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At least 433 records · Page 24Linked to original sources
PubMed2005

Why does tumor necrosis factor targeted therapy reactivate tuberculosis?

Treatment of chronic inflammatory conditions, such as rheumatoid arthritis and Crohn's disease, with tumor necrosis factor (TNF) targeted biologics is associated with an increased risk of infectious complications, especially tuberculosis (TB). Clinical studies have revealed that monoclonal anti-TNF antibodies (e.g., infliximab) more frequently reactivate TB than a TNF receptor p75 immunoglobulin fusion construct (etanercept). Experimental studies in mice have shown TNF to be an essential component of protective granuloma formation. Based on these studies and the known pharmacological properties of the 2 prototype TNF targeted biologic agents, this review discusses 3 hypotheses that might explain the unpredicted differential risk of infectious complications: differential induction of target cell death, differential TNF receptor signaling, and differential net inhibition of TNF bioavailability.

Animals↗
PubMed2004

Epidermal growth factor receptor-targeted therapy with ZD1839: symptom improvement in non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) is a common and frequently incurable disease. Patients with advanced Stage IIIB and Stage IV disease, although not candidates for curative resection, can benefit from receiving treatment (chemotherapy and radiation therapy) that prolongs survival, alleviates symptoms, and/or reduces complications. However, these therapies are often associated with significant adverse events. Treatments have recently been developed to selectively target cancer-specific molecules and signaling pathways. By acting preferentially on tumor cells, these drugs leave normal cells relatively undisturbed, thereby limiting toxic effects and preserving the patient's quality of life. ZD1839 is one of a new class of targeted anticancer agents known as tyrosine kinase inhibitors that has demonstrated activity in the treatment of NSCLC. In clinical trials, ZD1839 produced responses in patients with relapsed or refractory NSCLC, reduced disease-related symptoms, and was associated with an improvement in quality of life. Results from pivotal trials with single-agent ZD1839 are reviewed in this article, with an emphasis on its effects on quality of life and symptom improvement.

Carcinoma, Non-Small-Cell Lung↗
PubMed2006

Chemotherapy and targeted therapy combinations in advanced melanoma.

For three decades, clinical trials with chemotherapy in melanoma have failed to show superiority of any one regimen over another. Dacarbazine remains the only "standard" agent. With response rates of <10% and median progression-free survival of 2 months or less in contemporary trials, there is a need to improve systemic therapy. Combination chemotherapy is associated with higher response rates than single-agent therapy but this has not translated into improved survival. An increasing number of potential therapeutic targets have been identified. For some, pharmacologic inhibitors are available, including sorafenib for BRAF, farnesyltransferase inhibitors for NRAS, PD-0325901 for mitogen-activated protein kinase/extracellular signal-regulated kinase kinase, rapamycin analogues for mammalian target of rapamycin, and agents that inhibit either vascular endothelial growth factor or its receptors. Several multitargeted kinase inhibitors have potency against the fibroblast growth factor receptor, c-kit, and platelet-derived growth factor receptor. Small-molecule inhibitors of c-met and Akt are in preclinical development. Another class of agents indirectly affect aberrant signaling, including inhibitors of chaperones and proteasomes. Several targeted agents seem to enhance the cytotoxicity of chemotherapy in preclinical models. The mechanism by which signaling inhibition might synergize with chemotherapy requires more study so that rational combinations move forward. Very few targeted agents have been studied rigorously in this fashion.

Animals↗
PubMed2007

[Molecular pathology and targeted therapy of clear cell renal cancer].

The golden standard of care for advanced renal cell cancer (RCC) was until now the cytokine therapy with relatively low response rates. Advances of molecular genetics in RCC revealed several molecular targets such as VHL and angiogenic genotype or EGFR in the clear cell variant. Among the novel targeted agents, multiple tyrosine kinase inhibitors were proved to be clinically effective against advanced clear cell renal cancer, changing the standard of care. It is a further question how molecular diagnostics can improve these results by the detection of these targets or gene defects in individual tumors.

Adenocarcinoma, Clear Cell↗
PubMed2005

mTOR-targeted therapy of cancer with rapamycin derivatives.

