LIFE EXTENSION FOUNDATION
1100 West Commercial Blvd
Ft. Lauderdale FL 33309
January 2, 2000
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 value in treating
cancer in addition to other therapies. Here is an excerpt
from our latest research report:
Cancer cells often produce large
amounts of COX-2 and use it as a biological fuel to cause
rapid proliferation of cell division. An article in the journal
Cancer Research (1999 Mar 1;
59 (5) shows that COX-2 levels in pancreatic
cancer cells are 60 times greater than adjacent normal
tissue.
According 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. 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. When COX-2 drugs are given to patients with
colon polyps (pre-cancerous
lesions), the lesions completely disappear. 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.
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 study published in JAMA (1999 Oct 6;282(13), a 9.4 year
epidemiological study showed that COX-2 expression in colorectal
cancer was significantly related to survival. The doctors
concluded that "these data add to the growing epidemiological
and experimental evidence that COX-2 may play a role in colorectal
tumorigenesis".
The December 1999 issue of the British
Journal of Cancer showed that a COX-2 inhibiting drug
significantly reduced the metastasis of colon cancer cells
to the lungs of mice. The scientists concluded that COX-2
inhibitors may be a novel class of therapeutic agents to prevent
colon cancer metastasis.
In the January 1, 2000 issue of the Journal
of Immunology, COX-2 inhibition in human lung
cancer cells led to marked lymphocytic infiltration
of the tumor and reduced tumor growth. COX-2 inhibition was
accompanied by a significant decrease in immunosuppressive
cytokine IL-10 and a restoration of the more beneficial IL-12.
The doctors conducting this study concluded that COX-2 inhibition
suppresses tumor activity by restoring the balance of IL-10
and IL-12 in vivo.
- The Life Extension Foundation predicts that
COX-2-inhibiting drugs will eventually be approved to treat
cancer, but in the meantime, we are asking physicians to
consider prescribing a COX-2 inhibiting drug as an adjuvant
cancer therapy. The COX-2 drug of choice will be described
later, but first we want to briefly discuss another
prescription drug that may also benefit cancer patients:
The regulation of cancer cell growth is often governed by a
family of proteins known as RAS oncogenes. The RAS family is
responsible for modulating the regulatory signals that govern
the cancer cell cycle and proliferation. Mutations in genes
encoding RAS proteins have been intimately associated with
unregulated cell proliferation (i.e., cancer).
The "statin" class of cholesterol-lowering drugs have 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 in induces prostate cancer
cell G1 arrest and cell death in human androgen-independent
(hormone-refractory) lines. This study is confirmed by other
studies showing 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 is an arthritis drug approved by the FDA that 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 must. The most common complaints associated
with Lodine XL use relate to the gastrointestinal tract. Serious
GI toxicity such as perforation, ulceration, and bleeding
can occur in patients treated chronically with NSAID therapy.
Serious renal and hepatic reactions have been reported rarely.
Lodine XL should not be given to patients who have previously
shown hypersensitivity to it or in whom aspirin or other NSAIDs
induce asthma, rhinitis, urticaria, or other allergic reactions.
Fatal asthmatic reactions have been reported in such patients
receiving NSAIDs.
Nimesulide is a safer COX-2 inhibitor, but 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, but few members could obtain it because the
FDA was seizing personal use importations of unapproved drugs
like nimesulide back then.
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. A study published
in Nature Medicine (1999;5:1348-1349,
1418-1423) showed that suppression of COX-2 blocks angiogenesis,
a desirable effect for cancer patients. However, this same
study cautions that COX-2-inhibitors may limit the ability
of the stomach and intestinal lining to heal itself. Physicians
should therefore watch out for gastrointestinal complications
for some cancer patients undergoing cytotoxic chemotherapy
regimens.
- The COX-2 enzyme is involved via several different
mechanisms in propagation and metastasis of cancer cells. It
therefore appears highly desirable to suppress excess levels
of COX-2. 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 the maximum percentage of
COX-2. Avoiding excess suppression of COX-1 is critical
because the digestive tract requires COX-1 to maintain its
structure, whereas COX-2 is the enzyme that causes cancer
cells use to proliferate via several different
mechanisms.
- 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 induced 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
in suppressing COX-2.
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 PSA, CEA, CA 19.9) and imagery testing is suggested.
Especial care to guard against gastrointestinal toxicty
should be taken in the patient taking a COX-2-inhibitor and
cytotoxic chemotherapy.
- Scientific abstracts substantiating this aggressive
adjuvant approach to treating cancer can be found at the
Foundation's Website (www.lef.org).
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