the HIV virus
without cytotoxicity in a dose-dependent manner.1 Human studies
suggest that MGN-3 may also be extremely useful in the treatment of
hepatitis C. In these patients liver enzymes return to normal levels
within 1-8 weeks of treatment with MGN-3. The results of our ongoing
clinical research into the antiviral applications of MGN-3 will be the
subject of future reports.
The role of NK cells in the treatment of cancer
Over 150 different types of white blood cells have been
identified and, of these, NK cells are one of the most common, representing
up to 15% of total white blood cells. They are important because, unlike
other white blood cells, they are able to work more or less independently,
not requiring special instructions from the immune system in order to
recognize or attack a foreign cell. For this reason, they are often
considered to be the body’s first line of defense against cancer and
Circulating through the body by way of the blood and
lymph systems, the majority of NK cells present in the body are in a
resting state. NK cells become more active in response to immunoregulatory
proteins called cytokines. Once activated, the NK cells become quite
rapacious in their search-and-destroy activities. Upon encountering
a tumor cell, the activated NK cell attaches to the membrane of the
cancer cell and injects cytoplasmic granules that quickly dissolve (lyse)
the target cell. In less than five minutes, the cancer cell is dead
and the NK moves on to its next victim. A single NK cell can destroy
up to 27 cancer cells before it dies. Although quite small in comparison
to tumor or virus cells, a single NK cell can often bind to two or more
cancer cells at once.
The absolute number of NK cells present in the blood
gives little indication of the efficiency of immune function. Instead,
it is the activity of the NK cells – the avidity with which they recognize
and bind to tumor cells – that is important. Most immuno-modulators,
including MGN-3, do not increase the number or percentage of NK cells,
but instead increase their level of activation. NK cell activity can
be tested by means of a 4-hour radioactive-Chromium release assay. NK
cells are isolated from a blood sample and are incubated in vitro with
a fixed number of chromium-labeled tumor cells. After 4 hours, the percentage
of tumor cells that have been killed by the NK cells is determined,
and this percentage can be used to describe NK cell activity.
In a healthy immuno-competent individual, when NK cell
activity is examined at an effector:target ratio of 100:1, we would
expect to see NK cell activity ranging from 60-75%. However, in cancer
patients, NK cell activity typically ranges from near 0% to 30%. Although
it is not entirely clear whether this is a cause or result of the disease
process, there is evidence suggesting that low NK cell activity may
be a risk factor for malignancy or metastases, as well as a negative
prognostic indicator.2 Therefore, agents that stimulate NK
cell function are being sought as possible cancer therapeutic agents.
Proven human efficacy. We have previously
presented data on 32 cancer patients, with different types of advanced
malignancies.3-5 These patients had received and completed
conventional therapy such as surgery, chemotherapy, radiation or hormonal
therapy prior to participation in the study. The baseline NK cell activity
was found to be low in all patients (10.8-49%). Oral ingestion of MGN-3
at 45 mg/kg/day led to a significant increase in NK cell activity after
only 1-2 weeks. The increase in baseline NK cell activity after two
weeks of administration ranged from 145%-332% in breast cancer patients,
174%-385% in prostate cancer patients, 100% - 240% in leukemia patients,
and 100% -537% in multiple myeloma patients.
Longevity of response: One of the great and constant
frustrations of the immunologist is the phenomenon of hyporesponsiveness.
Science has identified many biological response modifiers (BRMs) that
can substantially increase NK cell activity. However, the effect frequently
attenuates over time, despite continued administration of the immunomodulator.6
One of the most exciting and distinguishing characteristics of MGN-3
is that it appears to maintain its immunomodulatory effect over time.
In long-term follow-up of our patients (up to 5 years), we have observed
that the enhancing effect of MGN-3 on NK cell activity is maintained
indefinitely with continued administration.
Lack of toxicity: Another disappointment regarding
synthetic immune boosters such as IL-2 and interferon is that these
therapies, while variously effective in boosting the immune response
against tumors and viruses, are exceedingly toxic and accompanied by
numerous side effects, the most serious of which is kidney failure.
By contrast, MGN-3 appears to be exceptionally non-toxic and well-tolerated.
In acute oral toxicity trials in rats, MGN-3 was found
to be without toxic effects at dosages up to 36 g/kg. In addition, human
trials using up to 45mg/kg/day of MGN-3 for six months have noted no
abnormalities in blood chemistry or liver enzymes (SGOT and SGPT).7
Moreover, in 4 years of use with hundreds of patients,
we have had no reports of side effects or interactions of any kind.
