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Non-steroidal Anti-inflammatory Drugs in
the Treatment of Prostate Cancer A
Patient’s Perspective Summary As an expansion of the
paper titled "NSAIDS and Prostate Cancer," discussing the general
class of NSAID drugs as they relate to statins with
emphasis on prevention of prostate cancer (see
www.prostate-help.org/cansaid.htm,)
below I would like to present a specific discussion of the use of COX-2
inhibitors as specific NSAID cytotoxic agents when systematically employed
alone, or in conjunction with other cytotoxic
protocols. Numerous trials/reports, in
vitro and in vivo, establish that prostate cancer cells express
significantly stronger COX-2 than in non-malignant cells; thus, express
hypoxia-induced VEGF and play a role in angiogensis
and metastasis; and that COX-2 inhibition suppresses tumor growth by direct
induction of cell death and down regulation of VEGF with decreased angiogensis. (See the writeup on VEGF and
radiation therapy for a patient’s discussion of VEGF and
its role in prostate cancer growth and proliferation.) CONCLUSION: It might be reasonable for all of us with PCa, regardless of the stage or cycle of the disease, to
consult with our medical team for possibly including the regular use of a COX-2
inhibitor NSAID for prevention of disease progress, as well inducing cell death
in existing prostate cancer; possibly in conjunction with other cytotoxic protocols. GLOSSARY angiogenesis - development of new blood vessels. apoptosis - programmed cell death. COX = cyclooxygenase
= prostaglandin endoperoxide synthase--- a.) prostaglandin = any of a
class of physiologically active substances present
in many tissues with effects of vasodilation
(widening of blood
vessels) and vasoconstriction (narrowing of blood vessels). b.) endoperoxide
synthase = a protein complex that catalyzes two steps
in biosynthetics. The two COX enzymes differ
in terms of genetics, biochemistry, and function: (1) COX-1 = constituitive
(exists in the system), functions in the gastrointestinal tract,
renal tract, platelet and microphage functions--thus, inhibition is undesirable as it maintains normal gastric
mucosa and kidney function.
(2) COX-2 = only induced by inflammation;
thus, inhibition is desirable. (2) cytotoxic
- treatment that kills cancer. VEGF - vascular endothelial growth factor
(see VEGF and Radiation Therapy). DISCUSSION The paper NSAIDS and Prostate Cancer
addressed the general class of NSAIDS, of which there are more than
thirty on the market (both over-the-counter and prescribed); and the controlled
versions of NSAIDS are the most widely prescribed class of drugs in the world. (1) The general class of NSAIDS includes ibuprophens (Advil, Motrin, and many over-the-counter pain pills),
as well as specific COX-2 inhibitors, Celebrex and Vioxx. But the
over-the-counter NSAIDS inhibit both COX-1 and 2. The inhibition of COX-1 is not always
desirable (1) as they inhibit gastrointestinal, renal, and hemopoietic (related to the formation of blood cells)
systems. COX-1 is present in most
tissues as the essential housekeeper enzyme.
In 1991 the second COX isoform
was cloned as COX-2 and is inductable (created) only
by inflammation and its inhibition is desirable. Celebrex is
375-fold more selective for COX-2 compared to COX-1 and does not inhibit
COX-1 in contrast to the thirty standard NSAIDS currently on the market; and it
does not inhibit gastrointestinal or renal functions vs. a placebo. (2) Since the discovery that COX-2 is derived
from and represents a gene, and represents a different enzyme system, many new
roles for its gene product have been determined: A.)
Carcinogenesis (production of cancer)--COX-2 is upregulated
in prostate cancer and inhibition is accomplished with Celebrex. B.)
Apoptosis (cell death)-- over-expression of COX-2 is associated with
expression of Bcl-2, a protein that makes cells resistant to apoptosis; and is
associated with decreased expression TGF-beta, an important factor for
transduction signals that inhibit cell growth. Both of these prostate cancer growth
factors (A. and B.) are affected by NSAIDS. (1) The following are specific summary
findings from in vitro and in vivo trials/reports which logically
and factually develop my thesis that it might be advantageous for all of us to
regularly take COX-2 inhibitors on a regular basis, regardless of the status of
our disease: The intensity of COX-2 is significantly
stronger in PCa cells than in non-malignant
prostate cells. (3) Concentrations of COX-2 have been found in PCa that were 3.4 times those in benign tissue. (4) COX-2 is present in 87% of PCa (5) and it is over-expressed in 83% of PCa cells. (6) Significant levels of VEGF are present in PCa, but not in BPH or normal prostate cells in vivo.
