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Blood Reviews Mar 2022Peripheral T-cell Lymphomas (PTCL) are a heterogenous group of aggressive non-Hodgkin lymphomas that are far less sensitive to chemotherapy than their B-cell... (Review)
Review
Peripheral T-cell Lymphomas (PTCL) are a heterogenous group of aggressive non-Hodgkin lymphomas that are far less sensitive to chemotherapy than their B-cell counterparts. Despite their poor prognosis, they are treated similarly to most aggressive B-cell lymphomas, heavily relying on CHOP or CHOP-like combination chemotherapy irrespective of their different subtypes or biology. The last decade has seen the emergence of many targeted therapies that include histone deacetylase inhibitors, hypomethylating agents, monoclonal antibodies and PIK3 inhibitors, among others. However, prognosis remains poor especially in the relapsed/refractory setting. Using an extensive pubmed search, the authors will be summarizing the different trials that led to these approved targeted agents as well as novel combination strategies. The fundamental recognition that different subtypes of PTCL have specific biological features that drive not only proliferation, but also responses to different treatment approaches, should be informing the design of future clinical trials.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Histone Deacetylase Inhibitors; Humans; Lymphoma, T-Cell, Peripheral; Prognosis
PubMed: 34716031
DOI: 10.1016/j.blre.2021.100889 -
BMC Cancer Jul 2021Pralatrexate (PDX) is a novel antifolate approved for the treatment of patients with relapsed/refractory peripheral T-cell lymphoma, but some patients exhibit intrinsic...
BACKGROUND
Pralatrexate (PDX) is a novel antifolate approved for the treatment of patients with relapsed/refractory peripheral T-cell lymphoma, but some patients exhibit intrinsic resistance or develop acquired resistance. Here, we evaluated the mechanisms underlying acquired resistance to PDX and explored potential therapeutic strategies to overcome PDX resistance.
METHODS
To investigate PDX resistance, we established two PDX-resistant T-lymphoblastic leukemia cell lines (CEM and MOLT4) through continuous exposure to increasing doses of PDX. The resistance mechanisms were evaluated by measuring PDX uptake, apoptosis induction and folate metabolism-related protein expression. We also applied gene expression analysis and methylation profiling to identify the mechanisms of resistance. We then explored rational drug combinations using a spheroid (3D)-culture assay.
RESULTS
Compared with their parental cells, PDX-resistant cells exhibited a 30-fold increase in half-maximal inhibitory concentration values. Induction of apoptosis by PDX was significantly decreased in both PDX-resistant cell lines. Intracellular uptake of [C]-PDX decreased in PDX-resistant CEM cells but not in PDX-resistant MOLT4 cells. There was no significant change in expression of dihydrofolate reductase (DHFR) or folylpolyglutamate synthetase (FPGS). Gene expression array analysis revealed that DNA-methyltransferase 3β (DNMT3B) expression was significantly elevated in both cell lines. Gene set enrichment analysis revealed that adipogenesis and mTORC1 signaling pathways were commonly upregulated in both resistant cell lines. Moreover, CpG island hypermethylation was observed in both PDX resistant cells lines. In the 3D-culture assay, decitabine (DAC) plus PDX showed synergistic effects in PDX-resistant cell lines compared with parental lines.
CONCLUSIONS
The resistance mechanisms of PDX were associated with reduced cellular uptake of PDX and/or overexpression of DNMT3B. Epigenetic alterations were also considered to play a role in the resistance mechanism. The combination of DAC and PDX exhibited synergistic activity, and thus, this approach might improve the clinical efficacy of PDX.
Topics: Aminopterin; Antineoplastic Agents; Apoptosis; Biomarkers; Cell Line, Tumor; DNA Methylation; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Folic Acid Antagonists; Gene Expression Profiling; Humans; Tumor Cells, Cultured
PubMed: 34332580
DOI: 10.1186/s12885-021-08607-9 -
Oncology Letters Jan 2019The clinical efficacy and mechanism of Pralatrexate (PTX) combined with Palbociclib Isethionate (PAL) in the treatment of bladder cancer patients was investigated. A...
The clinical efficacy and mechanism of Pralatrexate (PTX) combined with Palbociclib Isethionate (PAL) in the treatment of bladder cancer patients was investigated. A retrospective analysis of medical records of 82 bladder cancer patients admitted to Shengjing Hospital of China Medical University from February 2015 to February 2018 was performed. Patients treated with PTX combined with PAL served as study group (42 cases) and patients with conventional GC (gemcitabine plus cisplatin) chemotherapy regimen were the control group (40 cases). Changes in liver function indexes before and after treatment were observed, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBil). RT-qPCR was used for detection of relative expression levels of serum dihydrofolate reductase (DHFR) and vascular endothelial growth factor (VEGF) before and after treatment in the two groups. The clinical efficacy after treatment and adverse reactions during treatment were observed in the two groups. There was no significant difference in the clinical remission rate (RR) nor in the serum ALT, AST, ALP and TBil levels between the study and the control groups (P>0.05). Concentrations of serum ALT, AST, ALP and TBil were significantly higher than those before treatment in both groups (P<0.05). Serum ALT, AST, ALP and TBil concentrations in study group were significantly lower than those in control group (P<0.05). There was no significant difference in the incidence of thrombocytopenia and leukopenia between the two groups (P>0.05). There was no significant difference in relative expression levels of serum DHFR mRNA and VEGF mRNA before treatment between the study and control groups (P>0.05). Those after treatment were significantly lower than those before treatment in both groups (P<0.05), and those after treatment in study group were significantly lower than those in control group (P<0.05). PTX combined with PAL can reduce adverse reactions of nausea and vomiting and liver function impairment during treatment and suppress tumor neovascularization. This is achieved possibly by inhibiting expression levels of DHFR and VEGF, thereby killing cancer cells. PTX combined with PAL may become a new method for the treatment of bladder cancer patients. DHFR and VEGF are expected to become novel therapeutic targets for the treatment of bladder cancer.