In fact, our clinical experience suggests that MGN-3 can be safely and
advantageously used in conjunction with conventional treatment, including
chemotherapy and radiation, both to increase the cytotoxic effect of
the therapy and to decrease adverse side effects.
Clinical results: Enhanced immune function is,
however, only a theoretical victory if it does not lead to clinical
improvement. But in fact, the documented increase in NK cell activity
in cancer patients taking MGN-3 has been correlated to dramatic reductions
in corresponding tumor markers and other pathology indicators, and,
most importantly, to long-term stabilization or remission of disease
in the large majority of cases (>85%). The complete clinical data
for a total of 106 patients treated since 1995, including hematology
and pathology reports, as well as incidence of remission and length
of survival, are in the process of being collected and analyzed. It
can be stated, however, that very few have been lost to follow up and
virtually all continue to be in good health.
Mechanisms of action: In addition to direct cytotoxic
activity against tumor cells, activated NK cells also produce a variety
of cytokines, including the interferons, interleukins, tumor necrotic
factors and other growth factors. These cytokines, in turn, have direct
antiviral and anti-cancer activities, as well as further immunomodulatory
effects, such as upregulation of T- and B- cells, and further activation
of NK cells. Our research suggests that MGN-3 works by simulating the
body’s natural production of interferon-y and tumor-necrosis factor-a.8
These chemicals not only have direct anti-tumor activity themselves,
but also directly and indirectly activate NK cell, B-cell and T-cells.
Synthetic cytokines interleukin-2 (IL-2), interferon-gamma
(IFN-8) and tumor necrosis factor-alpha (TNF-a) have all been investigated
as possible cancer-therapeutic agents, and have shown varying success.
The most success has been seen with interleukin-2; however, the dosages
needed to achieve positive results are associated with extreme toxicity.
MGN-3 may offer a novel solution to this dilemma. In
vitro studies suggest that MGN-3 used in combination with low levels
of IL-2 may significantly potentize the effect of IL-2. Figure 1 shows
the effect on NK cell activity of MGN-3 and low doses of IL-2, separately
and in combination. The combined, synergistic effect of the two substances
is significantly greater than either alone. This suggests that the immunomodulatory
effect of low concentrations of IL-2 on NK cell activity could be greatly
augmented with the adjuvant use of MGN-3.9
Conventional medicine has excellent anti-tumor therapies that can significantly
reduce the number of cancer cells. Unfortunately, we have seen that
it is difficult to achieve a 100% kill rate without killing the patient
in the process. At best, we can hope to kill 95-98% of the cancer cells
with these therapies. At this point, a patient may be considered to
be “in remission.” Therapy is discontinued and the patient is closely
monitored. However, as most oncologists are painfully aware, these remissions
are frequently short-lived.
Most cytotoxic therapies are themselves immunosuppressive,
lowering the activity of anti-cancer effector cells. Following chemotherapy
or radiation, the few hardy cancer cells that survive the therapy are
left to replicate largely unchallenged by a damaged immune system. When
the cancer eventually resurfaces, it does so with increased ferocity
and often with increased drug resistance.
In my opinion, the practice of watchful waiting wastes
a golden opportunity to administer the coup de gr‰ce. At the
very early stages of detection, or, in more advanced stages, when the
tumor load has been reduced as far as possible by surgery and/or conservative
cytotoxic therapies, boosting the immune system with biological response
modifiers allows the body to eradicate the remaining cells that have
escaped the chemicals, radiation, or surgeon.
However, MGN-3 cannot and should not replace debulking
therapy, especially in the case of advanced malignancies. In these cases,
even an extremely active immune response is easily overwhelmed by the
huge numbers of cancer cells present. Instead, we recommend that cancer
patients with solid tumors begin MGN-3 immunotherapy concurrent with
or immediately following debulking therapies. With this strategy we
have the best chance of winning what essentially becomes a war of numbers.
In addition, we have found that cancers of the blood,
such as leukemia and multiple myeloma, have been particularly responsive
to MGN-3 therapy, presumably because the activated natural killer cells
have even better access to these cancer cells than to those forming
MGN-3 can also be used to advantage as a preventive
in high-risk populations. Unfortunately, the realities of our high-stress
modern lifestyle, which include increasing exposure to mutagenic environmental
toxins, the numbers of people who might be considered ‘high-risk’ are
increasing. In one particularly disturbing study, researchers found
persistently depressed NK cell activity in 14% of ‘healthy’ young adults.10
As figure 2 illustrates, MGN-3 at 30 mg/kg/day caused a steep (310%)
increase in NK cell activity after only one week. NK cell activity continued
to increase at a slower rate, to a peak activity of 500% over baseline
by week 8 of this particular study, which involved 24 healthy subjects.11
This study also illustrates the interesting dose-dependent nature of
MGN-3. Lower doses (15 mg/kg/day) yield a much slower initial increase,
however all dosage levels achieve maximum activity by week 8. Within
one month of cessation of treatment, NK cell activity returned to baseline.
