Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclooxygenase (COX)-1- and COX-2-derived prostaglandins are implicated in the development and progression of several malignancies. We have recently demonstrated that treatment of ovarian carcinoma cells with endothelin-1 (ET-1) induces expression of both COX-1 and COX-2, which contributes to vascular endothelial growth factor (VEGF) production. In this study, we show that in HEY and OVCA 433 ovarian carcinoma cells, ET-1, through the binding with ETA receptor (ETAR), induces prostaglandin E2 (PGE2) production, as the more represented PG types, and increases the expression of PGE2 receptor type 2 (EP2) and type 4 (EP4). The use of pharmacological EP agonists and antagonists indicates that ET-1 and PGE2 stimulate VEGF production principally through EP2 and EP4 receptors. At the mechanistic level, we prove that the induction of PGE2 and VEGF by ET-1 involves Src-mediated epidermal growth factor receptor transactivation. Finally, we demonstrate that ETAR-mediated activation of PGE2-dependent signaling participates in the regulation of the invasive behavior of ovarian carcinoma cells by activating tumor-associated matrix metalloproteinase. These results implicate EP2 and EP4 receptors in the induction of VEGF expression and cell invasiveness by ET-1 and provide a mechanism by which ETAR/ET-1 can promote and interact with PGE2-dependent machinery to amplify its proangiogenic and invasive phenotype in ovarian carcinoma cells. Pharmacological blockade of ETAR can therefore represent an additional strategy to control PGE2 signaling, which has been associated with ovarian carcinoma progression.
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PMID:Endothelin-1-induced prostaglandin E2-EP2, EP4 signaling regulates vascular endothelial growth factor production and ovarian carcinoma cell invasion. 1534 73

Pancreatic carcinoma is the fifth leading cause of cancer-related deaths in North America and Europe. Major reasons for the high mortality rate include the inability to detect pancreatic cancer at an early stage, extensive local invasion, and early formation of lymphatic and hematogenous metastases. Consequently, novel and effective therapies need to be developed urgently in order to improve the outcome of patients. Since overexpression of the epidermal growth factor receptor (EGFR) in pancreatic tumors correlates with advanced clinical staging, increased tumor size and reduced patient survival, this receptor represents an appropriate target for immunotherapy. We recently generated the recombinant immunotoxin 425(scFv)-ETA' by genetically fusing the anti-EGFR single chain variable fragment 425(scFv) to a truncated version of Pseudomonas aeroginosa exotoxin A (ETA'). The 425(scFv)-ETA' fusion protein was functionally expressed in the periplasmic space of Escherichia coli and was purified using a combination of metal-ion affinity and anion exchange chromatography. The protein showed specific binding to and toxicity against the EGFR-positive, metastatic pancreatic carcinoma cell line L3.6pl, but not to control cell systems. We report the anti-tumor activity of this recombinant immunotoxin in a disseminated human pancreatic cancer nude mouse model. After intravenous (i.v.) injection of L3.6pl cells into immunodeficient nude mice, both single (20 microg on day 1 after challenge) and repeated (10 microg on days 1, 2, 3 and 4 after tumor cell injection) i.v. administration of 425(scFv)-ETA' resulted in a significant reduction in the average number of lung metastases from 56.25 per animal in the control groups to 0.875 per animal (single injection) and 0.286 per animal (repeated injection), respectively, in the experimental groups. In summary, this is the first report showing an in vivo anti-tumor effect caused by the recombinant immunotoxin 425(scFv)-ETA' against disseminated growing metastatic human pancreatic carcinoma cells. Our data suggest that EGFR-specific antibody toxins could be suitable for further clinical investigation in the development of therapies for pancreatic carcinoma.
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PMID:Recombinant anti-EGFR immunotoxin 425(scFv)-ETA' demonstrates anti-tumor activity against disseminated human pancreatic cancer in nude mice. 1564 48

Current treatment of human T-cell leukemia and lymphoma is predominantly limited to conventional cytotoxic therapy and is associated with limited therapeutic response and significant morbidity. Therefore, more potent and leukemia-specific therapies with favorable toxicity profiles are urgently needed. Here, we report on the construction of a novel therapeutic fusion protein, scFvCD7:sTRAIL, designed to induce target antigen-restricted apoptosis in human T-cell tumors. ScFvCD7:sTRAIL consists of the death-inducing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) genetically linked to an scFv antibody fragment specific for the T-cell surface antigen CD7. Treatment with scFvCD7:sTRAIL induced potent CD7-restricted apoptosis in a series of malignant T-cell lines, whereas normal resting leukocytes, activated T cells, and vascular endothelial cells (human umbilical vein endothelial cells) showed no detectable apoptosis. The apoptosis-inducing activity of scFvCD7:sTRAIL was stronger than that of the immunotoxin scFvCD7:ETA. In mixed culture experiments with CD7-positive and CD7-negative tumor cells, scFvCD7:sTRAIL induced very potent bystander apoptosis of CD7-negative tumor cells. In vitro treatment of blood cells freshly derived from T-acute lymphoblastic leukemia patients resulted in marked apoptosis of the malignant T cells that was strongly augmented by vincristin. In conclusion, scFvCD7:sTRAIL is a novel recombinant protein causing restricted apoptosis in human leukemic T cells with low toxicity for normal human blood and endothelial cells.
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PMID:Target cell-restricted apoptosis induction of acute leukemic T cells by a recombinant tumor necrosis factor-related apoptosis-inducing ligand fusion protein with specificity for human CD7. 1583 72