Rapamycin and its derivatives (CCI-779, RAD001 and AP23576) are immunosuppressor macrolides that block mTOR (mammalian target of rapamycin) functions and yield antiproliferative activity in a variety of malignancies. Molecular characterization of upstream and downstream mTOR signaling pathways is thought to allow a better selection of rapamycin-sensitive tumours. For instance, a loss of PTEN functions results in Akt phosphorylation, cell growth and proliferation; circumstances that can be blocked using rapamycin derivatives. From recent studies, rapamycin derivatives appear to display a safe toxicity profile with skin rashes and mucositis being prominent and dose-limiting. Sporadic activity with no evidence of dose-effect relationship has been reported. Evidence suggests that rapamycin derivatives could induce G1-S cell cycle delay and eventually apoptosis depending on inner cellular characteristics of tumour cells. Surrogate molecular markers that could be used to monitor biological effects of rapamycin derivatives and narrow down biologically active doses in patients, such as the phosphorylation of P70S6K or expression of cyclin D1 and caspase 3, are currently evaluated. Since apoptosis induced by rapamycin is blocked by BCL-2, strategies aimed at detecting human tumours that express BCL-2 and other anti-apoptotic proteins might allow identification of rapamycin-resistant tumours. Finally, we discuss current and future placements of rapamycin derivatives and related translational research into novel therapeutic strategies against cancer.

Animals↗
PubMed2003

[Targeted therapy of human laryngeal squamous cell carcinoma in vitro with telomerase catalytic subunit mRNA].

OBJECTIVE: To study the effect of antisense oligonucleotide targeted human telomerase catalytic subunit (hTERT) on Hep-2 cell line. METHOD: Cells were treated daily with oligonucleotide (ODN) directed against hTERT, or control ODN-a mismatched sequence or only Lipofectamine. At 24 h, 48 h, 72 h cell viability after administration of ODNs was determined using the MTT assay. At 72 h, the morpholog alteration of the cells was observed by HE stain. At 72 h, telomerase activity was determined. RESULT: After daily transfection ASODN, some Hep-2 cells begin to stop growing up, but not in the mismatched ODN group or Lipofectamine group. Hep-2 cells treated with antisense against hTERT showed a decrease in telomerase activity. CONCLUSION: hTERT antisense ODN can inhibit telomerase activity and the growth of Hep-2 cells in short term.

DNA-Binding Proteins↗
PubMed2003

Targeted molecular therapy of GBM.

Major advances in molecular biology, cellular biology and genomics have substantially improved our understanding of cancer. Now, these advances are being translated into therapy. Targeted therapy directed at specific molecular alterations is already creating a shift in the treatment of cancer patients. Glioblastoma (GBM), the most common brain cancer of adults, is highly suited for this new approach. GBMs commonly overexpress the oncogenes EGFR and PDGFR, and contain mutations and deletions of tumor suppressor genes PTEN and TP53. Some of these alterations lead to activation of the P13K/Akt and Ras/MAPK pathways, which provide targets for therapy. In this paper, we review the ways in which molecular therapies are being applied to GBM patients, and describe the tools of these approaches: pathway inhibitors, monoclonal antibodies and oncolytic viruses. We describe strategies to: i) target EGFR, its ligand-independent variant EGFRvIII, and PDGFR on the cell surface, ii) inhibit constitutively activate RAS/MAPK and PI3K/Akt signaling pathways, iii) target TP53 mutant tumors, and iv) block GBM angiogenesis and invasion. These new approaches are likely to revolutionize the treatment of GBM patients. They will also present new challenges and opportunities for neuropathology.

Animals↗
PubMed2006

Chronic myelogenous leukemia: from molecular biology to clinical aspects and novel targeted therapies.

