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Life Extension Foundation
TO: The physician treating _______________(Type
in your name here)
RE: Adjuvant drug therapy for
cancer patients
Dear Doctor:
Our non-profit organization has uncovered
evidence that suggests two prescription drugs may be of significant
value in treating cancer in addition to other
therapies. Here is an excerpt from a research report we published
in 1999:
Cancer
cells often produce large amounts of the enzyme cyclooxygenase-2,
abbreviated COX-2. This enzyme acts as a biological fuel by
causing rapid cell division. An article in the journal Cancer
Research (1999 Mar 1; 59 (5) showed that COX-2 levels
in pancreatic cancer cells are 60 times greater
than in the adjacent normal tissue.
According to a study in the British
Journal of Cancer (1997;75 (8), human prostate
cancer cells sustain their growth by stimulating
themselves to up-regulate their production of COX-2, which
facilitates cell proliferation via several mechanisms. However,
COX-2 inhibition results in a decrease in cell replication
and a reduction in the synthesis of COX-2 and its metabolites,
such as the dangerous prostaglandin E2. The authors of this
study concluded that COX-2 is involved in the maintenance
of growth and homeostasis of human prostate cancer cells.
In the Sept 7, 1999 issue of the
Wall Street Journal, an investigative report revealed
that scientists are actively investigating COX-2 inhibitors
as drugs that would be effective in the prevention and treatment
of many cancers. COX-2 inhibiting drugs, given to small
numbers of patients with colon polyps (pre-cancerous
lesions), caused the completely disappearance of the lesions.
When a group of rats were given a potent carcinogen, there
was a 90% reduction in those, who developed cancer if they
were on COX-2 inhibition therapy. In the few rats that did
develop the tumors while taking COX-2 inhibition therapy,
the tumors were 80% smaller and less numerous than the group
not on COX-2 inhibition therapy. The Wall Street Journal
revealed that a handful of physicians, knowledgeable about
COX-2 and cancer, are prescribing COX-2 inhibitors to their
patients.
In a report published in JAMA
(1999 Oct 6;282(13), a nearly 10 year epidemiological study
showed that COX-2 expression in colorectal cancer
was significantly related to survival. The doctors concluded
that the data add to the growing epidemiological and experimental
evidence that COX-2 may play a role in colorectal tumorigenesis".
The Life Extension Foundation predicts
that COX-2 inhibiting drugs will eventually be approved to
treat cancer, but in the meantime, we are requesting physicians
to look into the matter and consider prescribing a COX-2 inhibiting
drug as an adjuvant cancer therapy. The COX-2 inhibitory drug
of choice will be described later in this article. But first
we want to briefly discuss another prescription drug that
may also benefit cancer patients:
The
protein products of res genes normally participate
in the signal transduction cascade of sending messages from
the cell surface to the nucleus. In addition, the Ras family
of oncoproteins can modulate the transduction of signals of
cancer cell growth, proliferation and metastasis. Mutations
in genes encoding Ras proteins have been intimately associated
with unregulated cell proliferation in a number of different
kinds of cancers, e.g., leukemia, brain tumors, breast and
pancreatic cancers.
The "statin" class of cholesterol-lowering
drugs has been shown to inhibit the activity of RAS oncogenes.
Some of the "statin" drugs that have shown efficacy are
lovastatin, simvastaton, and pravastatin.
There are mechanisms other than inhibition
of RAS oncogene activity that make the "statin" drugs attractive
as adjuvant anti-cancer agents. According to a study in
The Journal of Biological Chemistry (1998, Vo.
273, No.17), prostate cancer cells are
very sensitive to the induction of growth arrest and cell
death by lovastatin. This study showed that lovastatin was
particularly effective to induce prostate cancer cell G1
DNA replicative phase arrest and cell death in human androgen-independent
(hormone-refractory) lines. This study is confirmed by other
studies, which showed that "statin" drugs interfere with
critical growth pathways that enable cancer cells to proliferate
out of control.
