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At least 559 records · Page 31Linked to original sources
PubMed2004

The PML-RARalpha fusion protein and targeted therapy for acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is an unique subtype of acute myeloid leukemia typically carrying a specific reciprocal chromosome translocation t(15;17) leading to the expression of a leukemia-generating fusion protein, PML-RARalpha. Nearly all de novo APL patients undergo disease remission when treated with all trans retinoic acid (ATRA) plus chemotherapy. APL patients that relapse following this type of therapy respond to As2O3 with disease remission once again. The mechanism of action of both ATRA and As2O3 appears to be by inducing granulocytic differentiation and this cellular differentiation seems to depend on PML-RARalpha proteolysis. ATRA treatment results in partial cleavage and complete degradation of PML-RARalpha protein in differentiation sensitive, but not in differentiation resistant APL cells. As2O3 treatment results in only complete degradation of PML-RARalpha protein in both ATRA-sensitive and -resistant APL cells. PML-RARalpha appears to cause leukemia by acting as a transcriptional repressor of RARalpha target genes and by inhibiting activity of transcription factor C/EBPalpha. Therefore, PML-RARalpha proteolysis induced by ATRA and As2O3 may play an important role in overcoming the repressive activity of PML-RARalpha and allowing cellular differentiation to proceed. This review will focus on the status of the PML-RARalpha fusion protein and its relationship to gene and differentiation induction as well as differentiation resistance of APL cells.

Arsenic Trioxide↗
PubMed2004

Targeted therapies in oncology: in the crosshairs or at the crossroads?

Normal cellular behavior depends on functional integration of extracellular stimuli with intracellular signal transduction pathways. Coupling cell surface message reception to nuclear gene expression is no longer a linear model constructed with molecular components acting merely as conduits to relay signals that cascade toward the nucleus. What has emerged instead is a highly integrated circuit comprised of numerous molecular components harmoniously programmed to communicate a multitude of internal signals that controls cellular response. Despite increasing understanding of cell signaling, mutinous elements embedded in these pathways have defied complete resolution. Research indicates that propagation of signals emanating from the extracellular environment to the cell nucleus follows a complex internal circuit equipped with sophisticated molecular components that provide rigid control over a variety of cellular responses. Although increasing understanding of genetic aberrations and signaling pathway transgressions can lead to novel strategies for targeting cancer cells, the disappointing results from clinical trials suggest that the occult processes responsible for neoplastic transformation remain largely unexplained.

Antineoplastic Agents↗
PubMed2005

Molecular targeted therapy of lung cancer: EGFR mutations and response to EGFR inhibitors.

Somatic mutations within the kinase domain of the epidermal growth factor receptor (EGFR) are present in approximately 10% of non-small-cell lung cancer (NSCLC), with an increased frequency in adenocarcinomas arising in nonsmokers, women, and individuals of Asian ethnicity. These mutations lead to altered downstream signaling by the receptor and appear to define a subset of NSCLC characterized by "oncogene addiction" to the EGFR pathway, which displays dramatic responses to the reversible tyrosine kinase inhibitors gefitinib and erlotinib. The rapid acquisition of drug resistance in most cases, either through mutation of the "gateway" residue in the EGFR kinase domain or by alternative mechanisms, appears to limit the impact on patient survival. Irreversible inhibitors of EGFR display continued effectiveness in vitro against cells with acquired resistance and are now undergoing genotype-directed clinical trials. The molecular and clinical insights derived from targeting EGFR in NSCLC offer important lessons for the broader application of targeted therapeutic agents in solid tumors.

Antineoplastic Agents↗
PubMed1995

Diphtheria toxin-based receptor-specific chimaeric toxins as targeted therapies.

