Tisagenlecleucel (tisa‐cel) is a second‐generation autologous CD19‐targeted chimeric antigen receptor (CAR) T‐cell therapy approved for relapsed/refractory (R/R) large B‐cell lymphoma (LBCL). The ...approval was based on the results of phase II JULIET trial, with a best overall response rate (ORR) and complete response (CR) rate in infused patients of 52% and 40%, respectively. We report outcomes with tisa‐cel in the standard‐of‐care (SOC) setting for R/R LBCL. Data from all patients with R/R LBCL who underwent leukapheresis from December 2018 until June 2020 with the intent to receive SOC tisa‐cel were retrospectively collected at 10 Spanish institutions. Toxicities were graded according to ASTCT criteria and responses were assessed as per Lugano 2014 classification. Of 91 patients who underwent leukapheresis, 75 (82%) received tisa‐cel therapy. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 5% and 1%, respectively; non‐relapse mortality was 4%. Among the infused patients, best ORR and CR were 60% and 32%, respectively, with a median duration of response of 8.9 months. With a median follow‐up of 14.1 months from CAR T‐cell infusion, median progression‐free survival and overall survival were 3 months and 10.7 months, respectively. At 12 months, patients in CR at first disease evaluation had a PFS of 87% and OS of 93%. Patients with an elevated lactate dehydrogenase showed a shorter PFS and OS on multivariate analysis. Treatment with tisa‐cel for patients with relapsed/refractory LBCL in a European SOC setting showed a manageable safety profile and durable complete responses.
This article provides real‐world European data on the results of relapsed/refractory large B‐cell lymphoma patients treated with tisagenlecleucel.
The Cu(L)Cl22 and Pt(L)Cl2 complexes were prepared from the simple Schiff-base ligand (E)-phenyl-N-((pyridin-2-yl)methylene)methanamine (L) and respectively, CuCl2 and cis-PtCl2(DMSO)2. ...DNA-interaction studies revealed that the copper complex most likely acts as a DNA cleaver whereas the platinum complex binds to the double helix. Remarkably, cell-viability experiments with HeLa, MCF7 and PC3 cells showed that Cu(L)Cl22 is an efficient cytotoxic agent whereas Pt(L)Cl2 is not toxic, illustrating the crucial role played by the nature of the metal ion in the corresponding biological activity.
The ABCB1 transporter also known as P-glycoprotein (P-gp) is a transmembrane protein belonging to the ATP binding cassette super-family of transporters; it is a xenobiotic efflux pump that limits ...intracellular drug accumulation by pumping the compounds out of cells. P-gp contributes to a decrease of toxicity and possesses broad substrate specificity. It is involved in the failure of numerous anticancer and antiviral chemotherapies due to the multidrug resistance (MDR) phenomenon, where it removes the chemotherapeutics out of the targeted cells. Understanding the details of the ligand-P-gp interaction is therefore crucial for the development of drugs that might overcome the MRD phenomenon and for obtaining a more effective prediction of the toxicity of certain compounds. In this work, an in silico modeling was performed using homology modeling and molecular docking methods with the aim of better understanding the ligand-P-gp interactions. Based on different mouse P-gp structural templates from the PDB repository, a 3D model of the human P-gp (
P-gp) was constructed by means of protein homology modeling. The homology model was then used to perform molecular docking calculations on a set of thirteen compounds, including some well-known compounds that interact with P-gp as substrates, inhibitors, or both. The sum of ranking differences (SRD) was employed for the comparison of the different scoring functions used in the docking calculations. A consensus-ranking scheme was employed for the selection of the top-ranked pose for each docked ligand. The docking results showed that a high number of π interactions, mainly π-sigma, π-alkyl, and π-π type of interactions, together with the simultaneous presence of hydrogen bond interactions contribute to the stability of the ligand-protein complex in the binding site. It was also observed that some interacting residues in
P-gp are the same when compared to those observed in a co-crystallized ligand (PBDE-100) with mouse P-gp (PDB ID: 4XWK). Our in silico approach is consistent with available experimental results regarding P-gp efflux transport assay; therefore it could be useful in the prediction of the role of new compounds in systemic toxicity.
