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Cancer Chemotherapy and Pharmacology Nov 2014To investigate the ability of leucovorin (LV) to abrogate dose-limiting toxicities of pralatrexate (PDX) while maintaining efficacy, in vivo.
PURPOSE
To investigate the ability of leucovorin (LV) to abrogate dose-limiting toxicities of pralatrexate (PDX) while maintaining efficacy, in vivo.
METHODS
H2052 mesothelioma cells were treated with the antifolates methotrexate (MTX), PDX and pemetrexed, with and without LV rescue 24 h later. Cell killing was evaluated 48 h later. Female nude mice bearing H2052 xenografts were treated with varying doses and schedules of the antifolate PDX and LV.
RESULTS
In vitro, H2052 cells were more sensitive to PDX as compared to MTX and pemetrexed. Administration of LV 24 h after antifolate treatment reduced efficacy of antifolates MTX and pemetrexed, but not PDX. In vivo, LV was found to reduce toxicity of PDX at the maximum tolerated dose without sacrificing efficacy. Lethal doses of PDX were rescued by LV, and mice bearing the H2052 tumor demonstrated prolonged and enhanced tumor regression.
CONCLUSIONS
High-dose PDX with subsequent LV rescue may be a viable treatment strategy in mesothelioma and other cancers. The inclusion of LV rescue into new and existing PDX treatment protocols should be explored as a way to expand the tolerability and effectiveness of PDX in the clinic.
Topics: Aminopterin; Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Drug Synergism; Female; Folic Acid Antagonists; Glutamates; Guanine; Humans; Leucovorin; Mesothelioma; Methotrexate; Mice, Nude; Pemetrexed; Time Factors; Tumor Burden; Vitamin B Complex; Xenograft Model Antitumor Assays
PubMed: 25205429
DOI: 10.1007/s00280-014-2580-z -
The Journal of Clinical Endocrinology... Sep 2021Despite the use of aggressive multimodality treatment, most anaplastic thyroid carcinoma (ATC) patients die within a year of diagnosis. Although the combination of BRAF...
BACKGROUND
Despite the use of aggressive multimodality treatment, most anaplastic thyroid carcinoma (ATC) patients die within a year of diagnosis. Although the combination of BRAF and MEK inhibitors has recently been approved for use in BRAF-mutated ATC, they remain effective in a minority of patients who are likely to develop drug resistance. There remains a critical clinical need for effective systemic agents for ATC with a reasonable toxicity profile to allow for rapid translational development.
MATERIAL AND METHODS
Twelve human thyroid cancer cell lines with comprehensive genomic characterization were used in a high-throughput screening (HTS) of 257 compounds to select agents with maximal growth inhibition. Cell proliferation, colony formation, orthotopic thyroid models, and patient-derived xenograft (PDX) models were used to validate the selected agents.
RESULTS
Seventeen compounds were effective, and docetaxel, LBH-589, and pralatrexate were selected for additional in vitro and in vivo analysis as they have been previously approved by the US Food and Drug Administration for other cancers. Significant tumor growth inhibition (TGI) was detected in all tested models treated with LBH-589; pralatrexate demonstrated significant TGI in the orthotopic papillary thyroid carcinoma model and 2 PDX models; and docetaxel demonstrated significant TGI only in the context of mutant TP53.
CONCLUSIONS
HTS identified classes of systemic agents that demonstrate preferential effectiveness against aggressive thyroid cancers, particularly those with mutant TP53. Preclinical validation in both orthotopic and PDX models, which are accurate in vivo models mimicking tumor microenvironment, may support initiation of early-phase clinical trials in non-BRAF mutated or refractory to BRAF/MEK inhibition ATC.
Topics: Animals; Antineoplastic Agents; Carcinogenicity Tests; Cell Line, Tumor; Disease Models, Animal; High-Throughput Screening Assays; Humans; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Tumor Microenvironment
PubMed: 34120183
DOI: 10.1210/clinem/dgab424 -
Journal of Clinical and Experimental... 2020
Relapsed refractory nodal peripheral T-cell lymphoma with follicular helper T-cell phenotype was initially resistant to pralatrexate and confirmed to be unresponsive to subsequent forodesine, but responded to re-instituted pralatrexate.
