-
Journal of the American Academy of... Feb 2020
Topics: Aged; Aminopterin; Female; Humans; Lymphohistiocytosis, Hemophagocytic; Lymphoma, T-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Panniculitis; Retrospective Studies; Young Adult
PubMed: 31319088
DOI: 10.1016/j.jaad.2019.07.021 -
Leukemia & Lymphoma Dec 2019
Review
A peripheral T-cell lymphoma (PTCL) arising as a post-transplant lymphoproliferative disorder: efficacy of pralatrexate in primary refractory disease and review of the literature.
Topics: Adult; Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cardiomyopathies; Deoxycytidine; Drug Resistance, Neoplasm; Female; Folic Acid Antagonists; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Heart Failure; Heart Transplantation; Humans; Lymphoma, T-Cell, Peripheral; Organoplatinum Compounds; Peripartum Period; Positron Emission Tomography Computed Tomography; Postoperative Complications; Treatment Outcome
PubMed: 31184235
DOI: 10.1080/10428194.2019.1622102 -
International Journal of Dermatology Apr 2023
Topics: Humans; Sezary Syndrome; Electrons; Hematopoietic Stem Cell Transplantation; Skin Neoplasms; Mycosis Fungoides
PubMed: 36683181
DOI: 10.1111/ijd.16587 -
Pralatrexate Induces Long-Term Remission in Relapsed Subcutaneous Panniculitis-Like T-Cell Lymphoma.Annals of the Academy of Medicine,... Sep 2019
Topics: Adult; Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cisplatin; Cyclophosphamide; Deoxycytidine; Dexamethasone; Doxorubicin; Folic Acid Antagonists; Humans; Lymphohistiocytosis, Hemophagocytic; Lymphoma, T-Cell, Peripheral; Male; Neoplasm Recurrence, Local; Panniculitis; Prednisone; Remission Induction; Subcutaneous Fat, Abdominal; Vincristine; Gemcitabine
PubMed: 31737895
DOI: No ID Found -
Clinical Cancer Research : An Official... Dec 2013Folates are well known to be essential for many cellular processes, including cellular proliferation. As a consequence, antifolates, the fraudulent mimics of folic acid,...
Folates are well known to be essential for many cellular processes, including cellular proliferation. As a consequence, antifolates, the fraudulent mimics of folic acid, have been shown to be potent therapeutic agents in many cancers. Over the past several decades, efforts to improve on this class of drugs have met with little success. Recently, one analog specifically designed to have high affinity for the reduced folate carrier, which efficiently internalizes natural folates and antifolates, has been shown to be very active in T-cell lymphoma. Pralatrexate, approved by the U.S. Food and Drug Administration in 2009, is highly active across many lymphoid malignancies, including chemotherapy-resistant T-cell lymphoma. Emerging combination studies have now shown that pralatrexate is highly synergistic with gemcitabine, histone deacetylase inhibitors like romidepsin and bortezomib. These insights are leading to a number of novel phase I and II combination studies which could challenge existing regimens like CHOP, and improve the outcome of patients with T-cell lymphoma.
Topics: Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Deoxycytidine; Depsipeptides; Disease-Free Survival; Drug Approval; Drug Synergism; Humans; Lymphoma, T-Cell; Male; Pyrazines; Treatment Outcome; United States; United States Food and Drug Administration; Gemcitabine
PubMed: 23965902
DOI: 10.1158/1078-0432.CCR-12-2251 -
Clinical Cancer Research : An Official... Jul 2010Pralatrexate (10-propargyl-10-deazaaminopterin) is an antifolate with improved cellular uptake and retention due to greater affinity for the reduced folate carrier...
PURPOSE
Pralatrexate (10-propargyl-10-deazaaminopterin) is an antifolate with improved cellular uptake and retention due to greater affinity for the reduced folate carrier (RFC-1) and folyl-polyglutamyl synthase. Based on the PROPEL data, pralatrexate was the first drug approved for patients with relapsed and refractory peripheral T-cell lymphoma. Bortezomib is a proteasome inhibitor that has shown some activity in patients with T-cell lymphoma.