In the present study, the potential anti-neoplastic properties of a series of ruthenium half-sandwich complexes of formula Ru(η6-arene)Cl2(PR1R2(1-pyrenyl)) (η6-arene = p-cymene and R1 = R2 = ...methyl for 1; η6-arene = methylbenzoate and R1 = R2 = methyl for 2; η6-arene = p-cymene and R1 = R2 = phenyl for 3; η6-arene = methylbenzoate and R1 = R2 = phenyl for 4; η6-arene = p-cymene, R1 = methyl and R2 = phenyl for 5; η6-arene = methylbenzoate, R1 = methyl and R2 = phenyl for 6) have been investigated. The six structurally related organoruthenium(II) compounds have been prepared in good yields and fully characterized; the X-ray structures of three of them, i.e., 1, 2, and 4, were determined. Although the piano-stool compounds contain a large polycyclic aromatic moiety, viz. a 1-pyrenyl group, they do not appear to interact with DNA. However, all the piano-stool complexes show significant cytotoxic properties against five human cell lines, namely, lung adenocarcinoma (A549), melanoma (A375), colorectal adenocarcinoma (SW620), breast adenocarcinoma (MCF7), and nontumorigenic epithelial breast (MCF10A), with IC50 values in the micromolar range for most of them. In addition, the most active compound, i.e., 2, induces a remarkable decrease of cell viability, that is in the nanomolar range, against two human neuroblastoma cell lines, namely, SK-N-BE(2) and CHLA-90. Complexes 1–6 are all capable of inducing apoptosis, but with various degrees of magnitude. Whereas 1, 3, 5, and 6 have no effect on the cell cycle of A375 cells, 2 and 4 can arrest it at the G2/M phase; furthermore, 2 (which is the most efficient compound of the series) also stops the cycle at the S phase, behaving as the well-known anticancer agent cisplatin. Finally, 2 is able to inhibit/reduce the cell migration of neuroblastoma SK-N-BE(2) cells.
Post-transplant cyclophosphamide (PTCy) has become a promising option after allo-SCT, but infections may be more common than in traditional protocols. We herein report 117 consecutive adults who ...received PTCy-based alloSCT in our hospital: HaploSCT (34%), MRD (19%), and VUD (47%), respectively. The 18-month incidence of severe bacterial, viral, and IFI was 56%, 69%, and 8.7%, without differences between donor type, except for CMV infection and viral hemorrhagic cystitis, which had a higher incidence in the haploSCT cohort (58% vs. 43% and 30% vs. 8% on day +90, p < 0.05). Late infections by conventional respiratory viruses were common in all groups 33/87 (38%). The 2-year survival was 72% and did not differ by donor type. IRM at day 30, day 100, and 18 months was 1.7%, 4.4%, and 12%, without differences by donor type (p = 0.7). The primary cause of IRM was bacterial infection (42%). Grade 2-4 acute GvHD was the only independent predictor of IRM. Donor type had no impact on IRM or on survival. In our study, severe infections were common in all donor types using PTCy, with higher rates of early post-engraftment CMV-I and viral HC in haploSCT recipients, although lethal infections were uncommon and similar in all donor types.
Three thiosemicarbazone derivatives, namely 4-(dimethylamino)benzaldehyde 4,4-dimethylthiosemicarbazone (HL 1 ), 4-(dimethylamino)benzaldehyde thiosemicarbazone (HL 2 ), and ...4-(dimethylamino)benzaldehyde 4-methylthiosemicarbazone (HL 3 ), have been synthesized and characterized. The three palladium(II) complexes 1–3 were prepared respectively from HL 1 , HL 2 , and HL 3 . The crystal structures of two coordination compounds, namely Pd(L 2 )2 (2) and Pd(L 3 )2 (3), were obtained, which showed the expected square-planar environment for the metal centers. The ligand HL 3 and the Pd(II) complexes 1–3, which are stable in buffered solutions containing up to 5% DMSO, exhibit remarkable inhibitory properties against the aggregation of amyloid-β, reducing the formation of fibrils. HL 1 , HL 3 , 2, and 3 display IC50 values (i.e., the concentrations required to reduce Aβ fibrillation by 50%) below 1 μM, lower that of the reference compound catechin (IC50 = 2.8 μM). Finally, in cellulo studies with E. coli cells revealed that the palladium(II) compounds are significantly more efficient than the free ligands in inhibiting Aβ aggregation inside bacterial inclusion bodies, thus illustrating a beneficial effect of metal coordination.
The relationship of copper dyshomeostasis with neurodegenerative diseases has become evident in the last years. Because of the major role that this metal ion plays in biological processes, most of ...which being located in the brain, it is not surprising that changes in its distribution are closely related with the advent of neurodegenerative disorders such as Alzheimer’s disease (AD). An increasing number of works have dealt with this subject in the last years, and opened an intense debate in some points while raising new questions that still remain unanswered. This revision work puts together and discusses the latest findings and insights on how copper ions are involved in AD progression, including its interaction with Aβ and its consequently induced aggregation.
