scholarly journals Janex-1, a JAK3 inhibitor, ameliorates tumor necrosis factor‑α‑induced expression of cell adhesion molecules and improves myocardial vascular permeability in endotoxemic mice

2012 ◽  
Author(s):  
Kyung Kang
Keyword(s):  
Cell Adhesion ◽  
Tumor Necrosis Factor ◽  
Vascular Permeability ◽  
Adhesion Molecules ◽  
Cell Adhesion Molecules ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Jak3 Inhibitor ◽  
Factor Α ◽  
Necrosis Factor

scholarly journals R-CHOP preceded by blood-brain barrier permeabilization with engineered tumor necrosis factor-α in primary CNS lymphoma

Blood ◽  
2019 ◽  
Vol 134 (3) ◽  
pp. 252-262 ◽  
Author(s):  
Andrés J. M. Ferreri ◽  
Teresa Calimeri ◽  
Gian Marco Conte ◽  
Dario Cattaneo ◽  
Federico Fallanca ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Vascular Permeability ◽  
Blood Brain Barrier ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Brain Barrier ◽  
Emission Computed Tomography ◽  
Blood Brain ◽  
Factor Α ◽  
Necrosis Factor

Abstract Patients with primary central nervous system lymphoma (PCNSL) are treated with high-dose methotrexate-based chemotherapy, which requires hospitalization and extensive expertise to manage related toxicity. The use of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) could overcome these difficulties, but blood-brain barrier (BBB) penetration of related drugs is poor. Tumor necrosis factor-α coupled with NGR (NGR-hTNF), a peptide targeting CD13+ vessels, induces endothelial permeabilization and improves tumor access of cytostatics. We tested the hypothesis that NGR-hTNF can break the BBB, thereby improving penetration and activity of R-CHOP in patients with relapsed/refractory PCNSL (NCT03536039). Patients received six R-CHOP21 courses, alone at the first course and preceded by NGR-hTNF (0.8 μg/m2) afterward. This trial included 2 phases: an “explorative phase” addressing the effect of NGR-hTNF on drug pharmacokinetic parameters and on vessel permeability, assessed by dynamic contrast-enhanced magnetic resonance imaging and 99mTc-diethylene-triamine-pentacetic acid–single-photon emission computed tomography, and the expression of CD13 on tumor tissue; and an “expansion phase” with overall response rate as the primary end point, in which the 2-stage Simon Minimax design was used. At the first stage, if ≥4 responses were observed among 12 patients, the study accrual would have continued (sample size, 28). Herein, we report results of the explorative phase and the first-stage analysis (n = 12). CD13 was expressed in tumor vessels of all cases. NGR-hTNF selectively increased vascular permeability in tumoral/peritumoral areas, without interfering with drug plasma/cerebrospinal fluid concentrations. The NGR-hTNF/R-CHOP combination was well tolerated: there were only 2 serious adverse events, and grade 4 toxicity was almost exclusively hematological, which were resolved without dose reductions or interruptions. NGR-hTNF/R-CHOP was active, with 9 confirmed responses (75%; 95% confidence interval, 51-99), 8 of which were complete. In conclusion, NGR-hTNF/R-CHOP was safe in these heavily pretreated patients. NGR-hTNF enhanced vascular permeability specifically in tumoral/peritumoral areas, which resulted in fast and sustained responses.

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