EXPERIMENTAL DESIGN
Assays for cytotoxicity including mathematical analysis for synergism, flow cytometry, immunoblotting, and a xenograft severe combined immunodeficient-beige mouse model were used to explore the in vitro and in vivo activities of pralatrexate alone and in combination with bortezomib in T-cell lymphoid malignancies.
RESULTS
In vitro, pralatrexate and bortezomib exhibited concentration- and time-dependent cytotoxicity against a broad panel of T-lymphoma cell lines. Pralatrexate showed synergism when combined with bortezomib in all cell lines studied. Pralatrexate also induced potent apoptosis and caspase activation when combined with bortezomib across the panel. Cytotoxicity studies on normal peripheral blood mononuclear cells showed that the combination was not more toxic than the single agents. Western blot assays for proteins involved in broad growth and survival pathways showed that p27, NOXA, HH3, and RFC-1 were all significantly modulated by the combination. In a severe combined immunodeficient-beige mouse model of transformed cutaneous T-cell lymphoma, the addition of pralatrexate to bortezomib enhanced efficacy compared with either drug alone.
CONCLUSION
Collectively, these data suggest that pralatrexate in combination with bortezomib represents a novel and potentially important platform for the treatment of T-cell malignancies.
Topics: Aminopterin; Animals; Apoptosis; Boronic Acids; Bortezomib; Caspase 8; Caspase 9; Cell Line, Tumor; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Humans; Lymphoma, T-Cell; Mice; Mice, SCID; Neoplasm Transplantation; Pyrazines; Xenograft Model Antitumor Assays
PubMed: 20501616
DOI: 10.1158/1078-0432.CCR-10-0671 -
Pediatric Blood & Cancer Nov 2020
Topics: Adolescent; Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Drug Resistance, Neoplasm; Female; Humans; Liver Neoplasms; Lymphoma, T-Cell; Prednisone; Prognosis; Splenic Neoplasms
PubMed: 32860655
DOI: 10.1002/pbc.28460 -
Journal of Thoracic Oncology : Official... Nov 2011Pralatrexate is an antifolate designed for preferential tumor cell uptake and accumulation and received accelerated Food and Drug Administration approval in...
INTRODUCTION
Pralatrexate is an antifolate designed for preferential tumor cell uptake and accumulation and received accelerated Food and Drug Administration approval in relapsed/refractory peripheral T-cell lymphoma. Pralatrexate 135 to 150 mg/m(2) every 2 weeks without vitamin supplementation was active in non-small cell lung cancer (NSCLC) although mucositis was dose limiting. This phase 1 study evaluated the safety of higher pralatrexate doses with vitamin supplementation to minimize toxicities.
METHODS
Patients with stage IIIB/IV NSCLC received pralatrexate 150 to 325 mg/m(2) every 2 weeks with folic acid and vitamin B12 supplementation. Outcomes measured included adverse events (AEs), pharmacokinetics, and radiologic response.
RESULTS
Thirty-nine patients were treated for a median of two cycles (range 1-16+). Common treatment-related grade 3 and 4 AEs by dose (≤190 mg/m(2) and >190 mg/m(2)) included mucositis (33 and 40%) and fatigue (11 and 17%). Treatment-related serious AE (SAE) rates for doses ≤190 and >190 mg/m(2) were 0 and 20%, respectively. The response rate was 10% (95% confidence interval: 1-20%), including two patients with complete response (26+ and 32+ months) and two with partial response. Serum pralatrexate concentrations increased dose dependently up to 230 mg/m(2).