The results from the phase I/II studies of the intravenous administration of DAB486-IL-2 to patients with refractory haematological malignancies have now proven in principle the feasibility of fusion toxin therapy in man. Indeed, the cell-surface receptor-specific intoxication of neoplastic cells through the catalytic ADP-ribosylation of EF-2 is the prototype of a new class of biological response modifiers that may be generally applicable. In those circumstances where either the de novo expression or up-regulation of a cell-surface receptor can be associated with human disease [e.g. the up-regulation of the epidermal growth factor (EGF) receptor on breast cancer], it should be possible to construct genetically a DT-related/growth factor fusion protein to produce an experimental biological treatment of that malignancy. The EGF receptor-targeted fusion toxin DAB389-EGF has within the last year begun human phase I clinical trials. The pre-clinical development of DAB389-IL-7 has begun with the anticipation that this novel fusion toxin will be evaluated in the treatment of the acute leukaemias in which the IL-7R has been shown to be present.

Amino Acid Sequence↗
PubMed1994

Gene therapy targeted by radiation preferentially radiosensitizes tumor cells.

Transcriptional regulation of the promoter/enhancer region of the Egr-1 gene is activated by ionizing radiation. We linked DNA sequences from the promotor region of Egr-1 to a complementary DNA sequence which encodes human tumor necrosis factor (TNF) alpha, a radiosensitizing cytokine. The Egr-TNF construct was transfected into a human cell line of hematopoietic origin, HL525, which was used in an experimental animal system. HL525 (clone 2) cells containing the Egr-TNF construct which exhibits radiation induction of TNF-alpha were injected into human xenografts of the radioresistant human squamous cell carcinoma cell line SQ-20B. Animals treated with radiation and clone 2 demonstrated an increase in tumor cures compared with animals treated with radiation alone or unirradiated animals given injections of clone 2 alone. No increase in local or systemic toxicity was observed in the combined treatment group. The combination of gene therapy and radiation therapy enhances tumor cures without increasing normal tissue toxicity and is a new paradigm for cancer treatment.

Animals↗
PubMed2004

Angiogenesis-targeted therapies in prostate cancer.

Most patients with metastatic prostate cancer will respond initially to ablation of gonadal androgen production. Eventually, all patients will develop progressive disease despite continued androgen suppression, a condition called androgen-independent or hormone-refractory prostate cancer. Hormone-refractory prostate cancer is characterized by virulent biologic and clinical behavior. Recently, docetaxel-based chemotherapy has been shown to improve survival and quality of life in this disease when compared with mitoxantrone-based therapy. However, results remain suboptimal. Recently, there have been remarkable advances in the delineation of the mechanisms of cancer growth, metastasis, and the intricate interactions between tumor cells and the surrounding normal tissues. The accumulated evidence has confirmed the importance of angiogenesis in these processes and validated the theory that inhibition of neovascularization is a promising therapeutic anticancer strategy. Currently, dozens of compounds that interfere with different steps of the angiogenic cascade are in preclinical and clinical development. Some of these agents have exhibited promising antitumor activity in hormone-refractory prostate cancer. This review summarizes the molecular mechanisms implicating angiogenesis in the development and progression of advanced-stage prostate cancer, as well as the drug development efforts that are targeting this process.

Angiogenesis Inhibitors↗
PubMed1998

The molecular basis of the hypoxia response pathway: tumour hypoxia as a therapy target.

Hypoxia induces a cascade of physiological responses that includes glycolysis, erythropoiesis, angiogenesis, changes in adrenergic signal transduction and vascular cellular proliferation. Hypoxia-inducible genes are relevant to growth and behaviour of cancer as well as the adaptation and survival of normal tissues. Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric DNA binding complex composed of two basic-helix-loop-helix PAS-proteins: HIF-1 beta/ARNT (aryl hydrocarbon receptor nuclear translocator), which is constitutively expressed, and HIF-1 alpha, which is not present in normoxic cells but induced under hypoxic conditions. Recently another member of the bHLH-PAS family, EPAS-1 has been reported and shares similar properties with HIF-1 alpha, although it is considered endothelial specific. In addition, the presence of other DNA-binding motifs in the promoter of hypoxia-inducible genes highlight the occurrence of cross-talk between transcription factors in the modulation of hypoxic gene expression. In this review, we present a survey of the hypoxia response pathway and we discuss attempts to use gene therapy activated by the low oxygen environment or by necrotic regions of tumours.

Animals↗
PubMed2004

Molecularly targeted therapy in acute myeloid leukemia.

