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Ways to improve tumor uptake and penetration of drugs into solid tumors

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889193509 Year: Pages: 129 DOI: 10.3389/978-2-88919-350-9 Language: English
Publisher: Frontiers Media SA
Subject: Oncology --- Medicine (General) --- Therapeutics --- Science (General)
Added to DOAB on : 2016-03-10 08:14:32
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The main scope of this topic is to give an update on pharmacologic and non-pharmacologic approaches to enhance uptake and penetration of cancer drugs into tumors. Inadequate accumulation of drugs in tumors has emerged over the last decade as one of the main problems underlying therapeutic failure and drug resistance in the treatment of cancer. Insufficient drug uptake and penetration is causally related to the abnormal tumor architecture. Thus, poor vascularization, increased resistance to blood flow and impaired blood supply represent a first obstacle to the delivery of antitumor drugs to tumor tissue. Decreased or even inverted transvascular pressure gradients compromise convective delivery of drugs. Eventually, an abnormal extracellular matrix offers increased frictional resistance to tumor drug penetration. Abnormal tumor architecture also changes the biology of tumor cells, which contributes to drug resistance through several different mechanisms. The variability in vessel location and structure can make many areas of the tumor hypoxic, which causes the tumor cells to become quiescent and thereby resistant to many antitumor drugs. In addition, the abnormally long distance of part of the tumor cell population from blood vessels provides a challenge to delivering cancer drugs to these cells. We have recently proposed additional mechanisms of tumor drug resistance, which are also related to abnormal tumor architecture. First, increased interstitial fluid pressure can by itself induce drug resistance through the induction of resistance-promoting paracrine factors. Second, the interaction of drug molecules with vessel- proximal tumor cell layers may also induce the release of these factors, which can spread throughout the cancer, and induce drug resistance in tumor cells distant from blood vessels. As can be seen, abnormal tumor architecture, inadequate drug accumulation and tumor drug resistance are tightly linked phenomena, suggesting the need to normalize the tumor architecture, including blood vessels, and/or increase the accumulation of cancer drugs in tumors in order to increase therapeutic effects. Indeed, several classes of drugs (that we refer to as promoter drugs) have been described, that promote tumor uptake and penetration of antitumor drugs, including those that are vasoactive, modify the barrier function of tumor vessels, debulk tumor cells, and overcome intercellular and stromal barriers. In addition, also non-pharmacologic approaches have been described that enhance tumor accumulation of effector drugs (e.g. convection-enhanced delivery, hyperthermia, etc.). Some drugs that have already received regulatory approval (e.g. the anti-VEGF antibody bevacizumab) exert antitumor effects at least in part through normalization of the tumor vasculature and enhancement of the accumulation of effector drugs. Other drugs, acting through different mechanisms of action, are now in clinical development (e.g. NGR-TNF in phase II/III studies) and others are about to enter clinical investigation (e.g. JO-1).

Ethanol, Its Active Metabolites, and Their Mechanisms of Action: Neurophysiological and Behavioral Effects

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889455164 Year: Pages: 184 DOI: 10.3389/978-2-88945-516-4 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Neurology
Added to DOAB on : 2019-01-23 14:53:42
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Ethanol, the main psychopharmacologically active ingredient of alcoholic drinks, represents a paradigmatic example of a research subject intrinsically able to perpetually self-generate interdisciplinary cutting-edge investigations.This eBook was inspired by the aim of providing an up-to-date characterization of the diverse effects of ethanol, of the possible mechanisms of action on different intracellular systems as well as of the hypothesized actions of ethanol and/or its metabolites on various neurotransmitters and neuromodulators.Indeed, the eBook provides a factual example of an excellent synthesis on the complex relationship between ethanol and its main biologically active metabolites (Chapter 1), on the behavioral and molecular consequences of early exposure to them (Chapter 2), on the recent proposals, advanced by the preclinical research, for new therapeutic approaches to distinct aspects of alcoholism (Chapter 3) and on the most recent and original preclinical evidence of the interactions between ethanol and/or its metabolites and the dopaminergic, adenosinergic and endocannabinoidergic systems (Chapter 4).Overall we believe that this eBook accomplishes its main goals of widening the perspective on this research subject and offering the readership a newer and, simultaneously, up-to-date and comprehensive scenery on ethanol’s and ethanol's active metabolites neurophysiological and behavioral effects.

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