PubMed: 30655756
DOI: 10.3892/ol.2018.9617 -
Molecules (Basel, Switzerland) Sep 2022Antimetabolites of folic acid represent a large group of drugs and drug candidates, including those for cancer chemotherapy. In this current review, the most common... (Review)
Review
Antimetabolites of folic acid represent a large group of drugs and drug candidates, including those for cancer chemotherapy. In this current review, the most common methods and approaches are presented for the synthesis of therapeutically significant antimetabolites of folic acid, which are Methotrexate (MTX), Raltitrexed (Tomudex, ZD1694), Pralatrexate, Pemetrexed, TNP-351, and Lometrexol. In addition, the applications or uses of these folic acid antimetabolites are also discussed.
Topics: Antimetabolites; Folic Acid; Folic Acid Antagonists; Methotrexate; Pemetrexed; Quinazolines; Thiophenes
PubMed: 36234766
DOI: 10.3390/molecules27196229 -
Journal of Pharmaceutical and... Nov 2016Pralatrexate (PTXT) is an antineoplastic folate analog and the chemical name is (2S)-2-[[4-[(1RS)-1-[(2,4-diaminopteridin-6-yl)methyl]but-3-ynyl] benzoyl] amino]...
Pralatrexate (PTXT) is an antineoplastic folate analog and the chemical name is (2S)-2-[[4-[(1RS)-1-[(2,4-diaminopteridin-6-yl)methyl]but-3-ynyl] benzoyl] amino] pentanedioic acid. Degradation products of PTXT drug product (DP) under different forced degradation conditions have been studied using LC-PDA and LC-MS techniques. PTXT DP was subjected to forced degradation under the conditions of hydrolysis, photolysis, oxidation, and heat in accordance with ICH guidelines. The LC-MS compatible HPLC method was developed and stressed solutions were chromatographed on reversed phase HPLC. The degradation products were monitored at a wavelength of 242nm. Stress study revealed that PTXT was sensitive towards acid, alkali, peroxide, light and heat. The degradation impurities (I-IX) were identified and characterized using LC-PDA and mass spectral data.
Topics: Aminopterin; Chromatography, Liquid; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry
PubMed: 27643862
DOI: 10.1016/j.jpba.2016.08.023 -
Clinical Cancer Research : An Official... May 2015T-cell lymphomas (TCL) are aggressive diseases, which carry a poor prognosis. The emergence of new drugs for TCL has created a need to survey these agents in a rapid and...
PURPOSE
T-cell lymphomas (TCL) are aggressive diseases, which carry a poor prognosis. The emergence of new drugs for TCL has created a need to survey these agents in a rapid and reproducible fashion, to prioritize combinations which should be prioritized for clinical study. Mouse models of TCL that can be used for screening novel agents and their combinations are lacking. Developments in noninvasive imaging modalities, such as surface bioluminescence (SBL) and three-dimensional ultrasound (3D-US), are challenging conventional approaches in xenograft modeling relying on caliper measurements. The recent approval of pralatrexate and romidepsin creates an obvious combination that could produce meaningful activity in TCL, which is yet to be studied in combination.
EXPERIMENTAL DESIGN
High-throughput screening and multimodality imaging approach of SBL and 3D-US in a xenograft NOG mouse model of TCL were used to explore the in vitro and in vivo activity of pralatrexate and romidepsin in combination. Corresponding mass spectrometry-based pharmacokinetic and immunohistochemistry-based pharmacodynamic analyses of xenograft tumors were performed to better understand a mechanistic basis for the drug:drug interaction.
RESULTS
In vitro, pralatrexate and romidepsin exhibited concentration-dependent synergism in combination against a panel of TCL cell lines. In a NOG murine model of TCL, the combination of pralatrexate and romidepsin exhibited enhanced efficacy compared with either drug alone across a spectrum of tumors using complementary imaging modalities, such as SBL and 3D-US.
CONCLUSIONS
Collectively, these data strongly suggest that the combination of pralatrexate and romidepsin merits clinical study in patients with TCLs.