Meaningful progress has been made toward clarifying the molecular steps in the pathogenesis of acute myeloid leukemia (AML). Chromosome studies have established that translocations/inversions are the most common cytogenetic defects in AML. Cloning of chromosome breakpoints has shown that genes involved in the chromosome abnormalities are transcription factors, functional loss of which alters chromatin configuration and results in the disruption of myeloid differentiation. However, transgenic animal models have demonstrated that AML-specific translocations/inversions alone are insufficient to cause overt leukemia, which occurs only when point mutations affecting receptor tyrosine kinases (RTKs) develop. Therefore, development of AML is now considered a two-step process in which RTK mutations provide a proliferative and a survival advantage to a clonal cell population already marked by impaired differentiation. In addition, more accurate definition of such genetic lesions has led to a more precise insight as to how such lesions interact with cellular signaling pathways that are aberrantly regulated in AML. All these new data have profound clinical and therapeutic implications and will surely translate into the development of molecules that target specific mutations or signal transduction pathways.

Acetylation↗
PubMed2001

Interstitial fluid pressure in cervical cancer: guide to targeted therapy.

Interstitial fluid pressure (IFP) is elevated in most malignant tumors, mainly as a result of the abnormal tumor vasculature that develops from unregulated angiogenesis. Theoretical models predict that IFP should correlate with capillary flow resistance in tumors, and therefore also with perfusion and oxygenation. However, a prospective clinical study in patients with cervical cancer at Princess Margaret Hospital failed to demonstrate a relationship between IFP and oxygenation. Despite this, high IFP was strongly associated with inferior survival after radiotherapy independent of clinical prognostic factors and tumor oxygen status. This suggests that IFP and direct needle oxygen measurements may provide information about different aspects of tumor oxygenation, such as chronic versus intermittent hypoxia. Alternatively, IFP may reflect an aspect of tumor biology that is largely unrelated to perfusion and oxygenation. One possibility is that tumors with high pretreatment angiogenesis levels, as indicated by high IFP, may be more radioresistant because the vascular endothelium is more likely to survive during and after treatment. The mechanistic link between elevated IFP and the abnormal tumor vasculature and the strong prognostic effect of IFP in our cervix study together suggest that drugs targeted at angiogenesis, when combined with radiotherapy, may lead to improved tumor control and patient survival.

Angiogenesis Inhibitors↗
PubMed2003

Pathobiology, prognosis, and targeted therapy for renal cell carcinoma: exploiting the hypoxia-induced pathway.

Historically, clinical factors have been used as prognostic markers for patients with renal cell carcinoma (RCC). Recent advances in the understanding of the pathogenesis, behavior, and molecular biology of RCC have paved the way for developments that may enhance early diagnosis, better predict tumor prognosis, and improve survival for RCC patients. This report reviews the molecular mechanisms of the hypoxia-induced pathway that play an essential role in angiogenesis, glycolysis, and apoptosis of common cancers and may be responsible for the ability of the cancers to adapt to a hypoxic environment and also for their resistance to radiation and chemotherapy. The hypoxia-induced pathway has been linked genetically to RCC through the von Hippel-Lindau tumor suppressor gene, which is inactivated in a majority of clear cell RCCs. Therefore, RCC is a particularly attractive clinical model to exploit the hypoxia-induced pathway for new therapeutic interventions. von Hippel-Lindau, hypoxia inducible factor 1alpha, carbonic anhydrase IX, vascular endothelial growth factor, and other important members of the hypoxia-induced gene family, provide new molecular targets for diagnosis, prognosis, and immunotherapy of RCC.

Algorithms↗
PubMed1994

Serotonin, 5-HT2 receptors, and their blockade by naftidrofuryl: a targeted therapy of vascular diseases.

