Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein kinase C alpha (PKC-alpha) is a cytoplasmic serine threonine kinase involved in regulating cell differentiation and proliferation. Aprinocarsen is an antisense oligonucleotide against PKC-alpha that reduces PKC-alphain human cell lines and inhibits a human glioblastoma tumor cell line in athymic mice. In this phase 2 study, aprinocarsen was administered to patients with recurrent high-grade gliomas by continuous intravenous infusion (2.0 mg/kg/day for 21 days per month). Twenty-one patients entered this trial. Their median age was 46 years (range, 28-68 years), median Karnofsky performance status was 80 (range, 60-100), median tumor volume was 58 cm3 (range, 16-254 cm3), and histology included glioblastoma multiforme (n = 16), anaplastic oligodendroglioma (n = 4), and anaplastic astrocytoma (n = 1). The number of prior chemotherapy regimens included none (n = 3), one (n = 10), and two (n = 8). No tumor responses were observed. Patients on this therapy rapidly developed symptoms of increased intracranial pressure with increased edema, enhancement, and mass effect on neuroimaging. The median time to progression was 36 days, and median survival was 3.4 months. The observed toxicities were mild, reversible, and uncommon (grade 3 thrombocytopenia [n = 3] and grade 4 AST [n = 1]), and no coagulopathy or CNS bleeding resulted from this therapy. Plasma concentrations of aprinocarsen during the infusion exhibited significant interpatient variability (mean = 1.06 mug/ml; range, 0.34-6.08 mug/ml). This is the first study to use an antisense oligonucleotide or a specific PKC-alpha inhibitor in patients with high-grade gliomas. No clinical benefit was seen. The rapid deterioration seen in these patients could result from tumor growth or an effect of aprinocarsen on bloodbrain barrier integrity.
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PMID:Efficacy and toxicity of the antisense oligonucleotide aprinocarsen directed against protein kinase C-alpha delivered as a 21-day continuous intravenous infusion in patients with recurrent high-grade astrocytomas. 1570 Dec 80

Integrin-linked kinase (ILK) couples integrins and growth factors to downstream signaling pathways involving phosphatidylinositol 3-kinase, protein kinase B/Akt (PKB/Akt), and glycogen synthase kinase-3beta. The anticancer effects of ILK inhibitor QLT0254 were tested in an orthotopic primary xenograft model of pancreatic cancer. The pharmacodynamic effects of a single dose of QLT0254 on the phosphorylation of PKB/Akt were measured by immunohistochemistry and Western blotting, and showed a decrease of >80% after 2 hours, followed by recovery over 24 hours, consistent with the pharmacokinetic profile of this compound in mice. There was also suppression in phosphorylated PKB Thr(308), forkhead in rhabdomyosarcoma, S6K1, S6, 4E-BP1, and signal transducers and activators of transcription 3 Tyr(705) and Ser(727) protein levels with ILK inhibition by QLT0254. However, we did not observe an effect on phosphoinositide-dependent kinase 1, glycogen synthase kinase-3beta, and extracellular signal-regulated kinase phosphorylation or on total PKB and ILK protein expression levels with QLT0254 treatment. In tumor growth inhibition experiments, daily treatment with QLT0254 for 3 weeks was well tolerated and produced significant tumor growth inhibition compared with vehicle control (P = 0.001). When a single dose of QLT0254 and chemotherapy agent gemcitabine was administered, there was a significant 5.4-fold increase in acute apoptosis in the combination therapy group compared with vehicle controls (P = 0.002). However, the acute effects of QLT0254 on proliferation were not statistically significant. These results show in vivo evidence that ILK plays a prominent role in oncogenic phosphatidylinositol 3-kinase/PKB signaling in vivo with major impact on the mammalian target of rapamycin, signal transducers and activators of transcription 3, and forkhead in rhadomyosarcoma signaling pathways, suggesting that ILK inhibitors might show activity in pancreatic cancer patients.
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PMID:Inhibition of integrin-linked kinase by a selective small molecule inhibitor, QLT0254, inhibits the PI3K/PKB/mTOR, Stat3, and FKHR pathways and tumor growth, and enhances gemcitabine-induced apoptosis in human orthotopic primary pancreatic cancer xenografts. 1573 38

