Familial Lymphoma Risk – A Tale of Two Cytokines?
Michael Williams, MD
Dr. Williams indicated no relevant conflicts of interest.
Rothman N, Skibola CF, Wang SS, et al. Genetic variation in TNF and IL10 and risk of non-Hodgkin lymphoma: a report from the InterLymph Consortium. Lancet Oncol 2006;7:27-38.
A family history of lymphoma or related hematopoietic neoplasm has been reported to increase the risk of non-Hodgkin lymphoma (NHL) among close relatives of affected individuals. Postulating that genetic variants in immune and inflammatory response genes could affect the risk of developing NHL, Rothman and colleagues studied single nucleotide polymorphisms in nine genes relevant to lymphoid development. Genotyping was performed for NHL patient (n=3586) and control (n=4018) DNA samples collected from eight North American and European centers participating in the International Lymphoma Epidemiology Consortium (InterLymph). To maximize study population homogeneity, only white individuals, most of European descent, were included. Six laboratories performed the genotyping analyses, and risk estimates were determined by a random-effects logistic regression model. Positive associations were identified for two of the genes analyzed. The tumor necrosis factor polymorphism TNF-308G→A was associated with increased risk of NHL, especially diffuse large B-cell lymphoma (DLBCL). Similarly, the interleukin 10 polymorphism IL10 575T→A was also associated with increased risk of DLBCL but not follicular or other NHL histologies. Risk of DLBCL was doubled (odds ratio 2.13) in those individuals who were homozygous for the TNF polymorphism and who also carried the IL 10 polymorphism.
Epidemiologic studies have shown a two- to four-fold or greater risk of NHL among first-degree and other close relatives of patients with lymphoma, CLL, or related lymphoid malignancy. TNF and IL 10 are immune cytokines involved in the regulation of inflammatory and T cell responses, apoptosis, and lymphoid growth. Rothman and colleagues suggest that polymorphisms which alter cytokine expression levels or function, and perhaps immune and inflammatory responses, could in turn contribute to lymphomagenesis. These results, while showing the power of such a large-scale analysis across multiple epidemiologic data bases, will nonetheless need to be confirmed and extended in additional studies currently underway by the InterLymph Consortium.
Furthermore, parallel studies will need to be pursued for other ethnic groups and for additional subtypes of lymphoma and related neoplasms. The authors’ findings also provide important clues for investigators pursuing the mechanisms of lymphomagenesis and could lead to new insights regarding the interplay of genetic and environmental or infectious etiologies relevant to lymphoma pathogenesis. Such understanding would be an important step in devising screening and prevention approaches for NHL, now the fifth leading type of cancer in the United States.
Return to Top
Micro-RNA-223: The Stepwise Discovery of a New Player in the Regulatory Pathway of Granulopoiesis
Bob Löwenberg, MD, PhD
Dr. Löwenberg indicated no relevant conflicts of interest.
Fazi F, Rosa A, Fatica A, et al. A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPα regulates human granulopoiesis. Cell 2005;123(5):819-31
The identification of a class of noncoding RNAs of small size (micro-RNAs) that control the translation and stability of specific target messenger RNAs (mRNA) has set the stage for the discovery of new regulatory territories of hematopoiesis. In this paper, a group of Italian investigators describe an elegant series of experiments leading to the detection of a circuit involving a miRNA (i.e., miR-223) with a critical role in granulopoiesis.