The critical causative event in chronic myelogenous leukemia (CML) is the fusion of the head of the bcr gene with the body of the abl gene, named bcr/abl gene. This chimeric BCR/ABL molecule transforms primary myeloid cells to leukemic cells and induces a CML-like disease in mice. The mouse CML model expressing the BCR/ABL molecule has provided important new insights into the molecular pathophysiology of CML and has directly answered many questions regarding this disease. Furthermore, numerous clinical studies have demonstrated a correlation between leukemic clinical features and the position of the breakpoint in the BCR gene of the chimeric BCR/ABL gene. Understanding of the molecular pathogenesis of CML has led to the development of several novel therapies. The BCR/ABL molecule is unique oncogeneiety, having ABL tyrosine kinase activity, making it an ideal target for drug development. Subsequent clinical studies now realize the hypothesis that selective inhibition of the abl tyrosine kinase activity using imatinib mesylate might be useful for the treatment of CML. This article reviews the history of BCR/ABL molecular biology, including the CML model mouse, clinical molecular studies and the recent findings of imatinib mesylate and more potent tyrosine kinase inhibitors developed for the treatment of CML.

Animals↗
PubMed2003

[Targeting therapy of magnetic doxorubicin liposome in nude mice bearing colon cancer].

OBJECTIVE: To investigate the effect of magnetic doxorubicin liposome (MDL) in the targeting treatment of nude mice bearing colon cancer. METHODS: Human colon cancer line LoVo cells were implanted hypodermically into nude mouse. Two weeks after the mouse was killed and the tumor was taken out and cut into small pieces to be retransplanted into nude mice so as to establish an experimental model. MDL was prepared by reverse-phase evaporation method. The particle size and structure of MDL were evaluated. Eighteen nude mice with colon cancer were divided into 3 groups of 3 mice: free DOX group, MDL (-) group (no magnetic field was added to the tumor surface), and MDL (+) group (magnetic field with the strength of 4,500 G was added). DOX of the dosage of 5 mg/kg was injected through the caudal vein in these 3 groups. Then the mice were killed 30 minutes after. Fluorescence spectrophotometry was used to examine the concentrations of DOX in the tissues and plasma. Another 36 nude mice with colon cancer were divided into 6 groups of 6 mice: normal saline group (as controls), DOX group, blank liposome group, magnetic liposome group, MDL (-) group (non-magnetic alloy was implanted into the tumor), and MDL (+) group (rare earth magnet was implanted into the tumor). The body weight, longest diameter of tumor, and short diameter vertical to the longest diameter were calculated regularly. The mice were killed 11 days after. The tumors were taken out to undergo staining and light microscopy. Flow cytometry was used to examine the apoptosis of tumor cells. RESULTS: The particle size of MDL was 230 nm and the magnetic particles (Fe(3)O(4)) were evenly distributed within the liposome. The DOX concentration in tumor tissue of the MDL (+) group was remarkably higher than those of the DOX and MDL (-) groups (both P < 0.05). The DOX concentration in heart and kidney of the DOX group were higher than those of the other 2 groups, and the plasma DOX concentrations of the DOX group was significantly lower than those of the other groups (all P < 0.05). The growth speed of tumor in the MDL (+) group was significantly lower, and the tumor weight was significantly less than in other groups. CONCLUSION: Magnetic doxorubicin liposome, as a carrier of anticancer drug, has a good targeting function toward the magnetite and has a significant anticancer effect.

Animals↗
PubMed2005

Medulloblastoma: mouse models and novel targeted therapies based on the Sonic hedgehog pathway.

Understanding molecular pathways, signaling cascades, and genetic alterations activated during tumorigenesis is essential for the development of targeted cancer treatments. In children, tumors of the central nervous system are thought to arise from progenitor cells that show considerable temporal and spatial heterogeneity in a developmental environment that is different from that of the adult. Investigating the molecular basis of pediatric tumors is critical because it is likely to generate novel treatments. Animal models have brought many important advances in this field. In this review the authors discuss the mouse models based on the Sonic hedgehog pathway, which have provided a better knowledge of the genetic and molecular alterations of medulloblastoma.

Animals↗
PubMed2005

[Involvement of PI3K/Akt pathway in prostate cancer. Potential strategies for developing targeted therapies].

Because of the unavailability of effective therapies to block or reverse the progression of androgen-independent prostate cancer, it seems obvious to target growth signaling pathways for which frequently recurring mutations have been identified. Acquired mutations of the PTEN gene have been reported in several tumor types, including up to 30% - 60% of prostate cancer tumors. This results in constitutive activation of the PI3K/Akt pathway which then represents a major target to prevent dysfunctions in cell growth, survival and motility. Our experience and, therefore, our own tools allow us to design new inhibitors of growth factor receptor tyrosine kinase, PDK-1 and farnesyltransferase activities. These original compounds could selectively switch off one or several steps of the multifunctional pathway and constitute lead compounds in the design of new classes of potent drugs.

