KRN951, a Highly Potent Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinases, Has Antitumor Activities and Affects Functional Vascular Properties

Nakamura, Kazuhide; Taguchi, Eri; Miura, Tsuyoshi; Yamamoto, Atsushi; Takahashi, Kohei; Bichat, Francis; Guilbaud, Nicolas; Hasegawa, Koki; Kubo, Kazuo; Fujiwara, Yasunari; Suzuki, Rika; Kubo, Kin‐ya; Shibuya, Masabumi; Isae, Toshiyuki

doi:10.1158/0008-5472.can-05-4290

Cited by 197 publications

(146 citation statements)

References 36 publications

Supporting

Mentioning

139

Contrasting

Order By: Relevance

“…Furthermore, although the vascular casts presented clearly revealed the presence of transluminal pillars, the authors did not recognize the phenomenon of intussusceptive angiogenesis. Similar changes in vasculature have been observed in murine orthotopic B16/BL6 melanoma tumor model after treatment with either PTK/ZK (Rudin et al, 2005) or other tyrosine kinase inhibitors (Nakamura et al, 2004;Nakamura et al, 2006;Ruggeri et al, 2003). In each instance, the depicted changes in the vasculature corresponded to those associated with intussusception.…”

Section: B Asupporting

confidence: 58%

Escape mechanisms after antiangiogenic treatment, or why are the tumors growing again?

Hlushchuk

Makanya²,

Djonov

2011

Int. J. Dev. Biol.

View full text Add to dashboard Cite

�nhi�itors of angiogenesis an� ra�iation in�uce compensatory changes in the tumor �as� �nhi�itors of angiogenesis an� ra�iation in�uce compensatory changes in the tumor �as� culature �oth �uring an� after cessation of treatment. �n numerous preclinical stu�ies, angiogenesis inhi�itors were shown to �e efficient in the treatment of many pathological con�itions, inclu�ing soli� cancers. �n most clinical trials, howe�er, this approach turne� out to ha�e no significant effect, especially if applie� as monotherapy. Reco�ery of tumors after therapy is a major pro�lem in the management of cancer patients. The mechanisms un�erlying tumor reco�ery (or therapy resistance)ha�e not yet �een explicitly eluci�ate�. This re�iew �eals with the transient switch from sprouting to intussuscepti�e angiogenesis, which may �e an a�apti�e response of tumor �asculature to cancer therapy that allows the �asculature to maintain its functional properties. Potential can�i�ates for molecular targeting of this angioa�apti�e mechanism are yet to �e eluci�ate� in or�er to impro�e the currently poor efficacy of contemporary antiangiogenic therapies. KEY WORDS: antiangiogenic therapy, anticancer therapy, protein tyrosine kinase inhibitor, tumor recovery, intussusceptive angiogenesis, escape mechanism Tumor angiogenesisAngiogenesis, the process of formation of new blood vessels from pre-existing ones, plays an essential role in the tumour growth and progression. New vascular segments are needed to supply the increasing tumour mass with oxygen and nutrients. Hence, the crucial step for tumour growth above the size of 1-2 mm 3 is the "angiogenic switch", when the tumour gains capability to produce angiogenic factors and induce angiogenesis (Hanahan and Folkman, 1996). Modes of angiogenesisTwo major modes of angio ge nesis have been described, namely sprouting and intussusception (often also called "non-sprouting" or splitting) (Burri et al., 2004). Sprouting angiogenesis was described more than 150 years ago and has been in the focus of research groups for many decades. This mode of angiogenesis occurs by outgrowth of abluminal sprouts which subsequently merge with existing capillaries. Degradation of endothelial basement membranes (obviously associated with increased vessel permeability) as well as proliferation of endothelial cells are essential for this process (van Hinsbergh and Koolwijk, 2008). This mode of angiogenesis Int.

show abstract

Section: B Asupporting

confidence: 58%

Escape mechanisms after antiangiogenic treatment, or why are the tumors growing again?

Hlushchuk

Makanya²,

Djonov

2011

Int. J. Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…Anti-angiogenic agents such as anti-VEGF antibody and tyrosine kinase inhibitor were reported that decrease both K trans and IAUGC (O'Connor et al, 2007;Bradley et al, 2008;Bradley et al, 2009), and the decrease in K trans in solid tumours is concerned with the anti-tumour effect (Morgan et al, 2003;Marzola et al, 2004;Nakamura et al, 2006;Flaherty et al, 2008). In this study, K trans , IAUGC 60 , and v p were increased significantly 24 h after the A-83-01 treatment.…”

