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      Transport of drugs from blood vessels to tumour tissue

      research-article
      Author(s): 1 , 2
      Publication date (Electronic):
      Journal: Nature reviews. Cancer

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          Abstract

          The effectiveness of anticancer drugs in treating a solid tumour is dependent on delivery of the drug to virtually all cancer cells in the tumour. The distribution of drug in tumour tissue depends on the plasma pharmacokinetics, the structure and function of the tumour vasculature and the transport properties of the drug as it moves through microvessel walls and in the extravascular tissue. The aim of this Review is to provide a broad, balanced perspective on the current understanding of drug transport to tumour cells and on the progress in developing methods to enhance drug delivery. First, the fundamental processes of solute transport in blood and tissue by convection and diffusion are reviewed, including the dependence of penetration distance from vessels into tissue on solute binding or uptake in tissue. The effects of the abnormal characteristics of tumour vasculature and extravascular tissue on these transport properties are then discussed. Finally, methods for overcoming limitations in drug transport and thereby achieving improved therapeutic results are surveyed.

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          Most cited references114

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          Hypoxia in cancer: significance and impact on clinical outcome.

          Peter Vaupel, Arnulf Mayer (2007)
          Hypoxia, a characteristic feature of locally advanced solid tumors, has emerged as a pivotal factor of the tumor (patho-)physiome since it can promote tumor progression and resistance to therapy. Hypoxia represents a "Janus face" in tumor biology because (a) it is associated with restrained proliferation, differentiation, necrosis or apoptosis, and (b) it can also lead to the development of an aggressive phenotype. Independent of standard prognostic factors, such as tumor stage and nodal status, hypoxia has been suggested as an adverse prognostic factor for patient outcome. Studies of tumor hypoxia involving the direct assessment of the oxygenation status have suggested worse disease-free survival for patients with hypoxic cervical cancers or soft tissue sarcomas. In head & neck cancers the studies suggest that hypoxia is prognostic for survival and local control. Technical limitations of the direct O(2) sensing technique have prompted the use of surrogate markers for tumor hypoxia, such as hypoxia-related endogenous proteins (e.g., HIF-1alpha, GLUT-1, CA IX) or exogenous bioreductive drugs. In many - albeit not in all - studies endogenous markers showed prognostic significance for patient outcome. The prognostic relevance of exogenous markers, however, appears to be limited. Noninvasive assessment of hypoxia using imaging techniques can be achieved with PET or SPECT detection of radiolabeled tracers or with MRI techniques (e.g., BOLD). Clinical experience with these methods regarding patient prognosis is so far only limited. In the clinical studies performed up until now, the lack of standardized treatment protocols, inconsistencies of the endpoints characterizing the oxygenation status and methodological differences (e.g., different immunohistochemical staining procedures) may compromise the power of the prognostic parameter used.
          Article 0 comments Cited 692 times – based on 0 reviews     Review now
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            Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers.

            Rakesh Jain (2013)
            For almost four decades, my work has focused on one challenge: improving the delivery and efficacy of anticancer therapeutics. Working on the hypothesis that the abnormal tumor microenvironment-characterized by hypoxia and high interstitial fluid pressure--fuels tumor progression and treatment resistance, we developed an array of sophisticated imaging technologies and animal models as well as mathematic models to unravel the complex biology of tumors. Using these tools, we demonstrated that the blood and lymphatic vasculature, fibroblasts, immune cells, and extracellular matrix associated with tumors are abnormal, which together create a hostile tumor microenvironment. We next hypothesized that agents that induce normalization of the microenvironment can improve treatment outcome. Indeed, we demonstrated that judicious use of antiangiogenic agents--originally designed to starve tumors--could transiently normalize tumor vasculature, alleviate hypoxia, increase delivery of drugs and antitumor immune cells, and improve the outcome of various therapies. Our trials of antiangiogenics in patients with newly diagnosed and recurrent glioblastoma supported this concept. They revealed that patients whose tumor blood perfusion increased in response to cediranib survived 6 to 9 months longer than those whose blood perfusion did not increase. The normalization hypothesis also opened doors to treating various nonmalignant diseases characterized by abnormal vasculature, such as neurofibromatosis type 2. More recently, we discovered that antifibrosis drugs capable of normalizing the tumor microenvironment can improve the delivery and efficacy of nano- and molecular medicines. Our current efforts are directed at identifying predictive biomarkers and more-effective strategies to normalize the tumor microenvironment for enhancing anticancer therapies.
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              Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid

              D Senger, S Galli, A. Dvorak … (1983)
              Tumor ascites fluids from guinea pigs, hamsters, and mice contain activity that rapidly increases microvascular permeability. Similar activity is also secreted by these tumor cells and a variety of other tumor cell lines in vitro. The permeability-increasing activity purified from either the culture medium or ascites fluid of one tumor, the guinea pig line 10 hepatocarcinoma, is a 34,000- to 42,000-dalton protein distinct from other known permeability factors.
              Article 0 comments Cited 329 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101124168
                Journal ID (pubmed-jr-id): 27016
                Journal ID (nlm-ta): Nat Rev Cancer
                Journal ID (iso-abbrev): Nat. Rev. Cancer
                Title: Nature reviews. Cancer
                ISSN (Print): 1474-175X
                ISSN (Electronic): 1474-1768
                Publication date Nihms-submitted: 3 October 2018
                Publication date (Electronic): 10 November 2017
                Publication date (Print): December 2017
                Publication date PMC-release: 12 February 2019
                Volume: 17
                Issue: 12
                Pages: 738-750
                Affiliations
                [1 ]Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.
                [2 ]Department of Physiology, University of Arizona, Tucson, Arizona 85724, USA.
                Author notes
                Correspondence to M.W.D. mark.dewhirst@ 123456duke.edu

                Author contributions

                M.W.D. accepted the commission to prepare this Review and prepared the outline in collaboration with T.W.S. M.W.D. researched data in collaboration with T.W.S. M.W.D and T.W.S. contributed equally to writing and revising the text.

                Article
                Accession ID: PMC6371795 Pmcid ID: PMC6371795 Pmc-uid ID: 6371795 Manuscript ID: nihpa980688
                DOI: 10.1038/nrc.2017.93
                PMC ID: 6371795
                PubMed ID: 29123246
                SO-VID: 85a23922-86b2-41d0-8134-83a250b49cd6
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