(7) Upregulation
of VEGF expression induced by hypoxia (decrease of oxygen in blood) is a
crucial event leading to neovascularization; COX-2 is
induced by hypoxia and plays a role in angiogenesis and metastasis. (8) A selective COX-2 inhibitor suppresses PC-3
cell tumor growth by a combination of direct induction of tumor cell death and
down-regulation of VEGF with decreased angiogenesis. (9) Human PCa cells
generate COX-2 and play an important role in proliferation of PCa cells; and inhibition of COX-2 leads to
inhibition of such proliferation and metastasis, as well as inhibition of
prostate carcinogenesis. (10) Cells over-expressing COX-2 escape death,
have abnormal cell-to-cell interactions, and acquire invasive phenotypes
(character); angiogenesis is key in development of new tumors and
over-expression of COX-2 upregulates angiogenetic factors and promotes angiogenesis; COX-2
inhibitors suppress angiogenesis and tumor growth by inhibiting expression of angiogenetic factors and vascular endothelial cell migration;
COX-2 suppress host immunity against tumors. (11) COX-2 is highly expressed in PCa cells; inhibition thereof reduces tumor micro-vessel
density and prevents hypoxic up-regulation of a potent angiogenetic
factor, VEGF---COX-2 inhibitors serve as effective chemopreventative
and therapeutic agents in PCa (12) COX-2 increases proliferation of PCa and metastasis of cells and is a significant factor in
the progression of PCa; inhibition thereof suppresses
proliferation and induces apoptosis. (13) The regular use of NSAIDS is associated with
a reduced incidence of cancers. (14)
Dempke W et al. summarized the ways COX-2
contributes to cancer cell growth: 1.) inhibition of programmed cell death; 2.)
increased angiogenesis; 3.) increased invasiveness; 4.) modulation of
inflammation and immuno-suppression; and, 5.)
conversion of procarcinogens (inactive substance
foreign to an organism that is converted to carcinogens in the organisms) to
cancer cells; a clear positive correlation between COX-2 expression and cell
death has been established; this might lead to new perspectives that by
controlling the cancer cells, rather than trying to eradicate all affected
cells, may provide a new paradigm in cancer management (emphasis mine).
(15) The potency of celecoxib
(Celebrex) in cell death is significantly higher than
that of other COX-2 inhibitors by inhibiting Bcl-2 as well as a key
anti-apoptotic kinase Akt. (16) COX-2 inhibitors suppress angiogenesis and
tumor growth by inhibiting expression of angiogenetic
factors and vascular endothelial cell growth. (17) COX-2 plays a pivotal role in tumor
viability, growth, and metastasis and COX-2 inhibitors should be used in the
prevention and treatment of a broad range of cancers. (18) The inductable form
of cyclooxygenese, COX-2, has been shown to be
over-expressed in PCa and this places an additional
burden on antioxidative defenses of the cell, which
might contribute to DNA oxidation and the induction of mutations. (19) NOTE:
Goel A et al. had
an interesting finding: curcumin has a significant effect in the
growth HT-29 cells, and specifically inhibits COX-2 expression; thus, has a
safe chemopreventive action for cancer. (20) So, eat lots of turmeric? SO, WHAT DOES ALL
OF THIS MEAN FOR PCa PATIENTS? NSAIDS are the most widely prescribed
drugs on the market and are effective for decreasing pain and
inflammation by the inhibition of cyclooxygenase
(COX). A second form of
COX was discovered in 1991, the gene was cloned, and inhibitors were synthesized. Actions of COX-1 are considered to be
necessary housekeeping present in all tissues and
required for platelet aggregation, renal blood flow, and cytoprotection
in the stomach. Therefore, inhibition of
COX-1 is not desirable as it contributes to the risk of GI ulceration,
bleeding, inhibition of renal blood flow, and inhibition of platelet
aggregation. COX-2 does not exist in the basal state;
it is inducible and up-regulated by inflammation and significantly contributes
to cancer cell growth and metastasis.
Therefore, inhibition thereof is desirable as it yields
anti-inflammatory and analgesic effects and has definite anti-tumor activity,
without all the side effects of COX-1 inhibitors. (1.) Take home message: In my opinion
and based on the above summary of peer-reviewed journal abstracts/reports, all PCa patients can benefit from the regular use of COX-2
inhibitors and data exists that Celebrex is
preferable to Vioxx.
