Vasculature and microenvironmental gradients: the missing links in novel approaches to cancer therapy?

Denekamp, Juliana; Daşu, Alexandru; Waites, Anthony B.

doi:10.1016/s0065-2571(97)00015-0

Cited by 47 publications

(38 citation statements)

References 31 publications

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“…One such strategy has since recent years been approached through the means of angiogenesis for several reasons: (i) the passage from normal tissue to hyperplasia and to tumorigenesis is related to an angiogenic switch (Hanahan and Folkman, 1996); (ii) angiogenesis is a dynamic balance between stimulators and inhibitors (Hanahan and Folkman, 1996;IruelaArispe and Dvorak, 1997). In the absence of angiogenesis the balance is in favour of the inhibitors which as such can account for tumour and micrometastases 'dormancy' (Folkman, 1995a;Holmgren et al, 1995); (iii) Due to its specific characteristics, the tumour vasculature constitutes a common feature between the various tumoral tissues (Denekamp et al, 1998). These data have opened an extensive field of investigation to find new anti-angiogenic molecules.…”

Section: Discussionmentioning

confidence: 99%

“…One common element among their characteristics is the tumour vasculature which shares identical features throughout the tumoral tissues and which is different from the vasculature of normal tissues. The tumour vasculature has an immature endothelium and forms an abnormal network of leaky vessels with chaotic flow (Denekamp et al, 1998). Below a critical size of 1 -2 mm 3 metastases are supposed not to need to be vascularised for their nutritive supply (Folkman, 1990).…”

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confidence: 99%

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Anti-angiogenic effects of the thienopyridine SR 25989 in vitro and in vivo in a murine pulmonary metastasis model

Céraline

Deplanque

et al. 2002

Br J Cancer

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Neovascularisation is a key step in tumour growth and establishment of distant metastases. We have recently demonstrated that the thienopyridine SR 25989 an enantiomer of the anti-aggregant clopidogrel (Plavix 1 ) lacking anti-aggregant activity, inhibits endothelial cell proliferation in vitro by increasing the expression of endogenous thrombospondin-1, a natural potent inhibitor of angiogenesis. The anti-angiogenic effect of SR 25989 was further assessed in vitro in a quantitative assay of angiogenesis comprising a fragment of rat aorta embedded in a fibrin gel and in vivo in a pulmonary metastatic model using C57BL/6 mice inoculated in the foot pad with the highly metastatic melanoma cell line B16 F10. SR 25989 induced a dose dependent inhibition of spontaneous microvessel development in vitro reaching half maximal inhibition at around less than 50 mM and caused platelet derived growth factor induced angiogenesis to regress as a function of thienopyridine concentration. In vivo, SR 25989 did not alter significantly the growth rate of the primary tumour in the foot pad and did not inhibit development of inguinal nodes which appeared after amputation. However, the number and size of lung metastases were reduced in treated animals when examined at the time of sacrifice. In addition, the few metastases over 1 mm 3 did not show any neovascularisation, as confirmed by negative von Willebrand immunostaining and in contrast to intense vascularisation seen in metastases developed by control mice. These results confirm that SR 25989 possesses potent antiangiogenic properties and is able to inhibit metastatic dissemination and growth. The lack of effect on the primary tumour and inguinal nodes illustrates the complexity of the mechanisms involved in tumoural neo-angiogenesis and points out the possibility for distinct processes leading to neovascularisation in primary tumour as opposed to metastases.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Anti-angiogenic effects of the thienopyridine SR 25989 in vitro and in vivo in a murine pulmonary metastasis model

Céraline

Deplanque

et al. 2002

Br J Cancer

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“…This results in the establishment of a microenvironment that can have profound effects on tumour biology and response to chemotherapy. The tumour microenvironment is characterized by gradients of oxygen tension, nutrient status, catabolite concentrations, extracellular pH, cell proliferation rates and a multitude of biochemical changes that enable cells to adapt to these hostile conditions [2], unless conditions become so extreme that tumour cells cannot survive and regions of necrosis occur. Where delivery of cancer drugs to cells within the tumour microenvironment is impaired, these cells are 'pharmacokinetically resistant'; this form of resistance, distinct from cellular resistance, is increasingly recognized as a barrier to effective treatment [3].…”