The heptapeptide 1, NAc-Gly-Val-DIle-Thr-Arg-Ile-ArgNHEt, a structurally modified fragment derived from the second type-1 repeat of thrombospondin-1 (TSP-1), is known to possess antiangiogenic activity. However, therapeutic utility could not be demonstrated because this peptide has a very short half-life in rodents. To optimize the PD/PK profile of 1, we initiated a systematic SAR study. The initial structural modifications were performed at positions 5 and 7 of peptide 1 and at the N- and C-termini. Out of several hundred peptides synthesized, the nonapeptide 5 (ABT-526) emerged as a promising lead. ABT-526 inhibited VEGF-induced HMVEC cell migration and tube formation in the nanomolar range and increased apoptosis of HUAEC cells. ABT-526 showed acceptable PK in rodents, dog, and monkey. ABT-526, when incorporated in an angiogenic pellet implanted in the rat cornea at 10 microM, reduced neovascularization by 92%. Substitution of DalloIle in place of DIle in ABT-526 provided nonapeptide 6 (ABT-510), which was 30-fold less active than ABT-526 in the EC migration but 20-fold more active in the tube formation assay. In comparison to ABT-526, ABT-510 has increased water solubility and slower clearance in dog and monkey. Radiolabeled ABT-510 demonstrated saturable binding to HMVEC cells at 0.02-20 nM concentrations and was displaceable by TSP-1. ABT-510 and ABT-526 were shown to significantly increase apoptosis of HUAEC cells. ABT-510 was effective in blocking neovascularization in the mouse Matrigel plug model and inhibited tumor growth in the mouse Lewis lung carcinoma model. Previous studies had shown that ABT-510 was effective in inhibiting the outgrowth of murine melanoma metastases in syngeneic mice and in blocking the growth of human bladder carcinoma implanted in nude mice. It had been also shown that ABT-510 could regress tumor lesions in pet dogs or cause unexpected stabilization of the disease in advanced canine cancer. ABT-526 and ABT-510 are the first compounds in the class of potent inhibitors of angiogenesis that mimic the antiangiogenic function of TSP-1. ABT-510 is currently in phase II clinical studies.
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PMID:Thrombospondin-1 mimetic peptide inhibitors of angiogenesis and tumor growth: design, synthesis, and optimization of pharmacokinetics and biological activities. 1582 22

This paper reviews recent progress in the design and evaluation of MEK inhibitors as cancer therapeutics. Activation of the Ras / Raf / MEK / MAP kinase pathway has been implicated in uncontrolled cell proliferation and tumor growth. Mutated, oncogenic forms of Ras are found in 50% of colon, 90% of pancreatic and 30% of lung cancers. Recently, B-Raf mutations have been identified in more than 60% of malignant melanomas and from 40-70% of papillary thyroid cancers. MEK, a dual specificity kinase, is a key player in this pathway; it is downstream of both Ras and Raf and activates ERK1/2 through phosphorylation of key tyrosine and threonine residues. Representative examples of both ATP competitive and non-competitive inhibitors as well as natural product based inhibitors will be discussed.
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PMID:Progress towards therapeutic small molecule MEK inhibitors for use in cancer therapy. 1585 48

