Evaluations of vascular disrupting agents CA4P and OXi4503 in renal cell carcinoma (Caki-1) using a silicon based microvascular casting technique

Salmon, Howard W.; Mladinich, Christopher R.J.; Siemann, Dietmar W.

doi:10.1016/j.ejca.2006.06.016

Cited by 22 publications

(17 citation statements)

References 21 publications

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“…[83][84][85][86] This secondary mechanism is believed to be favourable for its in vivo activities and to be partly responsible for the slightly superior activity of CA-1P over CA-4P. 87,88 Moreover, compound 19 can act as a VDA. 89 …”

Section: Biological Activities Of Ca-1 and Its Corresponding Prodrugmentioning

confidence: 99%

ortho-Formylation of oxygenated phenols

Akselsen

Skattebøl

Hansen

2009

Tetrahedron Letters

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Section: Biological Activities Of Ca-1 and Its Corresponding Prodrugmentioning

confidence: 99%

ortho-Formylation of oxygenated phenols

Akselsen

Skattebøl

Hansen

2009

Tetrahedron Letters

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“…The effect of CA-4 was also evaluated in combination with Oxi4503, the diphosphate prodrug of CA1P (Pettit, 1989) in an orthotopically transplanted human renal cell carcinoma xenograft model, by the vascular casting and the chord-length distribution techniques (Salmon, 2006a;Salmon, 2006b). The results illustrated the loss of tumour vasculature and induction of wide scale necrosis in the central regions of the tumour.…”

Section: Targeting the Tumour Vasculature In Vivomentioning

confidence: 99%

“…Extensive haemorrhagic necrosis after treatments was observed in vascularized but not in avascular tumours in mice both at the primary and metastatic sites. This observation is the clearest evidence that a direct effect of these compounds on tumour vasculature is essential for anti-tumour activity in vivo.The effect of CA-4 was also evaluated in combination with Oxi4503, the diphosphate prodrug of CA1P (Pettit, 1989) in an orthotopically transplanted human renal cell carcinoma xenograft model, by the vascular casting and the chord-length distribution techniques (Salmon, 2006a;Salmon, 2006b). The results illustrated the loss of tumour vasculature and induction of wide scale necrosis in the central regions of the tumour.…”

mentioning

confidence: 99%

The use of the orthotopic model to validate antivascular therapies for cancer

Loi¹,

Paolo²,

Becherini³

et al. 2011

Int. J. Dev. Biol.

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The orthotopic model reproduces aspects of the tumour microenvironment and emulates a number of important biological features of cancer progression, angiogenesis, metastasis and resistance. Due to its parallels with human cancer, the model can be used to evaluate therapeutic responses to various therapies. This review outlines the importance of using the orthotopic implantation of tumour cells in mice models for evaluating the effectiveness of antivascular therapies. KEY WORDS: orthotopic model, vascular disrupting agent, antivascular therapy, cancer Tumour vasculature and antivascular therapiesA functioning and continuously expanding vascular network is essential for tumour development, growth, survival and metastasis (Hanahan and Folkman, 1996). Given its pivotal role in these processes, tumour vasculature is a highly attractive target in anticancer therapy. Compared with the vasculature in normal tissue, the tumour vasculature is strikingly disorganized and tortuous (Eberhard, 2000;Konerding, 2001;McDonald and Choyke, 2003), its wall is poorly developed, often with discontinuous endothelial-cell lining, has relatively poor investiture with vascular smooth muscle cells, poor connections between pericytes and endothelial cells (Dvorak, 1988;Eberhard, 2000;Hashizume, 2000;Kobayashi, 1993) and an irregular, structurally abnormal basement membrane (Baluk, 2003;Paku and Paweletz, 1991). Endothelial cells themselves are often irregularly shaped, forming an uneven luminal layer, with loose interconnections and focal intercellular openings (Hashizume, 2000). These features contribute to a high intrinsic vascular permeability of macromolecules into the vasculature (Dvorak, 1991;Jain, 1987) and the consequent development of high interstitial fluid pressure (Boucher, 1990), which is augmented by inadequate lymphatic drainage. Tumour vascular networks are chaotic, featuring complex branching patterns and lack of hierarchy (Gillies, 1999;Konerding, 1999;Less, 1991). Vessel diameters are irregular and lengths between branching points are often very long. The result is a high geometrical resistance to blood flow, that such as small decreases in perfusion pressure, which have little Int. J. Dev. Biol. 55: [547][548][549][550][551][552][553][554][555] doi: 10.1387/ijdb.103230ml www.intjdevbiol.com *Address correspondence to: Mirco Ponzoni or Fabio Pastorino. Experimental Therapies Unit, Laboratory of Oncology, G. Gaslini Children's Hospital, 16148-Genoa, Italy. Tel: +39-010-5636342. Fax: +39-010-3779820. e-mail: mircoponzoni@ospedale-gaslini.ge.it or fabiopastorino@ospedale-gaslini.ge.it # These Authors share the last co-authorship. effect in normal tissues, can be catastrophic in tumours (Sevick and Jain, 1989). Capillary blood contains abnormally high levels of deoxygenated blood (Mueller-Klieser, 1981), which, combined with heterogeneous blood flow and large intercapillary distances, contributes to micro-regional hypoxia in tumours (Vaupel and Hockel, 2000). The tumour is also starved of nutrient, under acidic cond...