CONCLUSIONS
Pralatrexate with vitamin supplementation was safely administered to patients with previously treated NSCLC, and durable responses were observed. The recommended starting dose for phase 2 is 190 mg/m(2). A similar safety profile was observed in patients treated at 230 mg/m(2), although a higher serious AE rate was evident. Mucositis remains the dose-limiting toxicity of pralatrexate, and this study failed to demonstrate that vitamin supplementation prevents mucositis and failed to identify clinical predictors of mucositis. Individualized dose-modification strategies and prospective mucositis management will be necessary in future trials.
Topics: Adenocarcinoma; Aged; Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Dietary Supplements; Female; Folic Acid; Folic Acid Antagonists; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Prognosis; Tissue Distribution; Vitamin B 12; Vitamin B Complex
PubMed: 21841501
DOI: 10.1097/JTO.0b013e31822adb19 -
Oncotarget Aug 2020Pralatrexate is a folate analogue inhibitor of dihydrofolate reductase exhibiting high affinity for reduced folate carrier-1 with antineoplastic and immunosuppressive...
INTRODUCTION
Pralatrexate is a folate analogue inhibitor of dihydrofolate reductase exhibiting high affinity for reduced folate carrier-1 with antineoplastic and immunosuppressive activities, similar to methotrexate. Despite advances in multi-modality treatment strategies, the survival rates for children with high-risk neuroblastoma have failed to improve. Therefore, the intense research continues in order to identify the ideal novel agent or combination of chemotherapy drugs to treat high-risk neuroblastoma.
MATERIALS AND METHODS
Four human neuroblastoma cell lines were used to determine IC values of select chemotherapy agents. Antiproliferative effects of pralatrexate were assessed by adherent and non-adherent colony formation assays. Cell cycle arrest and apoptosis were measured by flow cytometry and immunoblotting. PDX tissue culture was used to assess efficacy.
RESULTS
Treatment with pralatrexate in all four neuroblastoma cell lines blocked cell growth in 2D and 3D culture conditions in a time-dependent manner. The potency of pralatrexate was ten-fold stronger than methotrexate, as measured by IC. Pralatrexate-induced apoptosis was confirmed by caspase-3 activation and PARP cleavage. and mRNA expressions were decreased with pralatrexate in -amplified neuroblastoma cells.
CONCLUSIONS
Pralatrexate demonstrated effective inhibition of cell growth and viability. The higher potency of pralatrexate compared to methotrexate, a drug with high levels of toxicity, suggests pralatrexate may be a safer alternative to methotrexate as an effective chemotherapeutic agent in the treatment of patients with high-risk neuroblastoma.
PubMed: 32850011
DOI: 10.18632/oncotarget.27697 -
Analytical Methods : Advancing Methods... Feb 2023An attempt was made to develop a new sensitive biosensor for pralatrexate, as an anticancer drug, based on its interaction with the guanine of fish sperm DNA anchored on...
An attempt was made to develop a new sensitive biosensor for pralatrexate, as an anticancer drug, based on its interaction with the guanine of fish sperm DNA anchored on a screen-printed electrode (SPE) modified with polypyrrole (PP)/octahedral Pd-doped CoO composite (Oh-Pd-doped CoO C). Electrochemical techniques like differential pulse voltammetry verified the mechanism of such an interaction on the dsDNA/PP/Oh-Pd-doped CoO C/SPE surface. A reduction in the peak current of guanine oxidation elucidated the interaction in acetate buffer with pH = 4.8. The optimization of response was performed for the interaction method according to potential, accumulation time, reproducibility and drug content. The linear dynamic range was estimated at 1.0 nM to 150.0 μM as well as a limit of detection as low as 0.61 nM for the DNA and pralatrexate concentrations. The practical potential of the proposed sensor was verified by determining pralatrexate in its pharmaceutical matrices.
Topics: Animals; Male; Polymers; Reproducibility of Results; Pyrroles; Semen; Biosensing Techniques; DNA; Guanine
PubMed: 36651313
DOI: 10.1039/d2ay01909d