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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The efficacy of chemotherapeutic drugs is hampered by the occurrence of intrinsic and acquired drug resistance. A variety of mechanisms cause drug-resistance. A final common factor, however, is the reduced capacity of drug resistant cells to go into apoptosis following treatment with DNA damaging agents. This is due to defects in apoptotic pathways, for example, changes in p53. The presence of a common factor makes it of interest to search for ways that facilitate the cell to go into apoptosis following exposure to chemotherapeutic drugs. The death receptor ligands tumor necrosis factor (TNF), Fas ligand (FasL) and TNF-related apoptosis-inducing ligand (TRAIL) are able to induce apoptosis by binding to their cell membrane receptors. Recombinant forms of these ligands are capable to potentiate the effect of chemotherapeutic drugs in vitro and in vivo in the animal model. Based on preclinical toxicity and activity profiling, especially TRAIL is considered to be of interest for clinical use. Systemic treatment of non-human primates with TRAIL did not result in acute toxicity. Animal studies demonstrated antitumor activity of TRAIL and potentiation of the chemotherapy efficacy by TRAIL. Phase 1 studies with TRAIL will therefore be initiated. As TRAIL is supposed to be non-toxic, it will be a major challenge to design surrogate end points to find the optimal dose in the clinic. In analogy to the herceptin therapy, it may be helpful to characterize the tumor of the patient. In addition, ex vivo exposure of the tumor may also be useful to select the proper ligand therapy for the individual patient. For optimal effect it is most likely that ligand therapy will be combined with chemotherapy, but even a combination of ligands for patient treatments can be envisioned. It is to be expected that smart, small molecules targeting these death receptors will be designed in order to lower toxicity and increase antitumor activity.
Cancer Metastasis Rev 2001
PMID:Death receptor ligands, in particular TRAIL, to overcome drug resistance. 1183 47

We have constructed a new capsid-modified adenovirus (Ad) vector that specifically replicates in tumor cells and expresses TNF-related apoptosis-inducing ligand (TRAIL). The Ad capsid contains short-shafted fibers derived from Ad serotype 35, which allow for efficient infection of malignant tumor cells, and largely avoids innate toxicity after intravenous application. Replication-dependent homologous recombination in Ad genomes was used to achieve tumor-specific expression of Ad E1a (to mediate viral replication) and TRAIL (to mediate apoptosis and enhance release of progeny virus from infected cells). We demonstrated that our oncolytic vector (Ad5/35.IR-E1A/TRAIL) induced apoptosis in human tumor cell lines derived from colorectal, lung, prostate, and liver cancer. Both in vitro and in vivo tumor models showed efficient intratumoral spread of this vector. In a model for metastatic colon cancer, tail vein infusion of Ad5/35.IR-E1A/TRAIL resulted in elimination of preestablished liver metastases. Intravenous injection of this vector caused a transient elevation of serum glutamic pyruvic transaminase in tumor-bearing mice, which we attributed to factors released from apoptotic tumor cells. Liver histology analyzed at day 14 after virus injection did not show signs of hepatocellular damage. This new oncolytic vector represents a potentially efficient means for gene therapy of metastatic cancer.
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PMID:A tumor-targeted and conditionally replicating oncolytic adenovirus vector expressing TRAIL for treatment of liver metastases. 1509 80

Tumor-cell apoptosis is the basis of many cancer therapies, and tumor-specific T cells are the principal effectors of successful antitumor immunotherapies. Here we show that induction of tumor-cell apoptosis by an agonistic monoclonal antibody to DR5, the apoptosis-inducing receptor for TNF-related apoptosis-inducing ligand (TRAIL), combined with T-cell activation by agonistic monoclonal antibodies to the costimulatory molecules CD40 and CD137, potently and rapidly stimulated tumor-specific effector CD8+ T cells capable of eradicating preestablished tumors. Primary fibrosarcomas initiated with the carcinogen 3-methylcholanthrene (MCA), multiorgan metastases and a primary tumor containing as many as 90% tumor cells resistant to DR5-specific monoclonal antibody were rejected without apparent toxicity or induction of autoimmunity. This combination therapy of three monoclonal antibodies (trimAb) rapidly induced tumor-specific CD8+ T cells producing interferon (IFN)-gamma in the tumor-draining lymph node, consistent with a crucial requirement for CD8+ T cells and IFN-gamma in the tumor rejection process. These results in mice indicate that a rational monoclonal antibody-based therapy that both causes tumor-cell apoptosis through DR5 and activates T cells may be an effective strategy for cancer immunotherapy in humans.
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PMID:Eradication of established tumors in mice by a combination antibody-based therapy. 1668 Jan 49