The direct functionalization of low reactive C(sp
3
)-H and C(sp
2
)-H bonds of alkanes and arenes, respectively, by metal-induced carbene transfer from diazo compounds is reviewed. To date, this ...methodology has enabled the incorporation of CR
1
R
2
moieties from N
2
&z.dbd;CR
1
R
2
in a chemo, regio, enantio or diastereoselective manner in those substrates with the appropriate selection of metal and ligands.
The direct functionalization of low reactive C(sp
3
)-H and C(sp
2
)-H bonds of alkanes and arenes, respectively, by metal-induced carbene transfer from diazo compounds is reviewed.
Differentiation between hypoxic and normoxic tissues have been exploited for the development of selective chemotherapeutic agents. In this context, cobalt(III)-based coordination compounds have been ...designed and investigated as prospective hypoxia-responsive drug delivery systems. Three cobalt(III) complexes, namely CoIII(esc)(py2en)ClO4·(CH3OH)2 (1) CoIII(esc)(TPA)ClO4·3H2O (2) and CoIII(bipy)2(esc)ClO4·2.5H2O (3) (py2en = N,N′-bis(pyridin-2-ylmethyl)ethylenediamine, TPA = tris(2-pyridylmethyl)amine, bipy = 2,2′-bipyridine and esc = 6,7-dihydroxycoumarin or esculetin), were prepared and investigated as potential carriers of esculetin. The spectroscopic and electrochemical properties of 1–3 were investigated and compared. Reactions of the complexes with biologically relevant reducing agents, viz. ascorbic acid, cysteine and glutathione, were monitored spectroscopically for 24 h, in pH 6.2 and 7.4 PBS phosphate buffer saline (PBS) solutions at 37 °C, under air, argon and dioxygen atmospheres. Dissociation of esculetin was observed upon Co3+/Co2+ reduction preferably under hypoxic conditions, with more effective conversion rates for 3 > 2 > 1. These results illustrate the importance to modulate the Co3+/Co2+ redox potential through the donor-acceptor properties of the ancillary ligands. Complex 3 is cytotoxic against HCT-116 but not against HT-29 and HEK-293 cells. In addition, DNA-binding studies indicate that interactions of 1 and 3 with the biomolecule are electrostatic.
New cobalt(III)-esculetin complexes were designed for potential applications in hypoxia-selective drug-delivery systems. Modulation of the Co3+/Co2+ redox potential and reactivity through the donor-acceptor properties of the ancillary ligands was achieved. Hypoxia-selective dissociation of esculetin was observed upon reduction. Cytotoxic activity against HCT-116 cells and DNA interactions were investigated. Display omitted
•CoIII complexes have been designed for hypoxia-selective anticancer drug delivery.•Redox potential of CoIII-esculetin complexes has been tuned by ancillary ligands.•Ascorbate, cysteine and glutathione successfully simulate biological redox activation.•O2-dependent dissociation of the esculetin has been achieved upon Co3+/Co2+reduction.•Hypoxic conditions enhance activity of CoIII-esculetin complexes against tumor cells.
Two ruthenium(II) polypyridyl complexes were prepared with the {Ru(phen)
2
}
2+
moiety and a third sterically non-hindering bidentate ligand, namely 2,2′-dipyridylamine (dpa) and
N
...-benzyl-2,2′-dipyridylamine (Bndpa). Hence, complexes Ru(phen)
2
(dpa)(PF
6
)
2
(
1
) and Ru(phen)
2
(Bndpa)(PF
6
)
2
(
2
) were characterized and their photochemical behaviour in solution (acetonitrile and water) was subsequently investigated. Compounds
1
and
2
, which do not exhibit notably distorted octahedral coordination environments, contrarily to the homoleptic “parent” compound Ru(phen)
3
(PF
6
)
2
, experience two-step photoejection of the dpa and Bndpa ligand upon irradiation (1050–430 nm) for several hours. DNA-binding studies revealed that compounds
1
and
2
affect the biomolecule differently upon irradiation; while
2
solely modifies its electrophoretic mobility, complex
1
is also capable of cleaving it. In vitro cytotoxicity studies with two cancer-cell lines, namely A549 (lung adenocarcinoma) and A375 (melanoma), showed that both
1
and
2
are not toxic in the dark, while only
1
is significantly cytotoxic if irradiated,
2
remaining non-toxic under these conditions.
Graphical abstract
Light irradiation of the complex cation Ru(phen)
2
(dpa)
2+
leads to the generation of transient Ru species that is present in the solution medium for several hours, and that is significantly cytotoxic, ultimately producing non-toxic free dpa and Ru(phen)(OH
2
)
2
2+
.
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