Topics: Aged; Aminopterin; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Female; Humans; Lymph Nodes; Lymphoma, T-Cell, Peripheral; Neoplasm Recurrence, Local; Prednisone; Purine Nucleosides; Pyrimidinones; T-Lymphocytes, Helper-Inducer; Vincristine
PubMed: 32224563
DOI: 10.3960/jslrt.18031 -
Viruses May 2023During the COVID-19 pandemic, drug repurposing represented an effective strategy to obtain quick answers to medical emergencies. Based on previous data on methotrexate...
During the COVID-19 pandemic, drug repurposing represented an effective strategy to obtain quick answers to medical emergencies. Based on previous data on methotrexate (MTX), we evaluated the anti-viral activity of several DHFR inhibitors in two cell lines. We observed that this class of compounds showed a significant influence on the virus-induced cytopathic effect (CPE) partly attributed to the intrinsic anti-metabolic activity of these drugs, but also to a specific anti-viral function. To elucidate the molecular mechanisms, we took advantage of our EXSCALATE platform for in-silico molecular modelling and further validated the influence of these inhibitors on nsp13 and viral entry. Interestingly, pralatrexate and trimetrexate showed superior effects in counteracting the viral infection compared to other DHFR inhibitors. Our results indicate that their higher activity is due to their polypharmacological and pleiotropic profile. These compounds can thus potentially give a clinical advantage in the management of SARS-CoV-2 infection in patients already treated with this class of drugs.
Topics: Humans; SARS-CoV-2; COVID-19; Pandemics; Molecular Docking Simulation; Antiviral Agents; Drug Repositioning
PubMed: 37243214
DOI: 10.3390/v15051128 -
British Journal of Haematology Feb 2016Peripheral T-cell lymphomas (PTCL) have suboptimal outcomes using conventional CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. The...
A phase II study of cyclophosphamide, etoposide, vincristine and prednisone (CEOP) Alternating with Pralatrexate (P) as front line therapy for patients with peripheral T-cell lymphoma (PTCL): final results from the T- cell consortium trial.
Peripheral T-cell lymphomas (PTCL) have suboptimal outcomes using conventional CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. The anti-folate pralatrexate, the first drug approved for patients with relapsed/refractory PTCL, provided a rationale to incorporate it into the front-line setting. This phase 2 study evaluated a novel front-line combination whereby cyclophosphamide, etoposide, vincristine and prednisone (CEOP) alternated with pralatrexate (CEOP-P) in PTCL. Patients achieving a complete or partial remission (CR/PR) were eligible for consolidative stem cell transplantation (SCT) after 4 cycles. Thirty-three stage II-IV PTCL patients were treated: 21 PTCL-not otherwise specified (64%), 8 angioimmunoblastic T cell lymphoma (24%) and 4 anaplastic large cell lymphoma (12%). The majority (61%) had stage IV disease and 46% were International Prognostic Index high/intermediate or high risk. Grade 3-4 toxicities included anaemia (27%), thrombocytopenia (12%), febrile neutropenia (18%), mucositis (18%), sepsis (15%), increased creatinine (12%) and liver transaminases (12%). Seventeen patients (52%) achieved a CR. The 2-year progression-free survival and overall survival, were 39% (95% confidence interval 21-57) and 60% (95% confidence interval 39-76), respectively. Fifteen patients (45%) (12 CR) received SCT and all remained in CR at a median follow-up of 21·5 months. CEOP-P did not improve outcomes compared to historical data using CHOP. Defining optimal front line therapy in PTCL continues to be a challenge and an unmet need.
Topics: Adult; Aged; Aged, 80 and over; Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Disease Progression; Disease-Free Survival; Epirubicin; Female; Humans; Kaplan-Meier Estimate; Lymphoma, T-Cell, Peripheral; Male; Middle Aged; Prednisone; Treatment Outcome; Vincristine
PubMed: 26627450
DOI: 10.1111/bjh.13855 -
Journal of Family Medicine and Primary... 2017The peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) belongs to a heterogeneous class of aggressive neoplasms. Although several morphologic subtypes of...
The peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) belongs to a heterogeneous class of aggressive neoplasms. Although several morphologic subtypes of this tumor have been described, no particular genetic, immunological, or distinct clinical features define this disease. Patients can experience night sweats, fever, lymphadenopathy, weight loss, splenomegaly, and/or skin changes. Common laboratory tests reveal that patients have anemia, thrombocytosis, lymphocytosis, eosinophilia, hypergammaglobulinemia, or increased lactate dehydrogenase. In this case study, a patient presented with massive lymphadenopathy and right lower limb swelling, which he developed over 6 weeks. A tissue biopsy and supporting investigations confirmed the diagnosis of PTCL, NOS.