Bladder cancer mortality varies between the countries; whereas being highest in Western countries, it is lowest in Eastern countries, such as India. Cigarette smoking is one of the major risk factors for bladder cancer in affluent nations, such as United States. Localized early-stage bladder cancer is treated with resection and intravesical cytokine therapy, whereas metastatic cancer is typically treated with various combinations of systemic chemotherapy. Whether curcumin, a yellow curry pigment commonly consumed in countries, such as India, has any role in prevention or treatment of bladder cancer was investigated. We found that curcumin inhibited the proliferation, induced cell cycle arrest, and DNA fragmentation in both IFN-alpha-sensitive (RT4V6) and IFN-alpha-resistant (KU-7) bladder cancer cells. Curcumin also potentiated the apoptotic effects of the chemotherapeutic agents (gemcitabine and paclitaxel) and of cytokines [tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand]. This effect of curcumin was independent of sensitivity and resistance to IFN-alpha, commonly used for treatment of bladder cancer. Whether the effects of curcumin are mediated through modulation of the nuclear factor-kappaB (NF-kappaB) pathway known to mediate antiapoptosis was investigated. Both gemcitabine and TNF activated NF-kappaB in bladder cancer cells and curcumin suppressed this activation. Similarly, cigarette smoke, a major risk factor for bladder cancer, also activated NF-kappaB and curcumin suppressed it. Cigarette smoke-induced expression of the NF-kappaB-regulated gene products cyclooxygenase-2 and vascular endothelial growth factor, linked with proliferation and angiogenesis, respectively, was also down-regulated by curcumin.
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PMID:Curcumin potentiates the apoptotic effects of chemotherapeutic agents and cytokines through down-regulation of nuclear factor-kappaB and nuclear factor-kappaB-regulated gene products in IFN-alpha-sensitive and IFN-alpha-resistant human bladder cancer cells. 1736 95

The survival rate for patients with metastases versus localized cancer is dramatically reduced, with most deaths being associated with the formation of secondary tumors. Circulating cancer cells interact with the endothelial lining of the vasculature via a series of adhesive interactions that facilitate tethering and firm adhesion of cancer cells in the initial steps of metastasis. TNF-related apoptosis-inducing ligand (TRAIL) holds promise as a tumor-specific cancer therapeutic, by inducing a death signal by apoptosis via the caspase pathway. In this study, we exploit this phenomenon to deliver a receptor-mediated apoptosis signal to leukemic cells adhesively rolling along a TRAIL and selectin-bearing surface. Results show that cancer cells exhibit selectin-mediated rolling in capillary flow chambers, and that the rolling velocities can be controlled by varying the selectin and selectin surface density and the applied shear stress. It was determined that a 1 h rolling exposure to a functionalized TRAIL and E-selectin surface was sufficient to kill 30% of captured cells compared to static conditions in which 4 h exposure was necessary to kill 30% of the cells. Thus, we conclude that rolling delivery is more effective than static exposure to a TRAIL immobilized surface. We have also verified that there is no significant effect of TRAIL on hematopoietic stem cells and other normal blood cells. This represents the first demonstration of a novel biomimetic method to capture metastatic cells from circulation and deliver an apoptotic signal.
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PMID:Delivery of apoptotic signal to rolling cancer cells: a novel biomimetic technique using immobilized TRAIL and E-selectin. 1907 14

The members of the tumour necrosis factor (TNF) superfamily of cytokines play important roles in the regulation of various immune-cell functions. Likewise, induction of cell death by apoptosis is indispensable for the normal functioning of the immune system. There are two major pathways of apoptosis induction. The intrinsic, or mitochondrial, pathway is regulated by the activation and interaction of members of the Bcl-2 family. The extrinsic, or death receptor, pathway is triggered by certain TNF family members when they engage their respective cognate receptors on the surface of the target cell. Hence, cell-to-cell-mediated death signals are induced by activation of these death receptor-ligand systems. Besides TNF itself and the CD95 (Fas/APO-1) ligand (FasL/Apo1L), the TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) belongs to the subfamily of ligands that is responsible for extrinsic induction of cell death. Depending on their status of stimulation, TRAIL can be expressed by various cells of the immune system, amongst them natural killer (NK) cells, T cells, natural killer T cells (NKT cells), dendritic cells and macrophages. TRAIL has been implicated in immunosuppressive, immunoregulatory and immune-effector functions. With respect to pathological challenges, TRAIL and its receptors have been shown to play important roles in the immune response to viral infections and in immune surveillance of tumours and metastases. In this review we summarize the current knowledge on the role of TRAIL and its receptors in the immune system and, based on this, we discuss future directions of research into the diverse functions of this fascinating receptor-ligand system.
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PMID:Following TRAIL's path in the immune system. 1947 10