miR-223 had previously been shown to be expressed in murine hematopoietic tissues. The investigators show that mRNA of miR-223 is preferentially expressed in neutrophilic cells in marrow and blood, as well as in the blasts from patients with acute promyelocytic leukemia (APL). miR-223 was strongly induced in vitro in APL cells following exposure to retinoic acid (RA). miR-223 also increased in vivo in patients undergoing treatment with RA. Using a variety of cell lines, Fazi et al. sorted out that upregulation of miR-223 was critically dependent on RA responsiveness. Only the RA sensitive cell lines, not the RA resistant variants, showed increases of miR-223 expression. C/EBPα is an established key transcription factor in granulopoiesis, and it is rapidly induced by RA in APL cells (NB4 cells). The investigators identified two putative C/EBPα binding elements in the promoter of miR-223. This suggested that the C/EBPα sites might be involved in induction of miR-223 by RA. Using various reporter constructs, the investigators demonstrated that the increase of miR-223 in response to RA was absolutely dependent on the C/EBPα binding sites. In subsequent chromatin immunoprecipitation experiments, they further showed that C/EBPα is also physically recruited to the miR-223 promotor upon RA treatment. NFI-A is another protein that may bind to C/EBPα binding sites. A NFI-A site was noted in the miR-223 promoter. The physical association of NFI-A with the miR-223 promoter (chromatin IP) was demonstrated, but in this instance in undifferentiated cells, i.e., in the absence of RA. Following treatment with RA, a progressive dissociation of NFI-A from the promoter region was seen. The dissociation in response to RA was opposite to the enhanced association of C/EBPα. These findings clarified the interrelations between the three molecules, MiR-223, C/EBPα, and NFI-A. Apparently, RA activation results in the physical replacement of NFI-A by C/EBPα at the miR-223 promoter. miR-223 was stably expressed in NB4 cells and elicited cellular alterations (granulocytic surface makers, G-CSF- transcripts, granulocytic morphology) in APL cells that indicated enhanced granulocytic cell development. Conversely, knockdown of miR-223 blocked the granulocytic differentiation response to RA entirely. RNA-interference (RNAi) against C/EBPα (siRNA) in APL cells suppressed miR-223 in spite of RA treatment. On the other hand, knockdown of NFI-A enhanced miR-223. These observations demonstrate the impact of high levels of C/EBPα and suppression of NFI-A for activation of miR-223 and subsequent granulocytic differentiation.
Altogether these findings establish an important novel circuitry of regulation of two well-known transcription factors, C/EBPα and NFI-A, and a recently discovered micro-RNA in granulopoiesis (see Figure). It elucidates some of the molecular mechanisms of the therapeutic response in APL to RA. RA first induces the transcription factor CEBPα that will physically displace NFI-A from the promoter of miR-223. The displacement of the NFI-A block by C/EBPα and the binding of C/EBPα to the promoter activates miR223, which will induce cellular granulocytic differentiation.
Return to Top
Tumor Metastasis: Bone Marrow Progenitors Sow the Seeds for Spread
Robert Lowsky, MD, FRCPC
Dr. Lowsky indicated no relevant conflicts of interest.
Kaplan RN, Riba RD, Zacharoulis S, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 2005; 438:820-7
The cellular and molecular mechanisms by which tumor cells metastasize to distant sites remain largely unknown. One line of thought is that inherent molecular differences in the tumor cells and the influence of the surrounding stromal cells determine sites of metastasis. In this paper, Kaplan and colleagues report an alternate explanation and suggest that tumor metastasis results from a well-defined sequence of events: tumor cells mobilize normal bone marrow cells, cause them to migrate to particular areas in distant organs, and change the local milieu to attract and support metastatic tumor spread.
Using established murine models for lung cancer, melanoma, and lymphoma, Kaplan et al. tracked the fate of various populations of normal bone marrow-derived cells during tumor metastasis. Mice were lethally irradiated to destroy host bone marrow cells and transplanted with syngeneic whole bone marrow cells or purified populations of bone marrow cells tagged with a marker to allow tracking. After the tagged marrow cells engrafted (four weeks), the mice were injected with tagged cancer cells, known to metastasize to the lungs. It was reported that bone marrow-derived hematopoietic progenitor cells expressing vascular endothelial growth factor receptor 1 (VEGFR1) home to tumor specific pre-metastatic sites and form cellular clusters before the arrival of tumor cells. Preventing VEGFR1 function with antibodies or by removing VEGFR1+ cells from the marrow inoculum of wild-type mice abrogated the formation of the pre-metastatic clusters and prevented tumor metastasis. Conditioned media obtained from the tumor cells stimulated normal fibroblast cells in the future metastatic sites to produce fibronectin, an extracellular matrix protein that binds very late activation antigen-4 (VLA-4; also know as integrin α4β1) expressed on VEGFR1+ marrow cells that serves to "lock" the bone marrow cells to their niche. Blocking VLA-4 inhibited the binding and establishment of hematopoietic cell clusters in the lungs.
