BACKGROUND: Optimal discrimination between leukemic blasts and normal B-cell precursors (BCP) is critical for treatment monitoring in BCP acute lymphoblastic leukemia (ALL); thus identification of markers differentially expressed on normal BCP and leukemic blasts is required. METHODS: Multicenter analysis of CD73, CD86 and CD304 expression levels was performed in 282 pediatric BCP-ALL patients vs. normal bone marrow BCP, using normalized median fluorescence intensity (nMFI) values. RESULTS: CD73 was expressed at abnormally higher levels (vs. pooled normal BCP) at diagnosis in 71/108 BCP-ALL patients (66%), whereas CD304 and CD86 in 119/202 (59%) and 58/100 (58%) patients, respectively. Expression of CD304 was detected at similar percentages in common-ALL and pre-B-ALL, while found at significantly lower frequencies in pro-B-ALL. A significant association (p = 0.009) was found between CD304 expression and the presence of the ETV6-RUNX1 fusion gene. In contrast, CD304 showed an inverse association with MLL gene rearrangements (p = 0.01). The expression levels of CD73, CD86 and CD304 at day 15 after starting therapy (MRD15) were stable or higher than at diagnosis in 35/37 (95%), 40/56 (71%) and 19/41 (46%) cases investigated, respectively. This was also associated with an increased mean nMFI at MRD15 vs. diagnosis of +24 and +3 nMFI units for CD73 and CD86, respectively. In addition, gain of expression of CD73 and CD86 at MRD15 for cases that were originally negative for these markers at diagnosis was observed in 16% and 18% of cases, respectively. Of note, CD304 remained aberrantly positive in 63% of patients, despite its levels of expression decreased at follow-up in 54% of cases. CONCLUSIONS: Here we show that CD73, CD86 and CD304 are aberrantly (over)expressed in a substantial percentage of BCP-ALL patients and that their expression profile remains relatively stable early after starting therapy, supporting their potential contribution to improved MRD analysis by flow cytometry.

• Klíčová slova
• Acute lymphoblastic leukemia, CD304, CD73, CD86, Flow cytometry, Minimal residual disease,
• MeSH
• 5'-nukleotidasa analýza   biosyntéza   MeSH
• antigeny CD86 analýza   biosyntéza   MeSH
• dítě MeSH
• GPI-vázané proteiny analýza   biosyntéza   MeSH
• lidé MeSH
• nádorové biomarkery analýza   MeSH
• neuropilin-1 analýza   biosyntéza   MeSH
• pre-B-buněčná leukemie patologie   MeSH
• předškolní dítě MeSH
• prekurzorové B-lymfoidní buňky patologie   MeSH
• reziduální nádor MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 5'-nukleotidasa MeSH
• antigeny CD86 MeSH
• CD86 protein, human MeSH Prohlížeč
• GPI-vázané proteiny MeSH
• nádorové biomarkery MeSH
• neuropilin-1 MeSH
• NRP1 protein, human MeSH Prohlížeč
• NT5E protein, human MeSH Prohlížeč

• MeSH
• analgezie * MeSH
• bolest farmakoterapie   MeSH
• COVID-19 * MeSH
• lidé MeSH
• neuropilin-1 metabolismus   MeSH
• receptory vaskulárního endoteliálního růstového faktoru metabolismus   MeSH
• SARS-CoV-2 metabolismus   MeSH
• vaskulární endoteliální růstový faktor A metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• komentáře MeSH
• úvodníky MeSH
• Názvy látek
• neuropilin-1 MeSH
• receptory vaskulárního endoteliálního růstového faktoru MeSH
• vaskulární endoteliální růstový faktor A MeSH

Most therapeutic agents used for treating brain malignancies face hindered transport through the blood-brain barrier (BBB) and poor tissue penetration. To overcome these problems, we developed peptide conjugates of conventional and experimental anticancer agents. SynB3 cell-penetrating peptide derivatives were applied that can cross the BBB. Tuftsin derivatives were used to target the neuropilin-1 transport system for selectivity and better tumor penetration. Moreover, SynB3-tuftsin tandem compounds were synthesized to combine the beneficial properties of these peptides. Most of the conjugates showed high and selective efficacy against glioblastoma cells. SynB3 and tandem derivatives demonstrated superior cellular internalization. The penetration profile of the conjugates was determined on a lipid monolayer and Transwell co-culture system with noncontact HUVEC-U87 monolayers as simple ex vivo and in vitro BBB models. Importantly, in 3D spheroids, daunomycin-peptide conjugates possessed a better tumor penetration ability than daunomycin. These conjugates are promising tools for the delivery systems with tunable features.