Section: Discussionmentioning

confidence: 57%

“…Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is one of the evaluation methods of anti-angiogenic agents, such as anti-VEGF antibody and tyrosine kinase inhibitor, clinically (Morgan et al, 2003;O'Connor et al, 2007) and preclinically (Marzola et al, 2004;Nakamura et al, 2006;Bradley et al, 2009), by calculating pharmacokinetic parameters, including fractional plasma volume (v p ) and the volume transfer constant (K trans ) from the enhancement of tumour signal intensity by gadolinium (Gd) contrast agent (Tozer, 2003;Kiessling et al, 2007). To my knowledge, however, there are no reports to evaluate TbR-I inhibitor by DCE-MRI.…”

mentioning

confidence: 99%

Increase in tumour permeability following TGF-β type I receptor-inhibitor treatment observed by dynamic contrast-enhanced MRI

Minowa

Kawano

Kuribayashi³

et al. 2009

Br J Cancer

View full text Add to dashboard Cite

BACKGROUND: To enhance the success rate of nanocarrier-mediated chemotherapy combined with an anti-angiogenic agent, it is crucial to identify parameters for tumour vasculature that can predict a response to the treatment of the anti-angiogenic agent. METHODS: To apply transforming growth factor (TGF)-b type I receptor (TbR-I) inhibitor, A-83-01, to combined therapy, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was carried out in mice bearing colon 26 cells using gadolinium (Gd)-DTPA and for its liposomal formulation to evaluate changes in tumour microvasculature following A-83-01. Tumour vascular parameters from DCE-MRI were compared with histological assessment and apparent diffusion coefficient of water in tumour generated by diffusion-weighted MRI. RESULTS: Contrary to evaluations reported for anti-angiogenic agents, A-83-01 treatment increased the initial area under the Gd concentration -time curve (IAUGC 60 ), volume transfer constant (K trans ) and fractional plasma volume (v p ) significantly within 24 h, that was positively related to a-smooth muscle actin-positive pericyte coverage and tumour cell proliferation, and was correlated inversely with the apparent diffusion coefficient. The vascular function of the tumour improved by A-83-01 treatment was well assessed on post-liposomal Gd-DTPA-enhanced MR images, which predicted delivery of a liposomal drug to the tumour. CONCLUSION: These findings suggest that DCE-MRI and, in particular, K trans and v p quantitation, provide important additional information about tumour vasculature by A-83-01 treatment.

show abstract

“…In addition, nestin inhibits the growth of human primary cultured vascular endothelial cells in vitro. Thus, nestin may serve as a novel therapeutic target in PDAC angiogenesis similar to VEGFR inhibitors (58). Furthermore, expression of nestin in PDAC cells was detected in approximately 30% of PDAC cases (22).…”

Section: Discussionmentioning

confidence: 99%

Nestin as a novel therapeutic target for pancreatic cancer via tumor angiogenesis

Yamahatsu

Matsuda²,

Ishiwata

et al. 2012

Int J Oncol

View full text Add to dashboard Cite

Abstract. The class VI intermediate filament protein, nestin is reported to be a progenitor cell marker in various tissues. In the present study, we analyzed the expression and roles of nestin in angiogenesis of pancreatic ductal adenocarcinomas, and determined whether nestin is a potential target for inhibiting tumor angiogenesis using a gene silencing strategy. Nestin expression was detected only in small vessels, whereas CD34, CD31 and factor VIII were also expressed in large-sized blood vessels in PDAC. The number of nestin-positive vessels was approximately 20% the number of CD34-positive vessels, and the average dimension of nestin-positive vessels was approximately 75% that of CD34-positive vessels. The PCNA labeling indices of nestin-positive vessels were higher than those of CD34-positive vessels and nestin-negative vessels. Reducing nestin expression by use of siRNA targeting nestin transcripts inhibited growth of the vascular endothelial cell lines, but there was no difference in cell motility. In xenograft models, administration of siRNA targeting mouse-nestin suppressed subcutaneous human pancreatic cancer cell growth in nude mice. In conclusion, nestin was expressed in small proliferating blood vessels in pancreatic cancer tissues and may be a useful marker of angiogenesis in pancreatic ductal adenocarcinoma tissues. Furthermore, nestin is a potential novel therapeutic target in pancreatic cancers to inhibit tumor angiogenesis.

show abstract

KRN951, a Highly Potent Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinases, Has Antitumor Activities and Affects Functional Vascular Properties

Cited by 197 publications

References 36 publications

Escape mechanisms after antiangiogenic treatment, or why are the tumors growing again?

Escape mechanisms after antiangiogenic treatment, or why are the tumors growing again?

Increase in tumour permeability following TGF-β type I receptor-inhibitor treatment observed by dynamic contrast-enhanced MRI

Nestin as a novel therapeutic target for pancreatic cancer via tumor angiogenesis

Contact Info

Product

Resources

About