PubMed: 29302559
DOI: 10.4103/jfmpc.jfmpc_323_16 -
Frontiers in Chemistry 2022Desired drug candidates should have both a high potential binding chance and high specificity. Recently, many drug screening strategies have been developed to screen...
Desired drug candidates should have both a high potential binding chance and high specificity. Recently, many drug screening strategies have been developed to screen compounds with high possible binding chances or high binding affinity. However, there is still no good solution to detect whether those selected compounds possess high specificity. Here, we developed a reverse DFCNN (Dense Fully Connected Neural Network) and a reverse docking protocol to check a given compound's ability to bind diversified targets and estimate its specificity with homemade formulas. We used the RNA-dependent RNA polymerase (RdRp) target as a proof-of-concept example to identify drug candidates with high selectivity and high specificity. We first used a previously developed hybrid screening method to find drug candidates from an 8888-size compound database. The hybrid screening method takes advantage of the deep learning-based method, traditional molecular docking, molecular dynamics simulation, and binding free energy calculated by metadynamics, which should be powerful in selecting high binding affinity candidates. Also, we integrated the reverse DFCNN and reversed docking against a diversified 102 proteins to the pipeline for assessing the specificity of those selected candidates, and finally got compounds that have both predicted selectivity and specificity. Among the eight selected candidates, Platycodin D and Tubeimoside III were confirmed to effectively inhibit SARS-CoV-2 replication with EC values of 619.5 and 265.5 nM, respectively. Our study discovered that Tubeimoside III could inhibit SARS-CoV-2 replication potently for the first time. Furthermore, the underlying mechanisms of Platycodin D and Tubeimoside III inhibiting SARS-CoV-2 are highly possible by blocking the RdRp cavity according to our screening procedure. In addition, the careful analysis predicted common critical residues involved in the binding with active inhibitors Platycodin D and Tubeimoside III, Azithromycin, and Pralatrexate, which hopefully promote the development of non-covalent binding inhibitors against RdRp.
PubMed: 35903186
DOI: 10.3389/fchem.2022.933102 -
Current Treatment Options in Oncology Jun 2013Peripheral T-cell lymphomas (PTCL) are a group of uncommon and heterogeneous malignancies arising from a postthymic or mature T-lymphocyte. The treatment of PTCL remains...
Peripheral T-cell lymphomas (PTCL) are a group of uncommon and heterogeneous malignancies arising from a postthymic or mature T-lymphocyte. The treatment of PTCL remains a challenging endeavor. Compared with the more common aggressive B-cell lymphomas, more patients with PTCL will be refractory to initial therapy and those who achieve responses often will have shorter progression-free survival. Despite retrospective data that suggest that anthracycline-based multiagent chemotherapy regimens may not provide a benefit compared with nonanthracycline regimens, nonanthracycline-based regimens, with the notable exception of L-asparaginase regimens for extranodal NK/T-cell lymphoma, have been disappointing so far. Based on phase II evidence and subset analyses available, we believe that the addition of etoposide to standard regimens and consolidation of first remissions with autologous stem cell transplantation (autoSCT) provides the best outcome in patients with PTCL and currently use CHOEP followed by ASCT for eligible patients with the common PTCL subtype: PTCL-NOS, AITL, and ALK negative ALCL. For those with ALK-positive ALCL standard CHOP or CHOEP is appropriate with consideration of ASCT only for those with high-risk disease. Other strategies to incorporate additional agents, such as with dose-adjusted EPOCH or sequential CHOP-ICE regimens are logical options; however, they lack the supporting literature of CHOEP. Whereas the above recommendation is our current off-protocol approach, with the possible exception of low risk ALK positive ALCL, none of these choices is supported by strong enough data to supplant a well-conceived clinical trial as the truly preferred strategy in PTCL. The novel agents, romidepsin, pralatrexate, and brentuximab vedotin, are currently approved in the relapsed/refractory setting. These agents are being studied as additions or substitutions for other agents in up-front multiagent chemotherapy regimens. In the relapsed/refractory setting, both pralatrexate and romidepsin remain well-studied choices with some patients achieving a response with durability. Clinical trials of new agents in PTCL continue to be a valuable option and an important part of routine patient management as progressive disease often is seen. Lastly, we believe patients with relapsed/refractory PTCL should be considered for allogeneic stem cell transplantation if a suitable response is demonstrated and a willing donor is available.
Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Combined Modality Therapy; Disease-Free Survival; Humans; Lymphoma, T-Cell, Peripheral; Randomized Controlled Trials as Topic; Retrospective Studies; Stem Cell Transplantation
PubMed: 23568456
DOI: 10.1007/s11864-013-0232-x -
Journal of Clinical Oncology : Official... Sep 2009To determine the maximum-tolerated dose (MTD) and efficacy of pralatrexate in patients with lymphoma.
Phase II-I-II study of two different doses and schedules of pralatrexate, a high-affinity substrate for the reduced folate carrier, in patients with relapsed or refractory lymphoma reveals marked activity in T-cell malignancies.
PURPOSE
To determine the maximum-tolerated dose (MTD) and efficacy of pralatrexate in patients with lymphoma.
PATIENTS AND METHODS
Pralatrexate, initially given at a dose of 135 mg/m(2) on an every-other-week basis, was associated with stomatitis. A redesigned, weekly phase I/II study established an MTD of 30 mg/m(2) weekly for six weeks every 7 weeks. Patients were required to have relapsed/refractory disease, an absolute neutrophil greater than 1,000/microL, and a platelet count greater than 50,000/microL for the first dose of any cycle.
RESULTS
The every-other-week, phase II experience was associated with an increased risk of stomatitis and hematologic toxicity. On a weekly schedule, the MTD was 30 mg/m(2) weekly for 6 weeks every 7 weeks. This schedule modification resulted in a 50% reduction in the major hematologic toxicities and abrogation of the grades 3 to 4 stomatitis. Stomatitis was associated with elevated homocysteine and methylmalonic acid, which were reduced by folate and vitamin B12 supplementation. Of 48 assessable patients, the overall response rate was 31% (26% by intention to treat), including 17% who experienced complete remission (CR). When analyzed by lineage, the overall response rates were 10% and 54% in patients with B- and T-cell lymphomas, respectively. All eight patients who experienced CR had T-cell lymphoma, and four of the six patients with a partial remission were positron emission tomography negative. The duration of responses ranged from 3 to 26 months.
CONCLUSION
Pralatrexate has significant single-agent activity in patients with relapsed/refractory T-cell lymphoma.
Topics: Adult; Aged; Aged, 80 and over; Aminopterin; Constipation; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Fatigue; Female; Folic Acid Antagonists; Humans; Lymphoma, T-Cell; Male; Middle Aged; Recurrence; Remission Induction; Stomatitis; Treatment Outcome; Weight Loss; Young Adult
PubMed: 19652067
DOI: 10.1200/JCO.2008.20.8470 -
Journal of Medical Cases Jan 2022Patients with intestinal T-cell lymphomas (ITLs) usually present with perforation of the small intestine and colon at diagnosis. At relapse or in the advanced stage,...
Patients with intestinal T-cell lymphomas (ITLs) usually present with perforation of the small intestine and colon at diagnosis. At relapse or in the advanced stage, ITLs involve in other extranodal sites, but biopsy-proven lung involvement has been rarely reported. A 76-year-old male presented with sudden-onset abdominal pain, which was found to be caused by the perforation of colon. Emergency operation was carried out, and histopathological examination of the resected colon led to the diagnosis of ITL, not otherwise specified (NOS). He achieved complete metabolic remission (CMR) after eight courses of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy. Two months later, computed tomography showed infiltration and ground-glass opacity in the left pulmonary area in addition to the enlargement of mediastinal and left subclavian lymph nodes, although he did not complain of any pulmonary symptoms. Histopathological findings of the biopsied samples from the pulmonary area were consistent with relapsed ITL, NOS. He achieved CMR after three courses of GDP (gemcitabine, dexamethasone, and cisplatin) chemotherapy; but 1 month after the completion of GDP chemotherapy, he relapsed again with involvement of multiple lymph nodes, not in the pulmonary area. He died owing to the progression of disease. This is the third case of ITLs with lung involvement. Active biopsy should be performed when pulmonary nodules, infiltration, or ground-glass opacity are found in ITLs. A regimen for salvage chemotherapy specifically for ITLs is not yet established, and GDP chemotherapy may be an alternative option for relapsed ITLs in addition to new agents, such as romidepsin and pralatrexate.
PubMed: 35211230
DOI: 10.14740/jmc3830