Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1658953 (tumor vasculature)
 2,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Combretastatins are stilbene-based, tubulin depolymerization agents with selective activity against the tumor vasculature; two variants (A-1 and A-4) are currently undergoing clinical trials. Combretastatin A-1 (CA1) has a greater antitumor effect than combretastatin A-4 (CA4). We hypothesized that this reflects the enhanced reactivity conferred by the second (ortho) phenolic moiety in CA1. Oxidation of CA1 by peroxidase, tyrosinase, or Fe(III) generates a species with mass characteristics of the corresponding ortho-quinone Q1. After administration of CA1-bis(phosphate) to mice, the hydroquinone-thioether conjugate Q1H2-SG, formed from the nucleophilic addition of GSH to Q1, was detected in liver. In competition, electrocyclic ring closure of Q1, over a few minutes at pH 7.4, leads to a second ortho-quinone product Q2, characterized by exact mass and NMR. This product was also generated by human promyelocytic leukemia (HL-60) cells in vitro, provided that superoxide dismutase was added. Q2 is highly reactive toward glutathione (GSH) and ascorbate, stimulating oxygen consumption in a catalytic manner. Free radical intermediates formed during autoxidation of CA1 were characterized by EPR, and the effects of GSH and ascorbate on the signals were studied. Pulse radiolysis was used to initiate selective one-electron oxidation or reduction and provided further evidence, from the differing absorption spectra of the radicals formed on oxidation of CA1 or reduction of Q2, that two different quinones were formed on oxidation of CA1. The results demonstrate fundamental differences between the pharmacological properties of CA1 and CA4 that provide two possible explanations for their differential activities in vivo: oxidative activation to a quinone intermediate likely to bind to protein thiols and possibly to nucleic acids and stimulation of oxidative stress by enhancing superoxide/hydrogen peroxide production. The observation of the GSH conjugate Q1H2-SG in vivo provides a new marker for oxidative metabolism of relevance to current clinical trials of CA1-bis(phosphate) (OXi4503).
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PMID:Oxidative metabolism of combretastatin A-1 produces quinone intermediates with the potential to bind to nucleophiles and to enhance oxidative stress via free radicals. 1794 99

Nonintrusive and precise imaging for tumor angiogenesis is critical in accurate assessment of cancer diagnosis and prognosis. However, reticulo-endothelial system (RES) capture and inadequate accumulation remain major bottlenecks for current nanoparticle to retain at tumor angiogenesis site. Herein, we report the ultrasmall contrast agent (cNGR-Au:Gd@GSH NMs) could accumulate at tumor vasculature site and enhance the tumor angiogenesis-contrast. It is demonstrated that by loading Au and Gd atom into the naturally-occurring glutathione (GSH) shell with cNGR peptide modification, cNGR-Au:Gd@GSH NMs exhibit the high X-ray photon absorption, longer rotational correlation time and efficient tumor vascular endothelia cell targeting. In vivo studies further indicate the cNGR-Au:Gd@GSH NMs prominently enhance tumor angiogenesis-contrast both on the computed tomography (CT) and magnetic resonance imaging (MRI) modalities by escaping the RES capture and target delivering. Our data imply that the cNGR-Au:Gd@GSH NMs may serve as the high-efficiency contrast agent to assess tumor angiogenesis in a nonintrusive technique.
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PMID:Ultrasmall bimodal nanomolecules enhanced tumor angiogenesis contrast with endothelial cell targeting and molecular pharmacokinetics. 3035 56

Cancer is a big challenge that has plagued the human beings for ages and one of the most effective treatments is chemotherapy. However, the low tumor-targeting ability limits the wide clinical application of chemotherapy. The microenvironment plays a critical role in many aspects of tumor genesis. It generates the tumor vasculature and it is highly implicated in the progression to metastasis. To maintain a suitable environment for tumor progression, there are special microenvironment in tumor cell, such as low pH, high level of glutathione (GSH) and reactive oxygen species (ROS), and more special enzymes, which is different to normal cell. Microenvironment-targeted therapy strategy could create new opportunities for therapeutic targeting. Compared to other targeting strategies, microenvironment-targeted therapy strategy will control the drug release into tumor cells more accurately. Redox responsive drug delivery systems (DDSs) are developed based on the high level of GSH in tumor cells. However, there are also GSH in normal cell though its level is lower. In order to control the release of drugs more accurately and reduce side effects, other drug release stimuli have been introduced to redox responsive DDSs. Under the synergistic reaction of two stimuli, redox dual-stimuli responsive DDSs will control the release of drugs more accurately and quickly and even increase the accumulation. This review summarizes strategies of redox dual-stimuli responsive DDSs such as pH, light, enzyme, ROS, and magnetic guide to delivery chemotherapeutic agents more accurately, aiming at providing new ideas for further promoting the drug release, enhancing tumor-targeting and improving anticancer effects. To better illustrate the redox dual-stimuli responsive DDS, preparations of carriers are also briefly described in the review.
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PMID:Redox dual-stimuli responsive drug delivery systems for improving tumor-targeting ability and reducing adverse side effects. 3263 49