This paper provides evidence for a multi-step pathway of tumor metastasis. Rather than spread to random sites when cancer cells break from a primary tumor and enter the bloodstream, the primary tumor first secretes factors that induce fibronectin production in the pre-metastatic niche. The fibronectin acts as a "recruitment site" for circulating bone marrow progenitors via VLA-4 dependent mechanisms, and, after this pre-metastatic niche is further modified by the hematopoietic progenitor cells, the primary tumor sends cancer cells through the bloodstream to the newly colonized site. The report by Kaplan and colleagues provides substantial material to stimulate modelists and clinical trialists in the field. For the modelist, this work needs to be confirmed, the phenotype of the marrow progenitor cells better defined, and the mediators of recruitment and adherence of normal cells to the pre-metastatic cluster further elucidated. For the trialist, clinical protocols designed to test the efficacy of metastatic blockers need to be developed and the patient population defined (i.e., as adjuvant therapy?). This paper provides a greater understanding of tumor growth and spread and, in this way, we will eventually reap what we sow.
Return to Top
SMAD4 Hemochromatosis
Nancy Andrews, MD, PhD
Dr. Andrews indicated no relevant conflicts of interest.
Wang RH, Li C, Xu X, et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab 2005; 2:399-409.
Hepcidin is a potent peptide hormone that controls body iron distribution by turning off intestinal iron absorption and sequestering iron in tissue macrophages. Genetic hemochromatosis results from too little hepcidin production and consequent increases in dietary iron absorption and serum iron levels (Figure 1). In contrast, most features of the anemia of inflammation can be attributed to increased hepcidin production, induced by inflammatory cytokines (Figure 1). In spite of these clear associations, we understand relatively little about the molecular controls that determine how much hepcidin is made. In this article, Wang and colleagues report a surprising link between hepcidin gene expression and a classical molecular signaling pathway with prominent roles in development. They show that genetic removal of the protein SMAD4 from the liver cells interrupts hepcidin production and causes a hemochromatosis-like disease in mice.
SMAD4 is an essential component of cellular signaling pathways activated by binding of transforming growth factor β(TGFβ) ligands to their cell surface receptors. These pathways control cell proliferation, differentiation, and apoptosis in diverse processes from development to wound healing. Along with classical TGFβs, this signaling paradigm is used by bone morphogenetic proteins (BMPs) and activins. There are multiple TGFβ-like receptors and a host of cytoplasmic, receptor-activated regulatory SMADs (R-SMADs) that transduce their signals. But SMAD4 is unique because it is required by all of these pathways, interacting with R-SMADs to bring them into the nucleus to modulate gene transcription (Figure 2). Remarkably, removing SMAD4 from adult liver cells causes hemochromatosis. The powerful implication of this study is that hepcidin transcription is controlled by TGFβ-type signaling BE we just don't know which TGFβ-like ligands or receptors do the job. Could human SMAD4 mutations be another cause of clinical hemochromatosis? Very unlikely, because loss of SMAD4 function throughout the body is probably not compatible with life. So far, there are few clues as to how TGFβ signaling relates to the three proteins, HFE, TFR2, and hemojuvelin, which are known to be mutated in human hemochromatosis patients. Undoubtedly, new insights will develop over the coming year.
Figure 1
Figure 2
Return to Top
Two Nickels Are Worth a Dime, and Sometimes More: Proteasome Inhibitors for GVHD
Stephen Emerson, MD, PhD
Dr. Emerson indicated no relevant conflicts of interest.
Vodanovic-Jankovic S, Hari P, Jacobs P, et al. NF-kappaB as a target for the prevention of graft-versus-host disease: comparative efficacy of bortezomib and PS-1145. Blood 2006;107:827-34.
In this paper, Vodanovic-Jankovic and colleagues show that the proteasome inhibitors bortezomib and PS-1145 can block the induction of graft-versus-host disease (GVHD) in mice. Although PS-1145 is the less powerful proteasome inhibitor of the two drugs, it is more effective because it has fewer systemic side effects, likely reflecting its narrower specificity of activity. The impact of thalidomide and bortezomib in multiple myeloma has led to a new interest among experimental hematologists in understanding the biology of the 26S proteasome and a surge of curiosity among clinical researchers about the full potential of proteasome inhibitors as drugs for common hematologic disorders. Proteasome inhibitors block the degradation of intracellular "molecular breaks," such as IκBα, which leads to decreased activity of their molecular targets, such as NF-kB. This leads to blunted activation of downstream genes, and so cellular activity is depressed. Although the therapeutic efficacy of proteasome blockade first made its mark in the treatment of multiple myeloma, in theory any pathophysiologic process with overactive cell activation could be potentially targeted.