Recent analyses indicate that the expression of the Pim-1 protein kinase is elevated in biopsies of prostate tumors. To identify the mechanism by which the Pim kinases may affect the growth of prostate tumors, we expressed Pim-1, Pim-2, or a kinase-dead Pim-2 protein in human PC3 prostate cancer cells. On implantation of the transfectants in nude mice, the growth of the cells expressing Pim-1 or Pim-2 was significantly faster than the growth of the control cells transfected with the neomycin-resistant gene or the kinase-dead Pim-2 protein. When grown in medium, the doubling time of the Pim-1 and Pim-2 transfectants was faster (0.75 days) than that of the control cells (1.28 days). We, therefore, examined the ability of Pim to control the phosphorylation of proteins that regulate protein synthesis. On growth factor starvation or rapamycin treatment, the Pim-1 and Pim-2 transfectants maintained their ability to phosphorylate 4E-BP1 and S6 kinase, although this phosphorylation did not occur in the control-transfected PC3 cells. We have found that the cellular levels of c-Myc were elevated in the Pim-1 and Pim-2 transfectants under these conditions. The Pim-1 and Pim-2 transfectants have lower levels of serine/threonine protein phosphatase 2A (PP2A) activity and the alpha- and beta-subunit B56gamma of the PP2A phosphatase do not coimmunoprecipitate in these cells. Thus, the effects of Pim on PP2A activity may mediate the levels of c-Myc and the phosphorylation of proteins needed for increased protein synthesis. Both of these changes could have a significant impact on tumor growth.
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PMID:Pim family kinases enhance tumor growth of prostate cancer cells. 1612 40

Tumor metastasis is the major cause of morbidity and mortality in patients with breast cancer. It is critical to identify metastasis enabling genes and understand how they are responsible for inducing specific aspects of the metastatic phenotype to allow for improved clinical detection and management. Protein kinase C epsilon (PKC epsilon), a member of a family of serine/threonine protein kinases, is a transforming oncogene that has been reported to be involved in cell invasion and motility. In this study, we investigated the role of PKC epsilon in breast cancer development and progression. High-density tissue microarray analysis showed that PKC epsilon protein was detected in 73.6% (106 of 144) of primary tumors from invasive ductal breast cancer patients. Increasing PKC epsilon staining intensity was associated with high histologic grade (P = 0.0206), positive Her2/neu receptor status (P = 0.0419), and negative estrogen (P = 0.0026) and progesterone receptor status (P = 0.0008). Kaplan-Meier analyses showed that PKC epsilon was significantly associated with poorer disease-free and overall survival (log-rank, P = 0.0478 and P = 0.0414, respectively). RNA interference of PKC epsilon in MDA-MB231 cells, an aggressive breast cancer cell line with elevated PKC epsilon levels, resulted in a cell phenotype that was significantly less proliferative, invasive, and motile than the parental or the control RNA interference transfectants. Moreover, in vivo tumor growth of small interfering RNA-PKC epsilon MDA-MB231 clones was retarded by a striking 87% (P < 0.05) and incidence of lung metastases was inhibited by 83% (P < 0.02). PKC epsilon-deficient clones were found to have lower RhoC GTPase protein levels and activation. Taken together, these results revealed that PKC epsilon plays a critical and causative role in promoting an aggressive metastatic breast cancer phenotype and as a target for anticancer therapy.
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PMID:Protein kinase C epsilon is a predictive biomarker of aggressive breast cancer and a validated target for RNA interference anticancer therapy. 1616 14

Proteases are essential enzymes which regulate physiological processes such as inflammation, infection, fertilization, allergic reactions, cell growth and death, blood clotting, tumor growth and bone remodeling. The protease family consists of six major classes of enzymes which are aspartic-, serine-, cysteine-, threonine-, glutamic-, and metallo-proteases, all which are implicated in disease propagation. Therefore, protease inhibitors have been of great interest as possible targets for the development of novel therapies. Although, many protease inhibitors have followed a structural design based on either a peptidic or peptidomimetic backbone, other chemical scaffolds have recently emerged. Utilizing structure- and fragment-based design guided by X-ray crystallography, NMR spectroscopy, computational and/or extended tethering approaches, potential non-peptidic therapeutic agents could be identified. In this review, we will report on the recent developments of nonpeptidic cysteine- and metallo- protease inhibitors, focusing on their design by using such strategies.
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PMID:Structure- and fragment-based approaches to protease inhibition. 1661 Nov 45