Metastasis may arise years after removal of a primary tumor. The mechanisms allowing latent disseminated cancer cells to survive are unknown. We report that a gene expression signature of Src activation is associated with late-onset bone metastasis in breast cancer. This link is independent of hormone receptor status or breast cancer subtype. In breast cancer cells, Src is dispensable for homing to the bones or lungs but is critical for the survival and outgrowth of these cells in the bone marrow. Src mediates AKT regulation and cancer cell survival responses to CXCL12 and TNF-related apoptosis-inducing ligand (TRAIL), factors that are distinctively expressed in the bone metastasis microenvironment. Breast cancer cells that lodge in the bone marrow succumb in this environment when deprived of Src activity.
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PMID:Latent bone metastasis in breast cancer tied to Src-dependent survival signals. 1957 4

Breast cancer has a propensity to metastasize to bone, thus causing pathological fractures. Bisphosphonates are established drugs in the treatment of bone metastasis that inhibit osteoclast activity and interrupt the vicious cycle of osteoclast-tumor cell interactions. We evaluated the direct effects of zoledronic acid on estrogen receptor (ER)-negative MDA-MB-231 and ER-positive MCF-7 breast cancer cells. While zoledronic acid (100 microM) inhibited MDA-MB-231 cell proliferation after 72 h, and induced apoptosis via activation of caspase-3 and -7, it had only minor effects on MCF-7 cells. In addition, zoledronic acid induced apoptosis by up-regulating TNF-related apoptosis-inducing ligand (TRAIL) in MDA-MB-231 cells (p<0.01), but had no effect on the expression of its decoy receptor osteoprotegerin (OPG). In MCF-7 cells, both cytokines were suppressed by zoledronic acid. In conclusion, zoledronic acid enhanced the TRAIL-to-OPG ratio in TRAIL-sensitive MDA-MB-231 cells, indicating that the TRAIL/OPG cytokine system is a bisphosphonate-responsive target in breast cancer.
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PMID:Zoledronic acid induces apoptosis and changes the TRAIL/OPG ratio in breast cancer cells. 1957 59

Colorectal cancer is the third leading cause of cancer-related mortality in the world; death usually results from uncontrolled metastatic disease. Previously, we developed a novel strategy of TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) in combination with hyperthermia to treat hepatic colorectal metastases. However, previous studies suggest a potential hepatocyte cytotoxicity with TRAIL. Unlike TRAIL, anti-human TRAIL receptor antibody induces apoptosis without hepatocyte toxicity. In this study, we evaluated the anti-tumor efficacy of humanized anti-death receptor 4 (DR4) antibody mapatumumab (Mapa) by comparing it with TRAIL in combination with hyperthermia. TRAIL, which binds to both DR4 and death receptor 5 (DR5), was approximately tenfold more effective than Mapa in inducing apoptosis. However, hyperthermia enhances apoptosis induced by either agent. We observed that the synergistic effect was mediated through elevation of reactive oxygen species, c-Jun N-terminal kinase activation, Bax oligomerization, and translocalization to the mitochondria, loss of mitochondrial membrane potential, release of cytochrome c to cytosol, activation of caspases, and increase in poly(ADP-ribose) polymerase cleavage. We believe that the successful outcome of this study will support the application of Mapa in combination with hyperthermia to colorectal hepatic metastases.
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PMID:Hyperthermia-enhanced TRAIL- and mapatumumab-induced apoptotic death is mediated through mitochondria in human colon cancer cells. 2217 16

Despite evidence that antitumor immunity can be protective against renal cell carcinoma (RCC), few patients respond objectively to immunotherapy and the disease is fatal once metastases develop. We asked to what extent combinatorial immunotherapy with Adenovirus-encoded murine TNF-related apoptosis-inducing ligand (Ad5mTRAIL) plus CpG oligonucleotide, given at the primary tumor site, would prove efficacious against metastatic murine RCC. To quantitate primary renal and metastatic tumor growth in mice, we developed a luciferase-expressing Renca cell line, and monitored tumor burdens via bioluminescent imaging. Orthotopic tumor challenge gave rise to aggressive primary tumors and lung metastases that were detectable by day 7. Intra-renal administration of Ad5mTRAIL+CpG on day 7 led to an influx of effector phenotype CD4 and CD8 T cells into the kidney by day 12 and regression of established primary renal tumors. Intra-renal immunotherapy also led to systemic immune responses characterized by splenomegaly, elevated serum IgG levels, increased CD4 and CD8 T cell infiltration into the lungs, and elimination of metastatic lung tumors. Tumor regression was primarily dependent upon CD8 T cells and resulted in prolonged survival of treated mice. Thus, local administration of Ad5mTRAIL+CpG at the primary tumor site can initiate CD8-dependent systemic immunity that is sufficient to cause regression of metastatic lung tumors. A similar approach may prove beneficial for patients with metastatic RCC.
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PMID:Eradication of metastatic renal cell carcinoma after adenovirus-encoded TNF-related apoptosis-inducing ligand (TRAIL)/CpG immunotherapy. 2231 40


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