PORTLAND, OregonCyclooxygenase 2 (COX-2) inhibitors
are attracting attention as potential anti-cancer drugs because of evidence of
increased survival in patients with low levels of COX-2. Charles D. Blanke, MD,
FACP, associate professor of medicine, Oregon Health Sciences University in
Portland, reviewed current COX-2 research for participants at the Vanderbilt
"COX-2 is constitutively expressed in only a few cells but
is rapidly upregulated in response to any kind of insult," Dr. Blanke
said. "COX-2 expression is increased in many tumors, including 76% of
colorectal cancers [CRC]. In contrast, COX-2 expression is found in only 8% of
normal colon tissue specimens. Similarly, COX-2 mRNA is increased in 86% of CRC
and in over 40% of colorectal polyps. COX-2 expression in malignant cells also
appears to make them act more aggressively."
Dr. Blanke said that numerous studies have assessed the effects
on the development of colorectal cancer of a wide variety of nonsteroidal
anti-inflammatory drugs (NSAIDS), which inhibit COX-2, and acetaminophen.
"There was a consistent 50% decrease in the incidence of and mortality
from colorectal cancers only in those treated with NSAIDs," he said.
"There is a possible dose-response relationship, and the NSAID must be
taken for a prolonged period, perhaps more than 9 years."
Logical Next Step
Given this background, attempts to combine COX-2 inhibition
with chemotherapy constitute a logical next step. Work by Steinbach et al
showed that treatment with celecoxib (Celebrex) reduced the polyp burden in
patients with familial adenomatous polyposis (FAP), but this benefit occurred
only at the 400 mg BID dose, not at the 100 mg dose.
COX-2 overexpression is significantly associated with
metastasis, and transfection of COX-2 into human Caco-2 cells greatly increases
their metastatic potential. Dr. Blanke said that such transfected cells express
eight times more prostaglandin E than non-COX-2 transfected cells, easily
degrade the extracellular matrix, and are six times more invasive. This
invasiveness could be inhibited in a dose-dependent fashion by sulindac
COX-2 expression has also been implicated in tumor
angiogenesis. Dr. Blanke said that COX-2 is expressed in human colorectal
cancer neovasculature, including liver metastases, and that expression in the
neovasculature is actually greater than in the tumor cells. "Celecoxib
inhibits tumor growth and spread to lungs in nude mice implanted with human
colon cancer cells. The antiangiogenic properties of celecoxib lead to and are
apparently responsible for the inhibition of both growth and metastases,"
Dr. Blanke said.
COX-2 is also thought to play a role in survival of tumor cells
after radiation therapy. Dr. Blanke said that COX-2 inhibitors enhance the
efficacy of radiotherapy in mouse sarcomas. "These tumors are normally
very radioresistant. The effects of COX-2 inhibition and radiation are
synergistic, and treatment increases the actual cure rate. NSAIDs potentiate
tumor radiosensitivity without significantly increasing normal tissue
radioresponse," he said.
COX-2 expression is also associated with risk of colorectal
cancer recurrence. Dr. Blanke said that COX-2 overexpression is significantly
correlated with metastases, and particularly with hematogenous metastasis in
patients with resected large bowel malignancies. "COX-2 overexpression is
independently associated with disease-free survival, and COX-2 inhibition might
be useful in preventing hematogenous metastasis," he said.
Early studies have also found that COX-2 inhibitors can
increase the efficacy of cytotoxic drugs. "Mitomycin-C (Mutamycin) induces
COX-2 in MKN-74 gastric cancer cells, and this induction causes cellular
resistance to apoptosis. Selective COX-2 inhibition enhances
mitomycin-C-induced apoptosis," Dr. Blanke said.
In vitro studies of NSCLC cells treated with irinotecan
(Camptosar), docetaxel (Taxotere), etoposide (VePesid), or cisplatin
(Platinol), with or without the COX-2 inhibitor nimesulide showed that the
COX-2 inhibitor alone induced apoptosis at low concentrations and was
"near-synergistic" for selected anticancer agents, according to Dr.
Blanke. "Clinical trials should incorporate COX-2 inhibition into
treatment regimens," he concluded.
Some Potential Downsides
Adding COX-2 inhibition to chemotherapy has some potential
downsides, however. One is that inhibiting COX-2 might impede recovery of bone
marrow after myelosuppressive treatment, since COX-2 induction is a central
event in the accelerated hematopoiesis that occurs following chemotherapy.
Ongoing combination therapy trials include a phase I study of
celecoxib, plus the Mayo Clinic fluorouracil (5-FU) regimen for colorectal
cancer, and a phase II study of celecoxib plus trastuzumab (Herceptin) for
breast cancer. Studies on the drawing board include a phase I study of
rofecoxib (Vioxx)/5-FU/radiation therapy for rectal cancer, a phase I study of
rofecoxib/5-FU/radiation therapy for pancreatic cancer, and a phase III study
of rofecoxib as adjuvant therapy in colorectal cancer.
"Very preliminary data suggest that COX-2 inhibitors are
safe combined with irinotecan, and very, very preliminary data suggest that the
Saltz regimen plus celecoxib has activity in advanced colorectal cancer,"
Dr. Blanke noted. "COX-2 inhibition may truly shine with chemotherapy in
the adjuvant setting, and future trials might also look at irinotecan plus
COX-2 inhibition and radiation therapy. We suspect that these agents might
decrease the diarrhea associated with irinotecan use." he said.