Recent advances in the understanding of prostate cancer biology and its progression to bone metastasis have led to the development of drugs directed against precise molecular alterations in the prostate tumor cell and host cells in the normal bone environment such as osteoclasts and osteoblasts. Endothelins (ETs) and their receptors have emerged as a potential target in prostate cancer bone metastasis. By activating the ETA receptor, ET-1 is pathogenically involved in facilitating several aspects of prostate cancer progression, including proliferation, escape from apoptosis, invasion, and new bone formation, processes that are general to many malignancies. Notwithstanding, there are a number of features specifically driven by the ET axis in prostate cancer, such as creating and perpetuating a unique interaction between the metastatic prostate cancer cell and the bone microenvironment (osteoblast, osteoclast, and stroma) or altering the equilibrium in pain modulation. These features have led to the preferential clinical evaluation of atrasentan (ABT-627) as a biological therapy in prostate carcinoma, first in hormone-refractory prostate cancer. Biological activity of atrasentan in patients with prostate cancer has been shown by the suppression of biochemical markers of prostate cancer progression in bone, and clinical activity is evidenced by a consistent trend demonstrating a delay in time to disease progression when compared with placebo, especially in patients with bone metastases. Further studies of atrasentan and other selective ET-1 antagonists (ZD4054) are ongoing.
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PMID:Targeting bone metastasis in prostate cancer with endothelin receptor antagonists. 1706 17

Primary and metastatic cancers that effect bone are frequently associated with pain. Sensitization of primary afferent C nociceptors innervating tissue near the tumor likely contributes to the chronic pain and hyperalgesia accompanying this condition. This study focused on the role of the endogenous peptide endothelin-1 (ET-1) as a potential peripheral algogen implicated in the process of cancer pain. Electrophysiological response properties, including ongoing activity and responses evoked by heat stimuli, of C nociceptors were recorded in vivo from the tibial nerve in anesthetized control mice and mice exhibiting mechanical hyperalgesia following implantation of fibrosarcoma cells into and around the calcaneus bone. ET-1 (100 microM) injected into the receptive fields of C nociceptors innervating the plantar surface of the hind paw evoked an increase in ongoing activity in both control and tumor-bearing mice. Moreover, the selective ETA receptor antagonist, BQ-123 (3 mM), attenuated tumor-evoked ongoing activity in tumor-bearing mice. Whereas ET-1 produced sensitization of C nociceptors to heat stimuli in control mice, C nociceptors in tumor-bearing mice were sensitized to heat, and their responses were not further increased by ET-1. Importantly, administration of BQ-123 attenuated tumor-evoked sensitization of C nociceptors to heat. We conclude that ET-1 at the tumor site contributes to tumor-evoked excitation and sensitization of C nociceptors through an ETA receptor mediated mechanism.
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PMID:Tumor-evoked sensitization of C nociceptors: a role for endothelin. 1868 11

Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein with NADH oxidase activity that has a vital function in healthy cells but is also an important mediator of caspase-independent programmed cell death in stressed and damaged cells. Here, we generated a truncated AIF derivative (AIF(Delta100)) that lacks the mitochondrial import signal of the protein. Bacterially expressed AIF(Delta100) was functionally active and induced cell death on microinjection into Vero cells accompanied by clear signs of apoptosis. For specific targeting to tumor cells, AIF(Delta100) was genetically fused to the scFv(FRP5) antibody fragment that recognizes the ErbB2 (HER2) receptor tyrosine kinase frequently overexpressed in many human cancers. Recombinant scFv(FRP5)-AIF(Delta100) (5-AIF(Delta100)) protein and a similar scFv(FRP5)-ETA(252-366)-AIF(Delta100) (5-E-AIF(Delta100)) molecule harboring in addition the nontoxic translocation domain of Pseudomonas exotoxin A as an endosome escape function displayed binding to ErbB2-expressing cells followed by protein internalization and accumulation in intracellular vesicles. In the presence of the endosomolytic reagent chloroquine 5-E-AIF(Delta100) but not the similar 5-AIF(Delta100) protein displayed potent cell killing activity, which was strictly dependent on the expression of ErbB2 on the target cell surface. Our results show that recombinant AIF specifically targeted to human cancer cells and delivered into the cytosol has potent cell killing activity, suggesting this molecule as an effector function suitable for the development of humanized immunotoxin-like molecules.
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PMID:Induction of programmed cell death in ErbB2/HER2-expressing cancer cells by targeted delivery of apoptosis-inducing factor. 1950 41