The importance and the various effects of serotonin (5-HT) in cardiovascular diseases are reviewed, with particular emphasis on the involvement of 5-HT2 receptors as mediators of the biological responses of vessels and blood platelets to 5-HT. The importance of 5-HT in peripheral and cerebral ischemia is shown by the key role it plays in inducing vasoconstriction, platelet aggregation, vascular permeability, and cell proliferation. Of particular importance is the 5-HT-selective hypersensitivity developing in vessels/platelets shortly after acute ischemia or early in the development of chronic vascular diseases. The mechanisms of action of naftidrofuryl are described, showing that this drug offers a particularly interesting profile of having both metabolic and vascular effects. Naftidrofuryl improves glucose aerobic metabolism by an action on succinodehydrogenase and improves the blood supply and the ischemic damage of the vessel wall by blocking specifically 5-HT2 receptors. The latter property permits an inhibition of the deleterious, multiple effects of 5-HT at sites of vascular injury, without influencing the general circulatory bed. Therefore, naftidrofuryl appears to be an anticonstrictor and not, as previously thought, a vasodilator. As a consequence, naftidrofuryl has a targeted impact without vasodilator-linked side effects such as hypotension or the steal phenomenon.

Animals↗
PubMed2005

Oncogenic pathway signatures in human cancers as a guide to targeted therapies.

The development of an oncogenic state is a complex process involving the accumulation of multiple independent mutations that lead to deregulation of cell signalling pathways central to the control of cell growth and cell fate. The ability to define cancer subtypes, recurrence of disease and response to specific therapies using DNA microarray-based gene expression signatures has been demonstrated in multiple studies. Various studies have also demonstrated the potential for using gene expression profiles for the analysis of oncogenic pathways. Here we show that gene expression signatures can be identified that reflect the activation status of several oncogenic pathways. When evaluated in several large collections of human cancers, these gene expression signatures identify patterns of pathway deregulation in tumours and clinically relevant associations with disease outcomes. Combining signature-based predictions across several pathways identifies coordinated patterns of pathway deregulation that distinguish between specific cancers and tumour subtypes. Clustering tumours based on pathway signatures further defines prognosis in respective patient subsets, demonstrating that patterns of oncogenic pathway deregulation underlie the development of the oncogenic phenotype and reflect the biology and outcome of specific cancers. Predictions of pathway deregulation in cancer cell lines are also shown to predict the sensitivity to therapeutic agents that target components of the pathway. Linking pathway deregulation with sensitivity to therapeutics that target components of the pathway provides an opportunity to make use of these oncogenic pathway signatures to guide the use of targeted therapeutics.

Animals↗
PubMed1995

Renal accumulation of streptavidin: potential use for targeted therapy to the kidney.

Streptavidin exhibits a remarkable accumulation in the kidney. Biodistribution studies with radio-iodinated streptavidin showed that 70 to 80% of the injected dose per gram tissue (%/g) were retained in kidneys of Balb/C mice for three to four days compared to less than 5%/g levels in other tissues. This observation means that 15 to 20% of the injected dose is accumulated in the kidney, an organ that constitutes less than 1% of total body weight. Similar results of percent radioactivity per total kidney were obtained in other mouse strains as well as in rats and rabbits. Avidin, or the post-secretory form of streptavidin which is of a higher molecular weight, do not show any preferential affinity to the kidney. The kidney-accumulated streptavidin was mostly confined to the cortex, concentrated in the proximal tubular cells. Accumulation of streptavidin in the kidney was independent of biotin, since addition of biotin to radio-iodinated streptavidin prior to injection did not affect its kidney uptake. Therefore, streptavidin, which aquires its kidney accumulation property following truncation of the native form, may be utilized for renal specific delivery of chemotherapeutic agents, radioactive isotopes and other effector molecules. Such ligands can be linked to streptavidin via conventional coupling methods or following their biotinylation. Preliminary experiments showed that streptavidin can target to the kidney biotinylated ligands or high doses of chemically linked radionuclides.

Animals↗
PubMed2006

A new melanoma antigen fatty acid-binding protein 7, involved in proliferation and invasion, is a potential target for immunotherapy and molecular target therapy.