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“…A single cell suspension of approximately 5x10 3 to 10x10 3 cells prepared in serum-free DMEM was used to initiate tumors in window chambers of the experimental mice. Caki-1 tumor xenografts (18) were initiated in a single hind limb of donor mice by inoculating with 2x10 5 to 5x10 5 tumor cells. Tumors were excised when they reached about 200 mm 3 in size, and a single cell suspension was prepared in DMEM.…”

Section: Methodsmentioning

confidence: 99%

“…This surviving 'viable rim' can lead to subsequent tumor reperfusion and regrowth following drug treatment (11,12). In preclinical models and some clinical studies, functional and morphological parameters such as tumor perfusion, blood flow, vascular structure, permeability and vascular damage are used to evaluate the effect of OXi4503 and CA4-P on tumor and normal tissue (11,(16)(17)(18)(19). Some of the methods used cannot furnish continuous real-time in vivo information as they require animal euthanasia at the respective time-points and do not permit serial follow-up of the same tumor after VDA treatment.…”

Section: Introductionmentioning

confidence: 99%

In vivo functional differences in microvascular response of 4T1 and Caki-1 tumors after treatment with OXi4503

Sorg¹

2010

Oncol Rep

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Abstract. 4T1 mouse mammary adenocarcinomas and Caki-1 human renal cell carcinomas grown in mouse dorsal window chambers were serially treated with the vascular disrupting agent (VDA) OXi4503 and their responses compared. The real-time in vivo response was assessed using spectral imaging of microvascular hemoglobin saturation. To our knowledge this is the first use of spectral imaging technology for investigation of vascular disrupting agents. Previous research showing tumor size dependence in the treatment response to VDAs suggested that for the size of tumors used in this study only a moderate response would be observed; however, the tumors unexpectedly had very different responses to treatment. Caki-1 tumors showed little permanent vessel damage and experienced transient vessel collapse with time-dependent oxygenation changes followed by recovery starting at 6 h after treatment. Caki-1 tumors did not manifest necrotic avascular regions even after repeated treatments. These results are consistent with those obtained using other imaging modalities and histology. In contrast, similarly sized 4T1 tumors showed extensive vessel disintegration, minor vascular collapse, and a drop in tumor oxygenation up to 6 h post-treatment, after which reperfusion of collapsed vessels and extensive vascular remodeling and neovascularization of the tumor rim occurred from 8-48 h. The completely disintegrated vessels did not recover and left behind avascular and apparently necrotic regions in the tumor core. Spectral imaging appears to be a useful technique for in vivo investigation of vascular disrupting agents. The differential responses of these two tumor-types suggest that further investigation of the mechanisms of action of VDAs and individual characterization of tumor VDAresponses may be needed for optimal clinical use of these agents.

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Evaluations of vascular disrupting agents CA4P and OXi4503 in renal cell carcinoma (Caki-1) using a silicon based microvascular casting technique

Cited by 22 publications

References 21 publications

ortho-Formylation of oxygenated phenols

ortho-Formylation of oxygenated phenols

The use of the orthotopic model to validate antivascular therapies for cancer

In vivo functional differences in microvascular response of 4T1 and Caki-1 tumors after treatment with OXi4503

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