Since GVHD is fundamentally characterized by donor T cell activation and proliferation, Vodanovic-Jankovic et al. first asked whether bortezomib could block GVHD in mice irradiated and transplanted with bone marrow (BM) cells and lymphocytes from completely unrelated donors, mismatched at the major histocompatibility locus. The answer was "yes, but only partially, only if it is given in a very narrow dose range, and only if given for a short period of time, less than 10 days." Otherwise the mice suffered severe GVHD as well as an unusual colitis, and mortality was actually increased. Rather than throw in the towel on proteasome inhibitors for GVHD, the authors wondered whether the toxicity of bortezomib might be due not to its potent proteasome inhibitory ability, but rather to its diverse other mechanisms of action, such as mitochondrial inhibition. They reasoned that a purer proteasome inhibitor might be safer and more effective, even if one had to give higher doses for longer periods of time. Using the same mismatched mouse BMT model, the authors found that PS-1145, a slightly weaker inhibitor of T cell activation overall but a more selective proteasome inhibitor, was extraordinarily effective at preventing lethal GVHD if given from day 0-10, without the side effects seen with bortezomib. Thus, pulse prophylaxis with PS-1145 is an attractive candidate for the prevention of GVHD in the clinic.
These results teach two broader lessons for pre-clinical and clinical pharmacology in hematology. First, proteasome inhibitors may have a future as anti-immune drugs in many diseases. And second, the best drugs are the ones with the most specific and limited molecular targets, even if one needs to give higher doses of the drug to inhibit its target receptor. After all, broad activities mean more side effects, and, as we all know, two nickels are worth a dime.
Return to Top
Imaging mRNA in Live Cells
Peter Lee, MD
Dr. Lee indicated no relevant conflicts of interest.
Abe H, Kool ET. Flow cytometric detection of specific RNAs in native human cells with quenched autoligating FRET probes. Proc Natl Acad Sci USA 2006;103:263-8.
As many leukemic cells have unique genetic translocations leading to novel mRNA sequences, the ability to detect and image these molecules in live cells could find many useful applications, including rapid diagnosis and monitoring of disease, or purging cell products for transplantation. Efforts in this direction have been hampered by probes with insufficient sensitivity and signal-to-noise ratio to allow detection of moderate-to-low message levels, and need for reliable methods to deliver such probes into live cells. Recent advances in probe design by this paper's authors represent a significant step forward in this direction. Abe and Kool build on recent innovations including molecular beacon (MB) and quenched autoligating (QUAL) probes. The basic premise relies on self-directed reaction of two oligonucleotide probes which bind at adjacent positions on a target nucleic acid. One probe contains a fluorescent dye attached to one end and a quencher (non-fluorescent acceptor dye) attached to the other end. When the fluorescent dye and quencher are present in close proximity in this way, no fluorescence is detected upon excitation. The second probe contains a fluorescent acceptor dye which, upon energy transfer from a donor dye, would fluoresce BE a process called fluorescence resonance energy transfer (FRET). A unique aspect of the authors' design is the additional incorporation of a nucleophilic phosphorothioate group on one probe which could react with a 5'-electrophilic quenching dabsyl group on the other probe, causing displacement of the quencher and ligation of these two probes together (see Figure 1a). Importantly, the displacement of the quencher and the proximity of the donor (on probe one) and fluorescent acceptor dye (on probe two) would then allow fluorescence. Furthermore, since these two probes become covalently linked, the donor and acceptor dyes are locked into a fluorescent configuration, which serves as signal amplification when the probes leave the target and new probes bind. This novel combination both reduces background and increases signal to maximize signal-to-noise ratio. As proof-of-principle, these probes were delivered into live human HL-60 cells via transient permeabilization with streptolysin O (SLO). Using this novel scheme, the authors successfully detected 28S rRNA and GAPDH mRNA, which are abundant RNA species, both by flow cytometry and fluorescence microscopy (see Figures 3b and 5e). As would be expected, signal intensity in this system depends heavily on the abundance of the RNA target, as well as specific target site accessibility within each RNA molecule. As such, the authors were not able to detect S18 mRNA (estimated to be 11,000 copies per cell), but were able to detect JUN D mRNA (estimated at 5000 copies).