The identification of molecules that are preferentially expressed in melanoma cells and involved in their malignant phenotypes is important for understanding melanoma biology and the development of new diagnostic and therapeutic methods. By comparing the expression profile of a melanoma cell line with those of various normal tissues using GeneChip and by confirming the actual expression of the selected genes by reverse transcription-PCR and Northern and Western blot analyses, fatty acid-binding protein 7 (FABP7), which is frequently expressed in melanomas, was identified. Immunohistochemical examination revealed that FABP7 was expressed in 11 of 15 melanoma tissues. By down-regulating the FABP7 expression with FABP7-specific small interfering RNAs, in vitro cell proliferation and Matrigel invasion were suppressed in two of six melanoma cell lines. Overexpression of FABP7 in a FABP7-negative embryonic kidney cell line 293T by transfecting with the FABP7 cDNA resulted in enhanced cell proliferation and Matrigel invasion, indicating that FABP7 plays a role in the malignant phenotype of some melanoma cell lines. IgG antibodies specific for the phage or bacterial recombinant FABP7 protein were detected in 14 of 25 (56%) or in 8 of 31 (26%) sera from melanoma patients, respectively, but not in sera from healthy individuals, indicating that FABP7 is an immunogenic antigen in melanoma patients. These results showed that FABP7 is frequently expressed in melanoma, may be involved in cell proliferation and invasion, and may be a potential target for development of diagnostic and therapeutic methods.

Antibody Specificity↗
PubMed2026

Mechanisms by which carbamoylated high-density lipoprotein (C-HDL) promotes calcific aortic valve disease and exploration of potential targeted therapies.

Calcific aortic valve disease (CAVD) is a progressive fibrocalcific illness for which no effective pharmaceutical treatment exists. This study investigated whether carbamoylated high-density lipoprotein (C-HDL), a defective type of HDL that can develop during inflammation, contributes to CAVD progression and the involved molecular pathways. Male ApoE-/- mice were divided into three groups: CAVD model, cyanate-treated, and inhibitor, and analyzed after 12 weeks. C57BL/6 mice on a regular diet served as blank controls. Serum paraoxonase-1 (PON1), aortic valve calcification, cluster of differentiation 31 (CD31), phosphorylated nuclear factor kappa B p65 (p-p65), NOTCH receptor 1 (NOTCH1), and runt-related transcription factor 2 (RUNX2) were evaluated. In parallel, using RNA sequencing (RNA-seq), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, protein-protein interaction (PPI) network analysis, and quantitative real-time polymerase chain reaction. Cyanate treatment reduced serum PON1 levels, increased von Kossa-positive calcium deposition, and raised CD31, p-p65, NOTCH1, and RUNX2 levels compared with the model group, but Gly partially corrected these effects. Transcriptomic research identified 270 C-HDL-associated differentially expressed genes (DEGs) enriched in pathways associated with inflammatory signaling and NF-κB activity. Five potential hub genes (BIRC6, PIK3R1, ATM, IFIH1, and DDX58) were discovered and verified using qRT-PCR. These data show that C-HDL may accelerate CAVD by disrupting valve endothelial homeostasis and stimulating inflammatory signaling, and they identify potential molecular targets for future functional validation.

bioinformatics↗
PubMed2001

Gene therapy targeting for hepatocellular carcinoma: selective and enhanced suicide gene expression regulated by a hypoxia-inducible enhancer linked to a human alpha-fetoprotein promoter.

We previously reported that the retroviral vector expressing the herpes simplex virus-thymidine kinase gene under the control of 0.3-kb human alpha-fetoprotein (AFP) gene promoter (AF0.3) provided the cytotoxicity to ganciclovir (GCV) in high-AFP-producing human hepatoma cells but not in low-AFP-producing cells. Therefore, specific enhancement of AFP promoter activity is likely to be required to induce enough cytotoxicity in low-AFP-producing hepatoma cells. In this study, we constructed a hybrid promoter, [HRE]AF, in which a 0.4-kb fragment of human vascular endothelial growth factor 5'-flanking sequences containing hypoxia-responsive element (HRE) was fused to AF0.3 promoter. By means of the reporter gene transfection assay, hypoxia-inducible transcriptions that were mediated by [HRE]AF promoter were detected in low- and non-AFP-producing human hepatoma cells, but not in nonhepatoma cells. When the herpes simplex virus-thymidine kinase gene controlled by [HRE]AF promoter was transduced into hepatoma and nonhepatoma cells by a retroviral vector, the exposure to 1% O2 induced GCV cytotoxicity specifically in the hepatoma cells. Moreover, in nude mice bearing solid tumor xenografts, only the tumors consisting of the virus-infected hepatoma cells gradually disappeared by GCV administration. These results indicate that the hypoxia-inducible enhancer of the human vascular endothelial growth factor gene, which is directly linked to human AFP promoter, involves selective and enhanced tumoricidal activity in gene therapy for hepatocellular carcinoma.