Clinical experience indicates that once maximum levels of NK cell activity
have been attained, they can in most cases be maintained indefinitely
at the lower dosage level of 15 mg/kg/day.
In the fight against cancer, time is of the essence.
At the very early stages or immediately following debulking therapy,
the numbers of cancer cells are relatively low and more susceptible
to eradication by an aggressive immune system. Therefore, it is important
to increase NK cell activity as quickly as possible in these patients.
For these reasons, we recommend a loading dose of 30-45 mg/kg/day for
cancer patients. After two to three months, the dosage may be reduced
to 15 mg/kg/day. In some individuals, the higher dose needs to be continued
for a longer period of time. Sustained clinical improvement (for example,
normal tumor markers and negative imaging) is an indication that dosages
can safely be reduced to a maintenance level. For general prevention,
15mg/kg/day is appropriate. The product is typically administered in
2-3 divided doses, accompanied by a meal.
Those involved with alternative and holistic medicine
may be tempted to dismiss the introduction of yet another natural “immune
booster” as hype. Many products are promoted to cancer patients on the
strength of “scientific proof” of enhanced immune function. In most
cases, however, the only research has been conducted in test tubes,
or at most, in animals. But as many have noted, most recently apropos
the work of Dr. Judah Folkman, if curing cancer in mice were equivalent
to curing cancer in humans, this dread disease would already be a relic
of a bygone era, rather than accompanying us into the new millennium.
Unlike most natural preparations, MGN-3 offers solid
data collected from human clinical trials. This data offers compelling
evidence that MGN-3 is a powerful biological response modifier that
is free of toxicity or side effects. As such, it has enormous promise
as an immunotherapy in the treatment of cancer and other diseases.
Mamdooh Ghoneum, PhD
Charles D. Drew University of Medicine and Science
Department of Otolaryngology
1621 East 120th Street
Los Angeles, CA 90059 USA
1. Ghoneum, M, Anti-HIV activity in vitro of
MGN-3, an activated Arabinoxylane from rice bran, Biochemical Research
Communications 1998, 243:25-29.
2. Whiteside T, Herberman, R, Human Natural Killer Cells
in Health and Disease, Clinical Immunotherapeutics 1994, 1(1):56-66.
3. Ghoneum, M, Manatalla, G, NK immunomodulatory function
in 27 patients by MGN-3, a modified arabinoxylane from rice bran, Abstract,
87th Annual Meeting of the American Association for Cancer Research,
April, 1996, Washington, DC.
4. Ghoneum, M, Immunomodulatory and Anti-cancer properties
of MGN-3, a modified xylose from rice bran, in 5 patients with breast
cancer, Abstract, American Association for Cancer Research Special Conference:
The Interface between basic and applied research. November, 1995, Baltimore,
5. Ghoneum, M, NK Immunorestoration of Cancer Patients
by MGN-3, a modified arabinoxylane rice bran (study of 32 patients up
to 4 years), Abstract, 6th International Congress on Anti-Aging and
Bio-medical Technologies (American Academy of Anti-aging Medicine),
December, 1998, Las Vegas, NV
6. Sait O, Ruffman R, Development of hyporesponsiveness
of natural killer cells to augmentation of activity after multiple treatments
with biological response modifiers, Cancer Immunol Immunother
7. Ghoneum M, Enhancement of Human Natural Killer Cell
Activity by modified Arabinooxylane from rice bran, Int. J. Immunotherapy
8. Ghoneum M, Effect of MGN-3 on Human natural killer
cell activity and interferon-y synthesis in vitro, FASEB 1996,
9. Manuscript in preparation
10. Levy SM, Persistently low natural killer cell activity
in normal adults, Nat Immun Cell Growth Regul 1989; 8:173-86.
11. Op cit. #7.
Mamdooh Ghoneum, PhD is Associate Professor
and Chief of Research, Department of Otolaryngology, Charles D. Drew
University; Research Associate, Department of Neurobiology, UCLA School