While more work is needed to further increase the signal-to-noise ratio to allow detection of moderate-to-low copy number RNA species, such as most translocation products, this study represents exciting proof-of-concept that RNA molecules could be imaged within live cells in a sequence-specific manner. The authors made a number of elegant innovations to reduce background and increase signal. These include the clever combination of a quencher, a nontypical FRET pair system to minimize spectral overlap, and autoligation for signal amplification. Next generation probes for a range of leukemia-related translocations, each with a different color, may be introduced into patients' blood or marrow samples and rapidly analyzed by flow cytometry for diagnosis and quantitation of disease. Leukemic cells could also be readily removed from a cell product for transplantation. For research purposes, such probes could be used to isolate pure populations of leukemic cells for detailed analyses, and to better understand the localization of target RNA molecules within leukemic cells under different conditions using laser confocal microscopy. An array of exciting clinical and research applications in leukemia will be possible as we eagerly await the further refinement of this novel technology.
Return to Top
Alternative Means for Modulating Hematopoietic Stem Cell Recovery – GSK Wears Another Hat
Lilli Petruzzelli, MD, PhD
Dr. Petruzzelli indicated no relevant conflicts of interest.
Trowbridge JJ, Xenocostas A, Moon RT, et al. Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Nat Med 2006;12:89-98.
Glycogen synthase kinase 3, originally described for its effects on inactivating glycogen synthase, has emerged as a regulator of several divergent signaling pathways. More recently, its activity has been implicated in hematopoietic stem cell (HSC) function, and the work presented in this paper focuses on the effect of its activity on hematopoietic stem cell recovery. In a mouse model, the investigators used an ATP binding inhibitor of GSK (CHIR-911) to demonstrate the critical role of this enzyme in HSC function. GFP-labeled donor cells were transferred into sublethally irradiated recipient mice and those in which GSK activity was inhibited demonstrated doubling of the HSC population. The repopulating cells were able to reconstitute multiple hematopoietic cell lineages, and the distribution among the lineages, when compared to untreated mice, was not affected by the inhibitor. Furthermore, when peripheral counts were examined, both the neutrophil and platelet counts increased at two and four weeks after transplant and HSC repopulation was maintained for at least 11 weeks. The GSK-3 inhibitor affects the number of primitive hematopoietic cells by enhancing proliferation rather than affecting apoptosis; this occurs through a direct effect on the HSC rather than modulating the microenvironment. Using this model, the investigators were also able to show that human HSC reconstitution behaved similarly.
GSK-3 inhibitors are rapidly moving toward clinical use in diabetes and Alzheimer's disease. Here, the investigators put forth yet another potential role for this class of drugs and one that may work at several different branch points in bone marrow transplant. The time to engraftment, as measured by the appearance of platelets and neutrophils in the circulating blood, is shortened when mice are treated with this class of inhibitors. Treatment with this drug has the potential not only to overcome situations where collection of HSC may be suboptimal, but also to enable an approach where fewer cells are needed for collection. Whether this strategy has broader application to early progenitors where specific genetic material has been introduced to overcome a genetic defect and whether this can somehow enhance or sustain production of a population of cells will remain to be seen.
The inhibitor of GSK-3 used in these studies was shown to affect a number of pathways that include Hedgehog, Notch, and Wnt. The data presented in the manuscript add some conflicting information to the field in that the inhibitor activates Notch and Wnt signaling in primitive cells, but at least with Wnt, one of its downstream target genes is downregulated. It has been established that disruption of these pathways does not affect HSC function. Thus, although these pathways can be modulated by treatment of hematopoietic precursor cells with an inhibitor of GSK-3, it remains to be established whether its effects are through these pathways in the HSC, whether there are other important pathways to be delineated that are affected by GSK-3, and where in the development of the HSC GSK-3 is acting. Examination of other inhibitors of this enzyme may shed light on what pathways are critical to the observed effect on hematopoietic stem cells. Although the picture is not complete, it remains intriguing to pursue a class of drugs that may yield a tool that not only affects the time to engraftment but also may overcome the need for collection of large numbers of cells and may shorten engraftment so that the risk of morbidity from infection is reduced.
Return to Top
COX-2 Inhibitors – The Consequences of Fooling With Physiology
Kenneth Kaushansky, MD
Dr. Kaushansky indicated no relevant conflicts of interest.