Animals↗
PubMed2005

Targeted therapies for esophageal cancer.

Esophageal cancer is a highly aggressive neoplasm. In 2005, 14,520 Americans will be diagnosed with esophageal cancer, and more than 90% will die of their disease. On a global basis, cancer of the esophagus is the sixth leading cause of cancer death worldwide. In fact, gastric and esophageal cancers together accounted for nearly 1.3 million new cases and 980,000 deaths worldwide in 2000-more than lung, breast, or colorectal cancer. Although esophageal squamous cell carcinoma cases have steadily declined, the incidence of gastroesophageal junction adenocarcinoma has increased 4%-10% per year among U.S. men since 1976, more rapidly than for any other cancer type, and parallels rises in population trends in obesity and reflux disease. With advances in surgical techniques and treatment, the prognosis of esophageal cancer has slowly improved over the past three decades. However, the 5-year overall survival rate (14%) remains poor, even in comparison with the dismal survival rates (4%) from the 1970s. The underlying reasons for this disappointingly low survival rate are multifold: (a) ineffective screening tools and guidelines; (b) cancer detection at an advanced stage, with over 50% of patients with unresectable disease or distant metastasis at presentation; (c) high risk for recurrent disease after esophagectomy or definitive chemoradiotherapy; (d) unreliable noninvasive tools to measure complete response to chemoradiotherapy; and (e) limited survival achieved with palliative chemotherapy alone for patients with metastatic or unresectable disease. Clearly, additional strategies are needed to detect esophageal cancer earlier and to improve our systemic treatment options. Over the past decade, the field of drug development has been transformed with the identification of and ability to direct treatment at specific molecular targets. This review focuses on novel targeted treatments in development for esophageal squamous cell carcinoma and distal esophageal and gastroesophageal junction adenocarcinoma.

Antibodies, Monoclonal↗
PubMed1997

[Use of monoclonal antibody-pinyangmycin conjugate in experimental regional targeting therapy of tumor].

McAb 3A5, a rat monoclonal antibody, was linked to pingyangmycin (PYM), an antitumor antibiotic identical to bleomycin A5 currently in clinical use, employing Dextran T-40 as an intermediate agent. The 3A5-PYM conjugate retained complete immunoreactivity of McAb 3A5. Determined by clonogenic assay with colon cancer HT-29 cells, the IC50 values for 3A5-PYM conjugate and free PYM were 0.6 mumol.L-1 and 10.2 mumol.L-1, respectively. Hepatoma H22 ascites was transplanted into the peritoneal or thoracic cavity of mice. On the next day, 3A5-PYM or PYM, were injected into the cavity. Therapeutic effect was evaluated on the survival time of mice. For intraperitoneal tumor, the ILS(%) values were 238% for 3A5-PYM and 40% for PYM. For intrapleural tumor, the ILS(%) values were 384% for 3A5-PYM and 66% for PYM. Murine hepatoma H22 was transplanted s.c. into mice and 3A5-PYM conjugate or free PYM were injected peritumorally. As determined by antimicrobial assay, the administration of 3A5-PYM showed higher concentration and longer retention time in the tumor than that of free PYM. Tumor fragments of human colon cancer HT-29 were transplanted s.c. into nude mice. Then 3A5-PYM or PYM was injected i.v., i.p. or pt (peritumorally) 3 days after inoculation, twice a week, with a total of 7 injections. Tumor growth inhibition was evaluated 4 weeks later. The inhibition rates on the growth of colon cancer xenografts were as follows: (1) for i.v. route, 58% by PYM, 79% by 3A5-PYM; (2) for i.p. route, 52% by PYM, 61% by 3A5-PYM; and (3) for pt route, 73% by PYM, 96% by 3A5-PYM. These results indicate that 3A5-PYM conjugate is highly effective against targeted human cancer xenograft and mouse tumor when administered peritumorlly or intracavitarily.

Animals↗