ABT-869 is a structurally novel, receptor tyrosine kinase (RTK) inhibitor that is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor families (e.g., KDR IC50 = 4 nmol/L) but has much less activity (IC50s > 1 micromol/L) against unrelated RTKs, soluble tyrosine kinases, or serine/threonine kinases. The inhibition profile of ABT-869 is evident in cellular assays of RTK phosphorylation (IC50 = 2, 4, and 7 nmol/L for PDGFR-beta, KDR, and CSF-1R, respectively) and VEGF-stimulated proliferation (IC50 = 0.2 nmol/L for human endothelial cells). ABT-869 is not a general antiproliferative agent because, in most cancer cells, >1,000-fold higher concentrations of ABT-869 are required for inhibition of proliferation. However, ABT-869 exhibits potent antiproliferative and apoptotic effects on cancer cells whose proliferation is dependent on mutant kinases, such as FLT3. In vivo ABT-869 is effective orally in the mechanism-based murine models of VEGF-induced uterine edema (ED50 = 0.5 mg/kg) and corneal angiogenesis (>50% inhibition, 15 mg/kg). In tumor growth studies, ABT-869 exhibits efficacy in human fibrosarcoma and breast, colon, and small cell lung carcinoma xenograft models (ED50 = 1.5-5 mg/kg, twice daily) and is also effective (>50% inhibition) in orthotopic breast and glioma models. Reduction in tumor size and tumor regression was observed in epidermoid carcinoma and leukemia xenograft models, respectively. In combination, ABT-869 produced at least additive effects when given with cytotoxic therapies. Based on pharmacokinetic analysis from tumor growth studies, efficacy correlated more strongly with time over a threshold value (cellular KDR IC50 corrected for plasma protein binding = 0.08 microg/mL, >or=7 hours) than with plasma area under the curve or Cmax. These results support clinical assessment of ABT-869 as a therapeutic agent for cancer.
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PMID:Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. 1664 71

Protein kinase C (PKC) family comprises more than 12 serine-/threonine-specific isoenzymes. PKC isoenzymes play a complex role in the transduction of signal from tyrosine kinase receptor modulating proliferation, cell cycle, apoptosis, invasion, differentiation, and senescence in both cancer cells and endothelial cells. Thereby, inhibition and/or activation of specific PKCs is thought to control tumor growth by interacting directly with cancer cells and indirectly by blocking tumor angiogenesis. Furthermore, PKCs are known to modulate multi-drug resistance, providing a rational for the combination of PKCs modulators with classical cytotoxic drugs. During the past few years, preclinical and clinical data with first-generation PKC inhibitors/activators provided insight that PKCs may indeed represent attractive targets for the discovery of small molecules with new anticancer properties. In this review, we will provide an overview on the current understanding of PKC participation in chemotherapeutic resistance, the possible implications in cancer treatment, and the potential of most recent PKC inhibitors in molecular cancer therapeutics.
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PMID:Preclinical and clinical development of novel agents that target the protein kinase C family. 1689 Aug 1

Transforming growth factor-beta (TGF-beta) is a secreted polypeptide that signals via receptor serine/threonine kinases and intracellular Smad effectors. TGF-beta inhibits proliferation and induces apoptosis in various cell types, and accumulation of loss-of-function mutations in the TGF-beta receptor or Smad genes classify the pathway as a tumor suppressor in humans. In addition, various oncogenic pathways directly inactivate the TGF-beta receptor-Smad pathway, thus favoring tumor growth. On the other hand, all human tumors overproduce TGF-beta whose autocrine and paracrine actions promote tumor cell invasiveness and metastasis. Accordingly, TGF-beta induces epithelial-mesenchymal transition, a differentiation switch that is required for transitory invasiveness of carcinoma cells. Tumor-derived TGF-beta acting on stromal fibroblasts remodels the tumor matrix and induces expression of mitogenic signals towards the carcinoma cells, and upon acting on endothelial cells and pericytes, TGF-beta regulates angiogenesis. Finally, TGF-beta suppresses proliferation and differentiation of lymphocytes including cytolytic T cells, natural killer cells and macrophages, thus preventing immune surveillance of the developing tumor. Current clinical approaches aim at establishing novel cancer drugs whose mechanisms target the TGF-beta pathway. In conclusion, TGF-beta signaling is intimately implicated in tumor development and contributes to all cardinal features of tumor cell biology.
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PMID:Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. 1690 31


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