Grosser T, Fries S, Fitzgerald GA. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest 2006;116:4-15.
In this paper, Grosser and colleagues review our understanding of the physiology and pharmacology of the cyclooxygenase (COX)/hydroperoxidase arachadonate modifying systems, the clinical trials that led to FDA approval for the first three COX-2 inhibitors, the five larger clinical trials and post-marketing data that led to the withdrawal of many of the drugs because of cardiovascular complications, and the biological explanation(s) for these events. While a complete understanding of the reasons for the excess morbidity and mortality due to the thrombogenesis, hypertension, and atherogenesis associated with COX-2 inhibitor use is not yet available, the authors carefully discuss the critical physiology, the excitement engendered by the "COX-2 hypothesis," and the unfortunately all-too-brief clinical trials leading to FDA approval of several COX-2 specific inhibitory agents. They then deliver an insightful post-hoc analysis of the pathogenesis of the complications of these agents. Their conclusion is that the cardiovascular risks of COX-2 inhibition are likely due to a confluence of undesirable effects of these agents, and that a thorough understanding of prostaglandin (PG) physiology could/should have allowed prediction of these complications.
Cyclooxygenases (COX) 1 and 2 are highly-related bisfunctional enzymes that convert arachadonic acid into the PG endoperoxide intermediates PGG2 and PGH2, which are then converted to a wide array of biologically active PGs, prostacyclins (PGI), and thromboxanes (TX). The most pathologically relevant activities of these compounds are leukocyte recruitment and activation at sites of noxious stimuli (PGE2 and PGI2), events responsible for the signs and symptoms of inflammation. To combat the pain and tissue damage caused by inflammation, potent COX inhibitors (non-steroidal anti-inflammatory drugs [NSAIDs]) have found widespread use. Because another important physiological function of PGE2 is gastrointestinal mucosal protection, NSAID use is associated with significant toxicity. When it was realized that gastrointestinal mucosal PGE2 is produced primarily by COX-1, specific COX-2 inhibition became an attractive target for the pharmaceutical industry. However, a number of other physiological events are also mediated by PG, PGI, and TX, including enhancement of platelet aggregation and reactivity within the vascular wall by TxA2, maintenance of an anti-thrombotic phenotype in endothelial cells, down modulation of vascular smooth muscle tone, increased renal cortical renin response to baroreceptors, and reduced oxidative injury to cardiac myocytes by PGI2. COX-1 is constitutively expressed in most tissues, while COX2 is induced in inflammatory states. The "COX-2 hypothesis" posits that much or most of the pain and suffering of PG mediated inflammation is due to the induction of COX-2 and that the major complication of NSAIDs, GI intolerance, is due to COX-1 inhibition of PGE2 in the GI tract. Although it is well known that COX inhibition with NSAIDs blocks not only the anti-thrombotic phenotype mediated by PGI2 but also the prothrombotic effects of platelet TxA2, suggesting that COX-2 inhibition would only affect endothelial PGI2 and not platelets (which do not express COX-2) TxA2 (and give rise to a prothrombotic phenotype), it was claimed that the endothelial PG effect was redundant to vascular wall-derived nitric oxide (NO), so that untoward effects should not emerge following COX-2 inhibition. However, careful consideration of the prothrombotic phenotype of PGI2 receptor-null mice suggests that the untoward effects of COX-2 inhibition should have been better anticipated. Moreover, in the clinical realm, Grosser and colleagues critique the data used in support of drug effectiveness and safety. For example, all three safety studies were too small and underpowered to detect a significant influence on health. However, subsequent clinical studies which led to drug withdrawal demonstrated, like in several animal models, that persons who display an enhanced risk of cardiovascular morbidity (e.g., post coronary artery bypass grafting) were also at risk for the development of myocardial infarction and stroke, even in a small clinical trial of short duration. Based on their analysis, Grosser and colleagues conclude that several lessons are readily apparent in carefully considering the in vitro, pre-clinical, and clinical trial data relating to the COX-2 hypothesis; that an interdisciplinary, integrated, and real time approach to drug development is essential to avoid the silos of information that failed to inform clinical development of the COX-2 inhibitors, and that better post-marketing data collection must be established and be continuously monitored with formal clinical decision-making analyses, lest we repeat this example of an unfortunate outcome of fooling with normal physiology.
Return to Top
Return to Table of Contents
|
