Targeted therapy in oncology: the agony and ecstasy of personalized medicine.
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Bronchioloalveolar carcinoma is a fascinating and unusual variant of nonsmall-cell lung cancer that has a tendency towards an indolent course and to metastasize to the lung rather than distant organs. Chemotherapy has shown activity in advanced bronchioloalveolar carcinoma but response rates remain low. Epidermal growth factor receptor tyrosine kinase inhibitors have shown impressive activity against bronchioloalveolar carcinoma in trials. New data suggest that epidermal growth factor receptor mutations and gene copy number may predict subsets of patients who could most benefit from these novel agents. These new findings may point the way to a new era in which we can predict which patients will respond to epidermal growth factor receptor tyrosine kinase inhibitors and thus allow us to tailor therapy to the individual patient.
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Tumour necrosis factor (TNF)-alpha is a potent cytokine involved in the inflammatory reactions of many acute and chronic diseases. Recently, agents that block TNFalpha either directly or indirectly have been successful in the treatment of a variety of immune-mediated inflammatory disorders including rheumatoid arthritis and Crohn's disease. Sarcoidosis is an immune-mediated inflammatory disorder characterised by the formation of granulomas. TNFalpha is important in the initiation and perpetuation of inflammation in sarcoidosis, contributing to the initiation of granulomas and the progression of fibrosis, as well as to nongranulomatous inflammation. Various agents used to treat sarcoidosis affect TNF, including the most widely used drug class, corticosteroids, which are usually effective in blocking TNFalpha release from cells. Other agents that nonspecifically inhibit TNFalpha release include methotrexate, azathioprine and pentoxifylline. Specific TNF-antagonising biological agents such as infliximab and etanercept are being tested in patients with sarcoidosis, with mixed success. Infliximab has been shown to produce clinical improvement and reduce the requirement for corticosteroids in a small number of patients with sarcoidosis. However, as infliximab can be associated with reactivation of tuberculosis, which could be mistaken as worsening sarcoidosis, it should be used with caution in this patient group.
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The activity of genes encoded by the highly-condensed DNA in cellular nuclei must be precisely regulated. Regulation of the accessibility of gene promoters to transcription complexes is one level of gene regulation and is influenced by histone tail modifications such as acetylation, methylation, and phosphorylation. Acetylation is a reversible modification catalyzed by histone acetyl transferase (HAT) and histone deacetyltransferase (HDAC) enzymes. Histone deacetylation is associated with transcriptional repression of genes, as the removal of acetyl groups from lysine residues allows for tighter electrostatic interactions between DNA and histones, limiting accessibility of the DNA for transcription. Inhibition of HDAC activity permits histones to remain in an acetylated state, and through the resulting alterations in gene regulation, inhibits cell cycle progression, inhibits differentiation, and in some cases induces apoptosis. Inhibition of proliferation by HDAC inhibitors is characterized by arrest at the G1 or G2/M phases of the cell cycle. Many types of tumor cells then undergo programmed cell death. Exposure to HDAC inhibitors may also allow reactivation of tumor suppressor genes which had been silenced by hypoacetylation during tumorigenesis. HDAC inhibitors from a number of chemical classes have shown promise as anti-cancer agents in animal studies and early clinical trials. The development of HDAC inhibitors which specifically target HDAC isozymes, and more detailed understanding of their anti-neoplastic actions, heralds a new epigenetic antitumor therapeutic strategy.
This review presents some therapeutic interventions actually considered in prostate cancer therapy to compensate constitutive activation of the PI3K/Akt signalling pathway induced, particularly, by mutations of PTEN gene. Special emphasis is placed on applicability of EGF-R tyrosine kinase, COX-2, PDK-1, mTOR and farnesyltransferase inhibitors.
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The rapid developments of high-resolution imaging techniques are offering unique possibilities for the guidance and follow up of recently developed sophisticated anticancer therapies. Advanced biodegradable drug delivery systems, e.g. based on liposomes and polymeric nanoparticles or microparticles, are very effective tools to carry these anticancer agents to their site of action. Elements from the group of lanthanides have very interesting physical characteristics for imaging applications and are the ideal candidates to be co-loaded either in their non-radioactive or radioactive form into these advanced drug delivery systems because of the following reasons: Firstly, they can be used both as magnetic resonance imaging (MRI) and computed tomography (CT) contrast agents and for single photon emission computed tomography (SPECT). Secondly, they can be used for radionuclide therapies which, importantly, can be monitored with SPECT, CT, and MRI. Thirdly, they have a relatively low toxicity, especially when they are complexed to ligands. This review gives a survey of the currently developed lanthanide-loaded microparticulate systems that are under investigation for cancer imaging and/or cancer therapy.
Although the specific chromosomal translocation and fusion gene SYT-SSX in synovial sarcoma (SS) has been identified, the molecular mechanism of its tumorigenesis is largely unknown. Recent gene-expression profiles of soft-tissue tumors using cDNA microarray demonstrated that SS has the distinct gene-expression pattern from other sarcomas and has a similar pattern to that of malignant peripheral nerve sheath tumors, indicating that the origin of SS is likely to be the neural crest cells. Through this analysis, several genes were found to be specifically upregulated in SS and considered to play an important role in the proliferation of SS cells. Among them, Frizzled homolog 10 was identified as a good candidate molecule for the development of novel therapies to treat SS patients.