Section: Introductionmentioning

confidence: 99%

Mathematical and computational models of drug transport in tumours

Groh

Hubbard

Jones

et al. 2014

J. R. Soc. Interface.

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The ability to predict how far a drug will penetrate into the tumour microenvironment within its pharmacokinetic (PK) lifespan would provide valuable information about therapeutic response. As the PK profile is directly related to the route and schedule of drug administration, an in silico tool that can predict the drug administration schedule that results in optimal drug delivery to tumours would streamline clinical trial design. This paper investigates the application of mathematical and computational modelling techniques to help improve our understanding of the fundamental mechanisms underlying drug delivery, and compares the performance of a simple model with more complex approaches. Three models of drug transport are developed, all based on the same drug binding model and parametrized by bespoke in vitro experiments. Their predictions, compared for a 'tumour cord' geometry, are qualitatively and quantitatively similar. We assess the effect of varying the PK profile of the supplied drug, and the binding affinity of the drug to tumour cells, on the concentration of drug reaching cells and the accumulated exposure of cells to drug at arbitrary distances from a supplying blood vessel. This is a contribution towards developing a useful drug transport modelling tool for informing strategies for the treatment of tumour cells which are 'pharmacokinetically resistant' to chemotherapeutic strategies.

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“…One hypothesis that has received experimental support is the rapid regeneration of normal microvessels damaged in the direct paths of thin MBs (1,6,10,16). The MBs' preferential tumoricidal effects, or strong tumor palliation properties, are due, in part, to the lack of recovery of the tumor vasculature l (2,7,8), presumably because of structural differences between microvessels of tumor and those of the surrounding normal tissue (17).…”

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confidence: 99%

Interlaced x-ray microplanar beams: A radiosurgery approach with clinical potential

Dilmanian

Zhong²,

Bacarian³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

167

208

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Studies have shown that x-rays delivered as arrays of parallel microplanar beams (microbeams), 25-to 90-m thick and spaced 100 -300 m on-center, respectively, spare normal tissues including the central nervous system (CNS) and preferentially damage tumors. However, such thin microbeams can only be produced by synchrotron sources and have other practical limitations to clinical implementation. To approach this problem, we first studied CNS tolerance to much thicker beams. Three of four rats whose spinal cords were exposed transaxially to four 400-Gy, 0.68-mm microbeams, spaced 4 mm, and all four rats irradiated to their brains with large, 170-Gy arrays of such beams spaced 1.36 mm, all observed for 7 months, showed no paralysis or behavioral changes. We then used an interlacing geometry in which two such arrays at a 90°angle produced the equivalent of a contiguous beam in the target volume only. By using this approach, we produced 90-, 120-, and 150-Gy 3.4 ؋ 3.4 ؋ 3.4 mm 3 exposures in the rat brain. MRIs performed 6 months later revealed focal damage within the target volume at the 120-and 150-Gy doses but no apparent damage elsewhere at 120 Gy. Monte Carlo calculations indicated a 30-m dose falloff (80 -20%) at the edge of the target, which is much less than the 2-to 5-mm value for conventional radiotherapy and radiosurgery. These findings strongly suggest potential application of interlaced microbeams to treat tumors or to ablate nontumorous abnormalities with minimal damage to surrounding normal tissue.

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Vasculature and microenvironmental gradients: the missing links in novel approaches to cancer therapy?

Cited by 47 publications

References 31 publications

Anti-angiogenic effects of the thienopyridine SR 25989 in vitro and in vivo in a murine pulmonary metastasis model

Anti-angiogenic effects of the thienopyridine SR 25989 in vitro and in vivo in a murine pulmonary metastasis model

Mathematical and computational models of drug transport in tumours

Interlaced x-ray microplanar beams: A radiosurgery approach with clinical potential

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