The importance of endothelin-1 (ET-1) in cell growth, migration and stimulation of angiogenesis suggests that ET-1 may play a role in tumor progression. The expression of the ET-1 receptors ETA (ET(A)R) and ETB (ET(B)R) was analyzed by immunohistochemistry in fragments of human lung carcinomas. Samples were obtained from 11 patients with adenocarcinoma (ADK), 12 with squamous cell carcinoma (SCC) and 8 patients with small cell carcinoma (SCLC). Morphologically normal airway areas adjacent to the tumors served as controls. ADK and SCC samples had ET(A)R and ET(B)R levels similar to normal tissues; however, the ET(A)R/ET(B)R ratio was higher in ADK than in SCC. We also observed the presence of endothelin receptors in SCLC, although the ET(A)R levels and the ratio ET(A)R/ET(B)R were lower than in normal tissue and in other carcinomas. In conclusion, both ET(A)R and ET(B)R are present in lung carcinomas but at different levels, according to the histological type of tumor.
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PMID:Expression of endothelin receptor subtypes in bronchial tumors. 2004 7

Rhabdomyosarcoma (RMS) is the most common malignant soft tissue tumor in children and is highly resistant to all forms of treatment currently available once metastasis or relapse has commenced. As it has recently been determined that the acetylcholine receptor (AChR) gamma-subunit, which defines the fetal AChR (fAChR) isoform, is almost exclusively expressed in RMS post partum, we recombinantly fused a single chain variable fragment (scFv) derived from a fully human anti-fAChR Fab-fragment to Pseudomonas exotoxin A to generate an anti-fAChR immunotoxin (scFv35-ETA). While scFv35-ETA had no damaging effect on fAChR-negative control cell lines, it killed human embryonic and alveolar RMS cell lines in vitro and delayed RMS development in a murine transplantation model. These results indicate that scFv35-ETA may be a valuable new therapeutic tool as well as a relevant step towards the development of a fully human immunotoxin directed against RMS. Moreover, as approximately 20% of metastatic malignant melanomas (MMs) display rhabdoid features including the expression of fAChR, the immunotoxin we developed may also prove to be of significant use in the treatment of these more common and most often fatal neoplasms.
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PMID:A human recombinant autoantibody-based immunotoxin specific for the fetal acetylcholine receptor inhibits rhabdomyosarcoma growth in vitro and in a murine transplantation model. 2020 62

Endothelin-1 (ET-1) is a vasoactive peptide but also mitogenic and pro-angiogenic. ET-1 exerts its actions via two G protein-coupled receptors, ETA and ETB. ET-1 is involved in the progression of prostate cancer. Its actions affect the tumor cell proliferation, inhibition of apoptosis, angiogenesis, migration, invasion, metastasis to the bone growth. Inhibitors of receptors of ET-1 in clinical development are the atrasentan and ZD4054. This article reports on controlled, randomized, phase II and III studies on this new therapeutic class.
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PMID:[Inhibitors of the receptor A for endothelin-1]. 2049 52

Target-specific acute myeloid leukemia (AML) immunotherapy requires selective cell-surface antigens on AML blast cells. CD64 is a promising candidate antigen because it is abundantly expressed on monocytoid differentiated AML subtypes. In previous studies, a chemically linked full-length anti-CD64 immunotoxin based on ricin A showed promising results in several animal models, but further development has been hindered by its substantial, dose-limiting off-target effects. We recently constructed the recombinant immunotoxin H22(scFv)-ETA', comprising a truncated Pseudomonas exotoxin A (PE) and a humanized scFv antibody against CD64. This molecule was shown to kill CD64(+) AML-derived tumor cell lines and primary patient-derived AML cells specifically, both in vitro and ex vivo. Here we describe the in vivo efficiency of H22(scFv)-ETA' in the U937/SCID mouse xenograft model for human AML, by providing immunohistochemical evidence for the elimination of human CD64(+) tumor cells in mouse organs. H22(scFv)-ETA' showed potent antitumor activity against myeloid tumor cells and significantly prolonged the overall survival of AML xenograft animals. In conclusion, H22(scFv)-ETA' is efficacious against AML with monocytoid differentiation in vitro and in animal models in vivo, providing the basis for a novel therapeutic strategy for the treatment of AML patients.
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PMID:In vivo efficacy of the recombinant anti-CD64 immunotoxin H22(scFv)-ETA' in a human acute myeloid leukemia xenograft tumor model. 2107 60


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