Topics: Aminopterin; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Depsipeptides; Disease Models, Animal; Drug Synergism; Flow Cytometry; Humans; Luminescent Measurements; Lymphoma, T-Cell; Mice; Transfection; Xenograft Model Antitumor Assays
PubMed: 25677697
DOI: 10.1158/1078-0432.CCR-14-2249 -
Cancer Chemotherapy and Pharmacology Jun 2015To investigate the effectiveness of a combination of 6-thioguanine (6-TG) and pralatrexate (PDX) in methylthioadenosine phosphorylase (MTAP)-deficient T-cell acute...
PURPOSE
To investigate the effectiveness of a combination of 6-thioguanine (6-TG) and pralatrexate (PDX) in methylthioadenosine phosphorylase (MTAP)-deficient T-cell acute lymphoblastic leukemia (T-cell ALL).
METHODS
CCRF-CEM (MTAP(-/-)) and Molt4 (MTAP(+/+)) T-cell ALL cell lines were treated with 6-TG or PDX and evaluated for efficacy 72 h later. NOD/SCID gamma mice bearing CEM or Molt4 xenografts were treated with 6-TG and PDX alone or in combination to evaluate antitumor effects.
RESULTS
CEM cells were more sensitive to 6-TG and PDX in vitro than Molt4. In vivo, CEM cells were very sensitive to PDX and 6-TG, whereas Molt4 cells were highly resistant to 6-TG. A well-tolerated combination of PDX and 6-TG achieved significant tumor regression in CEM xenografts.
CONCLUSIONS
The loss of MTAP expression may be therapeutically exploited in T-cell ALL. The combination of 6-TG and PDX, with the inclusion of leucovorin rescue, allows for a safe and effective regimen in MTAP-deficient T-cell ALL.
Topics: Aminopterin; Animals; Antineoplastic Agents; Cell Line, Tumor; Heterografts; Humans; Male; Mice; Mice, Inbred NOD; Mice, SCID; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Purine-Nucleoside Phosphorylase; Thioguanine
PubMed: 25917288
DOI: 10.1007/s00280-015-2747-2 -
The Journal of Dermatology May 2021Pralatrexate has been approved for the treatment of relapsed/refractory peripheral T cell lymphomas. Studies in the U.S. also support the clinical efficacy of...
Pralatrexate has been approved for the treatment of relapsed/refractory peripheral T cell lymphomas. Studies in the U.S. also support the clinical efficacy of pralatrexate to treat advanced-stage cutaneous T-cell lymphomas, but outcomes in Japanese patients have not yet been reported. We herein describe two Japanese patients with heavily-pretreated relapsed/refractory mycosis fungoides that were successfully controlled by pralatrexate.
Topics: Aminopterin; Humans; Japan; Mycosis Fungoides; Neoplasm Recurrence, Local; Skin Neoplasms
PubMed: 33454985
DOI: 10.1111/1346-8138.15761 -
Blood Jan 2018
Topics: Aminopterin; Depsipeptides; Humans; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral
PubMed: 29371206
DOI: 10.1182/blood-2017-11-817734 -
Biomedicine & Pharmacotherapy =... Apr 2023Glioblastoma Multiforme (GBM) is known to be by far the most aggressive brain tumor to affect adults. The median survival rate of GBM patient's is < 15 months, while...
Glioblastoma Multiforme (GBM) is known to be by far the most aggressive brain tumor to affect adults. The median survival rate of GBM patient's is < 15 months, while the GBM cells aggressively develop resistance to chemo- and radiotherapy with their self-renewal capacity which suggests the pressing need to develop novel preventative measures. We have recently proved that GPR17 -an orphan G protein-coupled receptor- is highly expressed on the GBM cell surface and it has a vital role to play in the disease progression. Despite the progress made on GBM downregulation, there still remain difficulties in developing a promising modulator for GPR17, till date. Here, we have performed robust virtual screening combined with biased-force pulling molecular dynamic (MD) simulations to predict high-affinity GPR17 modulators followed by experimental validation. Initially, the database containing 1379 FDA-approved drugs were screened against the orthosteric binding pocket of the GPR17. The external bias-potentials were then applied to the screened hits during the MD simulations which enabled to predict a spectrum of rupture peak force values that were used to select four approved drugs -ZINC000003792417 (Sacubitril), ZINC000014210457 (Victrelis), ZINC000001536109 (Pralatrexate) and ZINC000003925861 (Vorapaxar)- as top hits. The hits selected turns out to demonstrate unique dissociation pathways, interaction pattern, and change in polar network over time. Subsequently the selected hits with GPR17 were measured by inhibiting the forskolin-stimulated cAMP accumulation in GBM cell lines, LN229 and SNB19. The ex vivo validations shows that Sacubitril drug can act as a full agonist, while Vorapaxar functions as a partial agonist for GPR17. The pEC of Sacubitril was identified as 4.841 and 4.661 for LN229 and SNB19, respectively. Small interference of the RNA (siRNA)- silenced the GPR17 to further validate the targeted binding of Sacubitril with GPR17. In the current investigation, we have identified new repurposable GPR17 specific drugs which are likely to increase the opportunity to treat orphan deadly diseases.
Topics: Humans; Receptors, G-Protein-Coupled; Lactones; Pyridines
PubMed: 36716660
DOI: 10.1016/j.biopha.2023.114320