Current cancer drug targets
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Curr Cancer Drug Targets · Dec 2010
Inhibition of membrane complement inhibitor expression (CD46, CD55, CD59) by siRNA sensitizes tumor cells to complement attack in vitro.
The efficacy of cancer-immunotherapy with complement-activating monoclonal antibodies is limited by over-expression of one or more membrane-bound complement regulatory proteins (mCRPs: CD46, CD55, CD59) on the surface of neoplastic cells. In this study we designed small interfering RNAs (siRNAs) for posttranscriptional gene knock down of CD46, CD55 and CD59 aiming at to sensitize tumor cells to complement attack and thereby to better exploit complement for tumor cell destruction. Tumor cell lines of different origin, such as Du145 (prostate), BT474 (breast) and K562 (erythroleukemia) were selected for the study. ⋯ The combined inhibition of all three inhibitors further enhanced CDC by up to 66%. Dependent on the cell line, CD46 and CD55 downregulation increased significantly C3 ospsonization, which is known to support cell-mediated defense mechanisms. mCRP blocking antibodies were only partly able to further augment the tumor cells' susceptibility to complement lysis. Thus, siRNA-induced inhibition of complement regulator expression clearly sensitizes malignant cells to complement attack and, if specifically targeted to the tumor, appears suited as adjuvant to improve antibody-based cancer immunotherapy.
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Curr Cancer Drug Targets · Nov 2010
ReviewThe role of oxidative stress and anti-oxidant treatment in platinum-induced peripheral neurotoxicity.
Platinum-based anticancer drugs are a cornerstone of the current antineoplastic treatment. However, their use is limited by the onset of peripheral nervous system dysfunction, which can be severe and persistent over a long period of time. ⋯ In fact, DRG energy failure has been suggested as a result of mitochondrial DNA-platinum binding and several antioxidant drugs have been tested in pre-clinical experiments and clinical trials. In this review, an update on the current knowledge on the relationship existing between oxidative stress and platinum drugs peripheral neurotoxicity will be given.
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The treatment of sarcoma urgently requires new, innovative therapeutic strategies. The most recent improvements in the cure of patients with localized disease have been achieved by dose-intensification, in turn paying the price of acute severe toxicity and secondary malignancies. ⋯ The present review highlights key examples of target identification in bone sarcomas, including chimeric oncoproteins, insulin-like growth factor receptor (IGF-IR), and tumor/microenvironment interactions. The review identifies questions and concerns that still need to be addressed before proceeding to safe clinical trials with agents against these promising new targets.
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Curr Cancer Drug Targets · Jun 2009
ReviewPotential uses of microRNA in lung cancer diagnosis, prognosis, and therapy.
Lung cancer is the leading cause of death from cancer in the world. Although the molecular network of lung carcinogenesis has been partly known at the levels of genes and proteins, and personalized therapy based on the genetic changes has made considerable progress in the last decade, the high mortality rate is not markedly changed. MicroRNAs (miRNAs), a class of short endogenous RNAs, acting as post-transcriptional regulators of gene expression, are similar with siRNAs in both the biosynthesis and the function steps. ⋯ Moreover, miRNAs may serve as either novel potential targets acting directly as oncogenes (e.g. miR-17-92 cluster) or directly therapeutic molecules working as tumor suppressor genes (e.g. let-7 family). RNAi technology based on miRNAs has many advantages over siRNAs, such as in vivo stability, highly RNA promoter-compatibility and no overt toxicity. Eventually, it might overcome the present disadvantages and become a good candidate for lung cancer therapy.
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Curr Cancer Drug Targets · Aug 2006
ReviewRadiation-induced bystander and other non-targeted effects: novel intervention points in cancer therapy?
A major problem in the search for new cancer drug targets is that the drugs are often toxic to normal tissues and require high doses to kill tumor cells. Therefore cellular targets which appear to involve low dose responses to cancer therapy are especially interesting since they could selectively target normal tissues which are not targeted by the treatment and thus may be responsible for unpleasant side effects or may be amenable to exploitation in order to improve the therapeutic ratio. One such target, which is the subject of this review, is radiation-induced bystander effects [RIBE], which result in the observation of radiation like responses in cells which have not been irradiated. ⋯ In this scenario, the level of harmful or beneficial response will be related to the background damage, carried by the cell population, and the genetic programme determining response to damage. This focus may be important when attempting to predict the consequences of mixed therapies involving radiation and other cytotoxic agents. In this review, our current knowledge of the mechanisms underlying the induction of bystander effects by ionizing radiation is reviewed, and the question of how bystander effects may be harnessed to produce a new generation of anti-cancer drugs aimed at stabilization of tissue homeostasis rather than tissue destruction is considered.