For the past 13 months I have taken 200 mg X 2 = 400 mg of Celebrex/day in conjunction with chemotherapy. February 2002 Copyright © 2002 NOTE : I am not a doctor and cannot render medical advice. I am not a medical researcher. I am not a Celebrex salesman, nor am I in any way associated with any pharmaceutical manufacturer. I am an out-of-work prostate cancer patient and I performed this layman’s analysis for my own decision-making purposes. I make no claim that this analysis is definitive or complete. In conjunction with a medical team, every cancer patient must make their own decision regarding treatment options. I invite any and all contributions/critiques that will improve this layman’s analysis. REFERENCES (1) J. Markenson, MD, FACP, FACR, Cancer Control Journal, Vol. 6, No2., March/April 1999 Suppl.--article
can be seen at
http://www.moffitt.usf.edu/pubs/ccj/v6ns/article5.htm
(2) DR. David Gotleib; COX-1 and 2: The cyclo-oxgenase
systems; revised Oct 2001 at www.arthritis.co.za/cox.html (3) Utiola et al.; Increased expression of COX-2 and nitroic oxide synthase-2 in human prostate cancer; Urol Res 2001 Feb;29(1):23-8. (4) Gupta S et
al.; Over-expression of COX-2 in human PCa; Prostate
2000 Jan;42(1):73-8. (5) Kirschenbaum A et al.; Expression of COX-1 and 2 in the
human prostate; Urology 2000 Oct 1;56(4):671-6. (6) Lee LM et
al.; Expression of COX-2 in prostate adenocarinoma
and BHP; Anticancer Res 2001 Mar-Apr;21(2B):1291-4. (7) Ferrer FA et al.; Vascular endothelial growth factor (VEGF)
expression in human PCa: in situ and in vitro
expression of VEGF by human PCa cells; J Urol 1997 Jun;157(6):2329-33. (8) Liu XH et
al.; Upregulation of VEGF by cobalt chloride-stimulated
hypoxia is mediated by persistent induction of COX-2 in a metastatic
human PCa cell line; Clin
Exp Metastasis 1999;17(8):687-94. (9) Liu XH et
al.; Inhibition of COX-2 suppresses angiogensis and
the growth of PCa in vivo; J Urol
2000 Sep;164(3 Pt 1):820-5. (10) Yoshimura R et al.; Expression of COX-2 in PCa; Cancer 2000 Aug 1;89(3):589-96. (11) Tsuji S et
al.; COX-2 upregulation as a perigenetic
change in carcinogenesis; J Exp Clin ancer Res 2001 Mar;20(1):117-29. (12) Kirschenbaum A et al.; The role of COX-2 in PCa; Urology 2001 Aug;58(2 Suppl 1):127-31. (13) Kamijo T et al.; Induction of apoptosis by COX-2 inhibitors
in PCa cell lines; Int J Urol 2001 Jul;8(7):S35-9. (14) Madaan S et al.; Cytoplasmic
induction and over-expression of COX-2 in hyman PCa: implications for prevention and treatment; BJU Int 2000 Oct;86(6):736-41. (15) Dempke W et al.; COX-2: a novel target for cancer
chemotherapy?; J Cancer Res Clin Oncol 2001 Jul;127(7):411-7. (16) Hsu AL et
al.; The COX-2 inhibitor celecoxib induces apoptosis
by blocking Akt activation in human PCa cells independently of Bcl-2; J Biol
Chem 20000 Apr 14;275(15)11397-403. (17) Sawaoka H et al.; COX inhibitors suppress angiogenesis and
reduce tumor growth in vivo; Lab Invest 1999 Dec;79(12):1469-77. (18) Kalgutkar AS and Zhao Z; Discovery and design of selective
COX-2 inhibitors as non-ulcerogenic,
anti-inflammatory drugs with potential utility as anti-cancer agents; Curr Drug Targets 2001 Mar;2(1):79-106. (19) Nikolic D and van Breeman RB; DNA
oxidation induced by COX-2; Chem Tes
Toxicol 2001 Apr;14(4):351-4. (20) Goel A et al.; Specific inhibition of COX-2 expresion by dietary curcumin in
HT-29 human colon cancer cells. |
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