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Celebrex, Vioxx
COX-2 Inhibitors May Stimulate Immune System to
Fight Cancer
Oct. 22, 2004 Vioxx, Celebrex and the other COX-2
inhibitors, which have mostly received bad news recently, are being
touted in a new study for their ability to boost the immune system to
fight brain and maybe other forms of cancer.
This finding suggest that medications attacking the
an enzyme in many tumors, including malignant brain tumors, may boost
the immune system's ability to recognize and target these tumors.
Blocking the enzyme's expression in laboratory tests interrupted the
series of cell-level events and led to the development of cells capable
of launching an immune response.
Results of the study on cyclooxygenase-2 (COX-2)
appear in the October 1 issue of the Journal of Immunology. While COX-2
inhibition has been considered an attractive anti-cancer strategy,
results of earlier studies on a variety of tumors have been
inconsistent, puzzling and sometimes seemingly contradictory.
Furthermore, because COX-2 is a complex enzyme that
is affected by a variety of conditions and biochemical substances, many
of its mechanisms and effects are not clearly understood.
COX-2 inhibitors, like Celebrex and Vioxx have
primarily been used to fight arthritis pain by blocking the
inflammation-causing COX-2 enzyme. Vioxx was recently withdrawn from the
market due to concerns it may cause heart and stroke problems.
Researchers at Cedars-Sinai's Maxine Dunitz
Neurosurgical Institute wrote the report describing the
immune-disruptive.
In the article, Institute researchers describe
COX-2's detrimental influence on dendritic cells the immune system
cells responsible for detecting foreign matter and eliciting an immune
response. Dendritic cells, highly specialized "antigen-presenting
cells," pick up debris left behind when cells die. When they take up and
process debris from tumor cells, they should present these antigens to
cytotoxic T lymphocytes (CTL), cancer killing cells, instructing them to
attack the tumor cells.
If functioning properly, the dendritic cells would
induce the production of a protein called interleukin-12 (IL-12), which
prompts the immune system's CD4+ T lymphocytes to launch a T helper type
1 (Th1) response attack mode. Lymphocytes would swarm to the source of
the antigens and attack the tumor cells.
Instead, the researchers found, COX-2 and a
hormone-like substance it synthesizes, prostaglandin E-2 (PGE-2), set in
motion a series of interactions that changed the message of the
dendritic cells and the function of the T cells. Instead of inducing the
production of IL-12, the dendritic cells prompted the overproduction of
IL-10 and transforming growth factor-beta (TGF-โ). Both of these
substances spur "regulatory" responses making lymphocytes "tolerant"
of the antigens and suppressing an attack.
According to John S. Yu, MD, the study's principal
investigator, "COX-2 expression by tumors may make them invisible to the
immune system. By using COX-2 inhibitors, these tumors may become more
detectable and therefore more vulnerable to destruction by the immune
system. We plan to exploit these findings by adding COX-2 inhibitors
like Celebrexฎ (celecoxib) to our clinical trials for brain tumors."
"We have recognized for some time that defects in
the process of antigen presentation were involved in the impaired
cellular immunity seen in patients with brain tumor," said Keith L.
Black, MD, director of the Institute, Cedars-Sinai's Division of
Neurosurgery and the Comprehensive Brain Tumor Program. "Our findings
indicate that COX-2 and PGE-2 expressed in brain tumor may be key
factors in the down-regulation of tumor-killing immunity at the level of
antigen presentation. Immature dendritic cells exposed to brain tumors
that overexpress COX-2 become mature dendritic cells that produce
significant levels of IL-10 and decreased levels of IL-12. This leads to
suppression of cellular immune responses at the site of the tumor and
systemically."
The study was conducted using two established brain
tumor cell lines and tumor cells taken from a patient at Cedars-Sinai.
"One of the intriguing findings was that helper
cells isolated from the bloodstream of a glioblastoma patient
predominantly displayed a regulatory response against the patient's
brain tumor cells. This points to the existence of an underlying
regulatory bias in the circulating T cells of patients with malignant
brain tumor," said Dr. Yu, co-director of the Comprehensive Brain Tumor
Program.
"Previous studies and experience have suggested
that CD4+ T cells taken from brain tumor patients have markedly impaired
tumoricidal responses," he added. "We now propose that this is secondary
to a skew in antigen presentation away from a tumoricidal Th response
and toward a regulatory response, resulting from the effects of PGE-2 by
COX-2 on dendritic cells exposed to these tumors."
By blocking the COX-2 expression in brain tumors
before dendritic uptake, the tumor-killing Th1 response can be restored,
the research team found.
"We suggest that high levels of dendritic cell
IL-12 secretion and a Th1 response can be induced following COX-2
inhibition," Dr Black said. "These findings support the use of COX-2
inhibitors as a means of promoting Th1-directed tumor antigen
presentation in clinical trials of dendritic cell-based vaccines."
Over the past several years, Institute researchers
have developed and fine-tuned an experimental vaccine therapy against
deadly brain tumors that hinges on culturing a patient's brain tumor
cells with his or her own dendritic cells. When these new dendritic
cells are reintroduced into the body, they are better able to recognize
and present brain tumor antigens. As new discoveries are made about the
immune system and the genetic makeup, cellular components, and
biochemical mechanisms of tumors, additional potential therapies are
devised and integrated to boost immune response and capitalize on
vulnerabilities of cancer cells.
Copyright: SeniorJournal.com |