Alkyl and Aryl Transferases↗
PubMed2005

Laser photocoagulation and, to a lesser extent, photodynamic therapy target and enhance adenovirus vector-mediated gene transfer in the rat retina.

PURPOSE: To evaluate the transduction efficiency and localization of a reporter gene after intravitreous injection of adenovirus vector in laser photocoagulation (PC)- and photodynamic therapy (PDT)-treated eyes. METHODS: Adult Lewis rats received fundus PC, fundus PDT, or no treatment. Intravitreous injection of an adenovirus vector containing the construct expressing beta-galactosidase (AdlacZ.11D) was performed in each group. All eyes were then enucleated for histochemistry and processed for quantitative image analysis. RESULTS: In eyes with no treatment, there was moderate to intense staining for lacZ in the anterior segment, but little in the retina. In eyes treated with PC and PDT, there was significantly more LacZ staining in the retina. The increased staining corresponded closely with the sites treated with PC and PDT. Gene transduction in PC-treated eyes was enhanced and extended to at least 135 days after virus delivery, but not extended in PDT-treated eyes. Gene transfer and expression were targeted and enhanced at the site of laser burns, at all doses tested (3 x 10(5) to 3 x 10(9) particles per eye). CONCLUSIONS: Compared with untreated eyes, eyes treated with PC and to a lesser extent PDT, manifest increased transduction efficiency, in areas of the retina that are targeted by laser treatment. This finding suggests a new and promising strategy for the treatment of retinochoroidal neovascularization. Adenovirus gene therapy in combination with PC or PDT would have the advantage of increased transduction efficiency; increased duration of transgene expression; targeted delivery; and, potentially, a lower effective dose of virus.

Adenoviridae↗
PubMed2006

The nuclear lamina and its proposed roles in tumorigenesis: projection on the hematologic malignancies and future targeted therapy.

The nuclear lamina, a network of lamin filaments and lamin-associated proteins, is located between the inner nuclear membrane and the peripheral chromatin. The nuclear lamina is involved in numerous nuclear functions including maintaining nuclear shape, determining nuclear positioning, organizing chromatin and regulating the cell cycle, DNA replication, transcription, cell differentiation, apoptosis, and aging. Alterations in the composition of nuclear lamins and their associated proteins are currently emerging as an additional event involved in malignant transformation, tumor propagation and progression, thus identifying potential novel targets for future anti-cancer therapy. Here, we review the current knowledge on lamin expression patterns in cells of hematologic malignancies and give an overview on the roles of the nuclear lamina proteins in heterochromatin organization, apoptosis, and aging with special emphasis on the relevance in cancer development.

Animals↗
PubMed2006

Molecularly targeted therapy in renal cell carcinoma: where do we go from here?

The angiogenic phenotype of renal cell carcinoma results from vascular endothelial growth factor pathway activation. Several different strategies targeting various aspects of the pathway have emerged as clinically relevant therapeutics in metastatic renal cell carcinoma. Key clinical data regarding these approaches are presented in this article. Furthermore, there are several considerations as to the further development of these agents and their appropriate application in metastatic renal cell carcinoma, such as timing of therapy, choice of initial therapy, continued role of debulking nephrectomy and toxicity concerns. These issues are discussed in light of current data and strategies for further drug development are presented.

Angiogenesis Inhibitors↗
PubMed2003

Targeted therapies for stage III non-small cell lung cancer: integration in the combined modality setting.

Combined modality therapy represents current standard therapy for locoregionally advanced non-small cell lung cancer. In particular, concomitant chemoradiotherapy has emerged as the preferred approach. At the same time, efforts to increase locoregional and systemic antitumor activity are necessary to further improve long-term survival rates for these patients. In recent years, multiple cellular targets have emerged in the development of novel antitumor therapies. Several of these are of high relevance in the carcinogenesis of lung cancer including the epidermal growth factor receptor (EGFR), the ras signaling pathway, tumor angiogenesis, and cyclooxygenase-2 (COX-2) expression. Novel agents directed against these targets are currently under development with promising early results in non-small cell lung cancer when administered as single agents or in combination with chemotherapy in stage IV or recurrent disease. Similarly their use with concurrent radiation therapy is supported by preclinical models. Selected early clinical trials utilizing these agents in combination with radiotherapy or chemoradiotherapy are discussed.