• MeSH
• buněčné sféroidy účinky léků   metabolismus   MeSH
• endoteliální buňky pupečníkové žíly (lidské) MeSH
• glioblastom farmakoterapie   metabolismus   MeSH
• hematoencefalická bariéra metabolismus   MeSH
• krysa rodu Rattus MeSH
• lékové transportní systémy MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádorové buňky kultivované MeSH
• nádory mozku farmakoterapie   metabolismus   MeSH
• neuropilin-1 metabolismus   MeSH
• nosiče léků chemie   farmakokinetika   farmakologie   MeSH
• oligopeptidy chemie   farmakokinetika   farmakologie   MeSH
• penetrační peptidy chemie   farmakokinetika   farmakologie   MeSH
• protinádorové látky chemie   farmakokinetika   farmakologie   MeSH
• tuftsin analogy a deriváty   farmakokinetika   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• neuropilin-1 MeSH
• nosiče léků MeSH
• oligopeptidy MeSH
• penetrační peptidy MeSH
• protinádorové látky MeSH
• SynB3 peptide MeSH Prohlížeč
• tuftsin MeSH

PURPOSE: Tivozanib, a selective inhibitor of VEGFR-1, -2, and -3, plus mFOLFOX6 in an advanced gastrointestinal cancer phase Ib study had encouraging antineoplastic activity and a tolerable safety profile. This randomized, open-label, phase II trial of tivozanib/mFOLFOX6 versus bevacizumab/mFOLFOX6 in patients with previously untreated metastatic colorectal cancer (mCRC) evaluated tivozanib activity versus bevacizumab. EXPERIMENTAL DESIGN: Treatment-naïve patients received mFOLFOX6 every 2 weeks of each 28-day cycle plus either tivozanib orally 1.5 mg once daily for 21 days or bevacizumab intravenously 5 mg/kg every 2 weeks. Investigator-assessed progression-free survival (PFS) was the primary endpoint; some secondary endpoints included safety, overall survival, overall response rate (ORR), duration of response, time to treatment failure, and biomarker subgroup analyses. RESULTS: A prespecified interim futility analysis demonstrated that the futility boundary for superiority of tivozanib/mFOLFOX6 over bevacizumab/mFOLFOX6 for PFS in the intent-to-treat population was crossed; median PFS was 9.4 versus 10.7 months [HR = 1.091; confidence interval (CI), 0.693-1.718; P = 0.706]. Tivozanib/mFOLFOX6 resulted in PFS and ORR comparable with bevacizumab/mFOLFOX6; interim analyses biomarker results revealed no significant PFS association. Post hoc final analyses demonstrated a potential difference in tivozanib-specific PFS in patients with low neuropilin-1 (NRP-1), but not in patients with high NRP-1. Tivozanib/mFOLFOX6 was tolerable and adverse events were comparable with both bevacizumab/mFOLFOX6 and previous tivozanib studies. CONCLUSIONS: The efficacy of tivozanib/mFOLFOX6 was comparable with but not superior to bevacizumab/mFOLFOX6 in patients with previously untreated mCRC. Since data from the prespecified interim analysis did not demonstrate superiority, this resulted in discontinuation of the study. The safety and tolerability profile of tivozanib/mFOLFOX6 was consistent with other tivozanib trials. NRP-1 is a potential predictive biomarker for tivozanib activity, but these results require further validation. Clin Cancer Res; 22(20); 5058-67. ©2016 AACR.

• MeSH
• bevacizumab škodlivé účinky   terapeutické užití   MeSH
• chinoliny škodlivé účinky   terapeutické užití   MeSH
• fenylmočovinové sloučeniny škodlivé účinky   terapeutické užití   MeSH
• fluoruracil škodlivé účinky   terapeutické užití   MeSH
• inhibitory angiogeneze terapeutické užití   MeSH
• kolorektální nádory farmakoterapie   patologie   MeSH
• leukovorin škodlivé účinky   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery krev   MeSH
• neuropilin-1 krev   MeSH
• organoplatinové sloučeniny škodlivé účinky   terapeutické užití   MeSH
• přežití bez známek nemoci MeSH
• progrese nemoci MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• receptory vaskulárního endoteliálního růstového faktoru antagonisté a inhibitory   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• bevacizumab MeSH
• chinoliny MeSH
• fenylmočovinové sloučeniny MeSH
• fluoruracil MeSH
• inhibitory angiogeneze MeSH
• leukovorin MeSH
• nádorové biomarkery MeSH
• neuropilin-1 MeSH
• organoplatinové sloučeniny MeSH
• receptory vaskulárního endoteliálního růstového faktoru MeSH
• tivozanib MeSH Prohlížeč