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Individual oncology
pharmaceutical projects are described in more detail under "Pipeline
Drugs."
With the exception of
a tumor vaccine investigational program, our primary effort is oriented
to investigation of novel botanical extracts that have shown
preliminary efficacy in destroying cancer tumors.
Nanotherapy
Our nanotherapy
investigation has its origins in research surrounding our
investigational drug Xenavex™. In
our current generation of investigational nanoparticle research, we are
attempting to devise a mechanism of
targeted delivery of a nanoparticle that is non-toxic to the patient,
and enters only cancer cells. In in vitro studies, we have
observed that this is destructive to neoplastic cells when externally
triggered with a brief pulse of a small amount of low-frequency (118
kHz) alternating magnetic field (AMF) energy.
This project's
objective is to destroy cancer cells through a process called
"apoptosis." This process works when a cancer cell (but not a normal
cell) ingests a treated magnetite or gold nanoparticle which is later
heated by the AMF. Cancer
cells normally die when heated beyond 109 degrees F. In practical
terms, the approach is to kill cancer cells while sparing adjacent
normal cells. An advantage to killing the cells in serial treatment
cycles rather than ablating the cell on the first pass may be a
phenomena discovered and reported by researchers at Nagoya University
in Japan. In the Nagoya model, researchers killed tumors they induced
in test animals by treating them in three cycles.
There appears to be a relationship between induced immunity in the
Nagoya animals and their time vs. temperaature model.
In their experience,
test animals were able to mount an innate immune response to tumors
that had not been treated with hyperthermia. The result was that large
untreated tumor masses were subsequently destroyed by the animal's own
immune system as a result of CD4+, CD8+ and targeted T-cell activity.
Attempts to later reinfect and regrow these same animals with the
original cancer cell line repeatedly failed on rechallenge, and the
animals were observed mounting an immune response to the cancer cell
line.
Other companies
pursuing nanotherapies are dealing with particles in the one to ten
nanometer
size range. While those companies are using monoclonal antibodies to
attach their particles to cancer cells, we endeavor to attach a
glucose (sugar) to the nanoparticles of magnetite or gold, which enters
into neoplasm
of a cancer cell through pinocytosis. By administering the nanparticles
through an intratumoral injection, we believe we can achieve a
low-toxicity therapy protocol that will have the greatest likelihood of
duplicating the Nagoya small-animal model in a human patient.
Our investigational
drug is actually a nanostructure approximately 50-nanometers in size.
It is designed to resonate and heat-up when excited with an external
alternating magnetic field in the 50 ~ 120 kHz frequency
spectrum. In in
vitro studies, we have experimented with short duration AMF at
power levels of less than 250 watts/cm2 with suitable
particle response. Our present design would allow for treatment of a
targeted tumor at a distance of up to 20 cm from the energy source,
thereby allowing treatment of deep-seated thoracic tumors.
Using a larger coated
delivery vehicle labeled with glucose and other moities, we are able to
take advantage of a phenomena associated with the vasculature in tumor
structure capillaries - large fenestrations. These fenestrations, or
"holes" result in openings some 20-times larger than a health
capiillary. While a normal capillary opening is about 5nm, a tumor's
capillaries have large openings, usually about 100nm.
Our delivery package
cannot pass into normal cells through ordinary fenestrations. It does
pass easily, however, into a tumor structure. The glucose labeling
encourages a cancer cell to take the package inside the cell structure.
In addition to that
schema, we are conducting preliminary research into a polyethylene
glycol coated metal colloid that can be used to carry cytotoxic agents
to a
tumor structure, deliver the cytotoxins, and then function as a laser
ablation target, thereby giving our drug repeated "shots" at a tumor
cell through a multimodal therapy approach.
Xenavex™
Our Xenavex™
Phase II FDA clinical trial program will initially explore the
effectiveness of a nerium oleander L. derivative, oleandrin, as
a potential monotherapy for mesothelioma and non-small cell lung
cancer. In the near term, additional Phase II studies are planned for
the purpose of exploring efficacy of Xenavex™ in treating cancer
of the breast, the prostate, BRO melanoma and pediatric
medulloblastoma.
Xenavex™
(NDC14213-001/01/02/03) is an
ethanolic botanical extract compound of various cardioglycosides
derived from oleander, a toxic plant that has been investigated and
used as a "traditional medicine" for over 1,000 years. Modern oleander
based drugs have previously been made in both China and Russia, where
they are used as cardiology drugs. Our experience thus far is that the
ethanolic extraction process results in higher ratios of the active
moieties than extractions made from other processes.
Pediatric cancers,
such as primitive neuroectodermal tumor (PNET) (medulloblastomas) are
very difficult to treat. Even successful cases result in devastating
side effects to the patient. Xenavex™ crosses the blood/brain
barrier, thereby suggesting its possible use in treating pediatric
brain cancers. We anticipate a separate Phase II program to investigate
the potential of Xenavex™ as a pediatric cancer monotherapy.
We anticipate filing
for a small-scale Phase I/II clinical study in a local population
(northwest Arkansas) of treatment refractory AIDS and Hepatitis C
patients. That project is, however, currently on hold pending funding.
Xenavex™ is a
prescription item for its labeled indications related to cardiovascular
disease. It is not approved for any other indication such as a
proliferative cell disorder. In October, 2004, after extensive
consideration, ShimodaAtlantic changed its pollicy regarding
availability of Xenavex™ to patients seeking access to the drug
under single patient investigational new drug applications (FDA Form
1571). Since then, we have provided access to the drug to qualified
physicians for investigational or "off-label" usage. It is the policy
of the company to discourage off-label use of the drug and to pursue
access via the FDA's single patient IND program.
In late February 2005,
we obtained a NDC (National Drug Code) numerical
assignment for Xenavex™ in 3ml, 10ml and 30ml packages.
Vaccine &
Immune Response Stimulation
Our early-stage
vaccine project is investigating whether the human immune system can be
stimulated to react to, and, destroy tumor cells, based on their unique
protein structure.
European investigators
have reported some success in triggering the body's natural immune
response to cancer cells, by introducing protein fragments similar to
those created by cancer cells, but in much larger quantities than a
tumor normally produces.
Our current research
focuses on cytokeratin-19 fragments and its CYFRA-21 subunits as being
potential immune system stimulators.
The investigation will
seek to determine if by introducing a large amount of the protein
fragments, the immune response is enhanced, thereby triggering the
body’s natural defense against cell disorders.
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