Alkyl and Aryl Transferases↗
PubMed1996

Targeted therapy using alpha emitters.

Radionuclides such as 211At and 212Bi which decay by the emission of alpha-particles are attractive for certain applications of targeted radiotherapy. The tissue penetration of 212Bi and 211At alpha-particles is equivalent to only a few cell diameters, offering the possibility of combining cell-specific targeting with radiation of similar range. Unlike the beta-particles emitted by radionuclides such as 131I and 90Y, alpha-particles are radiation of high linear energy transfer and thus greater biological effectiveness. Several approaches have been explored for targeted radiotherapy with 212Bi- and 211At-labelled substances including colloids, monoclonal antibodies, metabolic precursors, receptor-avid ligands and other lower molecular weight molecules. An additional agent which exemplifies the promise of alpha-emitting radiopharmaceuticals is meta-[211At]astatobenzylguanidine. The toxicity of this compound under single-cell conditions, determined both by [3H]thymidine incorporation and by limiting dilution clonogenic assays, for human neuroblastoma cells is of the order of 1000 times higher than that of meta-[131I] iodobenzylguanidine. For meta-[211At] astatobenzylguanidine, the Do value was equivalent to only 6-7 211At atoms bound per cell. These results suggest that meta-[211At] astatobenzylguanidine might be valuable for the targeted radiotherapy of micrometastatic neuroblastomas.

Alpha Particles↗
PubMed2006

Expression profile analysis in multiple human tumors identifies L1 (CD171) as a molecular marker for differential diagnosis and targeted therapy.

L1 cell adhesion molecule (CD171) represents a strongly unfavorable prognostic biomarker for ovarian and endometrial carcinomas. Here we carried out an immunohistochemical survey of L1 expression in normal adults and in a broad range of benign and malignant tumors using monoclonal antibody L1-11A and the novel monoclonal antibody L1-14.10. In normal tissues, L1 was expressed in the collecting tubules of adult tissues and pediatric kidney and in peripheral nerve bundles. In tumors of the female genital tract, L1 was detected in adenocarcinomas of the cervix and fallopian tubes, in addition to ovarian and endometrial carcinomas. Nongynecological tumors expressing L1 comprised malignant melanoma, colon adenocarcinoma positive to chromogranin, clear-cell adenocarcinoma of the urinary bladder, pheochromocytoma, small cell lung carcinoma, and tumors of the nervous system. L1 was absent in breast carcinoma, gastrointestinal tract carcinomas, gastrointestinal carcinoids, renal clear-cell carcinomas, prostate adenocarcinomas, and mesotheliomas. Surprisingly, L1 expression in established breast and renal carcinoma cell lines was not a predictor for its presence in these human tumors in vivo. Our results suggest that L1 expression in tumors is not ubiquitous but restricted to certain subtypes and may be a helpful molecular marker for differential diagnosis and target for antibody-based therapy.

Antibodies, Monoclonal↗
PubMed2003

Anticancer therapy targeting the apoptotic pathway.

Apoptosis, or programmed cell death, has an essential role in controlling cell number in many developmental and physiological settings and in chemotherapy-induced tumour-cell killing. It is a genetically regulated biological process, guided by the ratio of proapoptotic and antiapoptotic proteins. Recently, inducers of apoptosis have been used in cancer therapy. Several studies have attempted to induce apoptosis by triggering the tumour-necrosis-factor-related apoptosis-inducing ligand receptor and the BCL2 family of proteins, and others have targeted the caspases, and proteins that inhibit apoptosis. Most of these therapies are still in preclinical development because of their low efficacy and susceptibility to drug resistance, but some of them have shown promising results. In this article, we review the development and clinical efficacy of proapoptotic drugs that have shown promise.

Antineoplastic Agents↗