A suggested combination therapy
to inhibit COX-2 and provide "statin" regulatory control of
cell hyperproliferation is as follows:
Lodine
XL, an FDA approved arthritis drug, interferes with COX-2
metabolic processes. The maximum dosage for Lodine is 1,000
mg daily. The most convenient dosing schedule for the patient
involves the prescribing of two Lodine XL 500 mg tablets in
a single daily dose. As with any nonsteroidal anti-inflammatory
drug (NSAID), extreme caution and physician supervision is
a required. The most common complaints associated with Lodine
XL use is related to the gastrointestinal tract. Serious GI
toxicity such as perforation, ulceration, and bleeding can
occur in patients treated chronically with NSAID therapy.
Occasionally serious renal and hepatic reactions have been
reported. Lodine XL should not be given to patients, who have
previously shown hypersensitivity to it, or in whom aspirin
or other NSAID's induce asthma, rhinitis, urticaria, or other
allergic reactions. In such cases, even fatal reactions may
be the consequence of NSAID administration.
Nimesulide is a safer COX-2 inhibitor,
however, it is not approved by the FDA. It is available
from Mexican pharmacies, or can be ordered by mail from
European pharmacies. The suggested dose for nimesulide is
two 100 mg tablets a day. The Life Extension Foundation
recommended nimesulide as an adjuvant cancer therapy in
1997. Unfortunately, only a few members could obtain it
because the FDA's seizure of personal use unapproved drug
importation.
The two newest COX-2 inhibitors are
Celebrex and Vioxx, but we suggest that cancer patients
consider other drugs that have a more predictable safety
history. Suppression of COX-1 is associated with the severe
gastrointestinal complications induced by NSAIDs in humans,
whereas selective inhibition of COX-2 reduces this side
effect risk. It seems that it is the COX-2 enzyme that fuels
cancer cell proliferation, so the objective of choosing
the proper NSAID in the treatment of cancer is to find one
that suppresses the minimum percentage of COX-1 and maximum
COX-2. Said differently, it is critical to not overly suppress
COX-1 because the digestive tract needs it to maintain its
structure, whereas it is important to suppress COX-2 because
it is, amongst the other factors, an enzyme that cancer
cells use to multiply.
In a meticulous study published in
the Proceedings of the National Academy of Sciences
(1999;Vol 96), Lodine (etodolac) was compared with other
nonsteroidal antinflammatory (NSAID) drugs, including Celebrex
and Vioxx, to assess its effect on suppressing COX-1 and
COX-2. This study showed that Lodine caused an 80% suppression
of dangerous COX-2, while only inhibiting 25% of the important
COX-1. This study showed that Lodine was slightly more effective
than Celebrex in suppressing COX-2, and slightly less effective
than Vioxx.
A novel treatment approach would
be to combine a COX-2 inhibitor with a "statin" drug such
as Lovastatin. A study published in the journal, Gastroenterology
(1999, Vol.116, No. 4, Supp A369) showed that Lovastatin
augmented by up to five-fold, the cancer cell killing effect
of a drug with COX-2 inhibiting properties (Sulindac). In
this study, three different colon cancer
cell lines were killed (made to undergo programmed cell
death) by depriving them of COX-2. When Lovastatin was added
to the COX-2 inhibitor, the kill rate increased by up to
five fold.
We thus suggest that physicians consider
prescribing a COX-2 inhibitor and a "statin" drug to cancer
patients, in addition to other conventional and integrative
therapies, for a period of three months. Here is a suggested
doing schedule:
- 80 mg a day of Mevacor (lovastatin)
and
- 1000 mg a day of Lodine XL
Blood tests to assess liver and kidney
function are critical in protecting against potential side
effects. To ascertain efficacy, regular serum tumor marker
testing (such as the CEA, PSA, CA 19.9 depending on the typr
of cancer) and imagery scanning is suggested.
Scientific abstracts substantiating
this aggressive adjuvant approach to treating cancer can be
found at the Foundation's Website (www.lef.org). cancer update abstracts
Sincerely,
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