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Dermatologic Clinics Oct 2015This article reviews methotrexate and the more potent, related compound, pralatrexate, for the treatment of cutaneous T-cell lymphomas, including mycosis fungoides,... (Review)
Review
This article reviews methotrexate and the more potent, related compound, pralatrexate, for the treatment of cutaneous T-cell lymphomas, including mycosis fungoides, Sézary syndrome, and CD30+ lymphoproliferative disorders. Although these folate antagonists are traditionally viewed as antiproliferative cell cycle inhibitors, it is recognized that they inhibit DNA methylation, providing a rationale for their use as epigenetic regulators and cell proliferation inhibitors. The underlying mechanisms are outlined, key supporting data presented, followed by brief mention of recent mathematical modeling supporting the general superiority of combination therapy. Several novel examples involving folate antagonists are proposed.
Topics: Aminopterin; Antimetabolites, Antineoplastic; Apoptosis; DNA Methylation; Epigenesis, Genetic; Folic Acid Antagonists; Humans; Lymphoma, T-Cell, Cutaneous; Methotrexate; S Phase; Skin Neoplasms
PubMed: 26433846
DOI: 10.1016/j.det.2015.05.009 -
Journal of Clinical Oncology : Official... Mar 2011Peripheral T-cell lymphoma (PTCL) is a poor prognosis subtype of non-Hodgkin's lymphoma with no accepted standard of care. This study evaluated the efficacy and...
PURPOSE
Peripheral T-cell lymphoma (PTCL) is a poor prognosis subtype of non-Hodgkin's lymphoma with no accepted standard of care. This study evaluated the efficacy and tolerability of pralatrexate, a novel antifolate with promising activity.
PATIENTS AND METHODS
Patients with independently confirmed PTCL who progressed following ≥ 1 line of prior therapy received pralatrexate intravenously at 30 mg/m(2)/wk for 6 weeks in 7-week cycles. Primary assessment of response was made by independent central review using the International Workshop Criteria. The primary end point was overall response rate. Secondary end points included duration of response, progression-free survival (PFS), and overall survival (OS).
RESULTS
Of 115 patients enrolled, 111 were treated with pralatrexate. The median number of prior systemic therapies was three (range, 1 to 12). The response rate in 109 evaluable patients was 29% (32 of 109), including 12 complete responses (11%) and 20 partial responses (18%), with a median DoR of 10.1 months. Median PFS and OS were 3.5 and 14.5 months, respectively. The most common grade 3/4 adverse events were thrombocytopenia (32%), mucositis (22%), neutropenia (22%), and anemia (18%).
CONCLUSION
To our knowledge, PROPEL (Pralatrexate in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma) is the largest prospective study conducted in patients with relapsed or refractory PTCL. Pralatrexate induced durable responses in relapsed or refractory PTCL irrespective of age, histologic subtypes, amount of prior therapy, prior methotrexate, and prior autologous stem-cell transplant. These data formed the basis for the US Food and Drug Administration approval of pralatrexate, the first drug approved for this disease.
Topics: Adult; Aged; Aged, 80 and over; Aminopterin; Drug Resistance, Neoplasm; Female; Folic Acid Antagonists; Humans; International Agencies; Lymphoma, T-Cell, Peripheral; Male; Middle Aged; Neoplasm Recurrence, Local; Prospective Studies; Remission Induction; Salvage Therapy; Standard of Care; Survival Rate; Treatment Outcome; Young Adult
PubMed: 21245435
DOI: 10.1200/JCO.2010.29.9024 -
Australian Prescriber Apr 2019
Review
PubMed: 31048945
DOI: 10.18773/austprescr.2019.020 -
Blood Mar 2017Peripheral T-cell lymphoma, not otherwise specified, is a broad category of biologically and clinically heterogeneous diseases that cannot be further classified into any... (Review)
Review
Peripheral T-cell lymphoma, not otherwise specified, is a broad category of biologically and clinically heterogeneous diseases that cannot be further classified into any other of the existing entities defined by the World Health Organization classification. Anthracycline-containing regimens, namely cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), nowadays represent the standard first-line treatment; for patients who achieve a satisfactory response, a consolidation by means of autologous stem cell transplantation may offer a greater chance of long-term survival. Several patients, however, display treatment refractoriness or relapse soon after obtaining a response, and just a few of them are suitable transplant candidates. This is why several new agents, with innovative mechanisms of action, have been investigated in this context: pralatrexate, romidepsin, belinostat, and brentuximab vedotin have been approved for relapsed and refractory peripheral T-cell lymphomas based on their activity, although they do not significantly affect survival rates. The incorporation of such new drugs within a CHOP backbone is under investigation to enhance response rates, allow a higher proportion of patients to be transplanted in remission, and prolong survival.
Topics: Antineoplastic Combined Chemotherapy Protocols; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, T-Cell, Peripheral
PubMed: 28115372
DOI: 10.1182/blood-2016-08-692566 -
British Journal of Cancer Jan 2011Pralatrexate is a dihydrofolate reductase (DHFR) inhibitor with high affinity for reduced folate carrier 1 (RFC-1) and folylpolyglutamate synthetase (FPGS), resulting in...
BACKGROUND
Pralatrexate is a dihydrofolate reductase (DHFR) inhibitor with high affinity for reduced folate carrier 1 (RFC-1) and folylpolyglutamate synthetase (FPGS), resulting in extensive internalization and accumulation in tumour cells. Pralatrexate is approved in the US for the treatment of relapsed or refractory peripheral T-cell lymphoma and is being investigated in various malignancies. Here, we evaluated molecular correlates of sensitivity to pralatrexate and explored combinations with a variety of anticancer agents.
METHODS
Antiproliferative effects of pralatrexate were evaluated in 15 human-cancer cell lines using the MTT assay. Gene expression was evaluated using qRT-PCR.
RESULTS
Pralatrexate and methotrexate had a similar pattern of cytotoxicity, pralatrexate being more potent. Pralatrexate potentiated the effects of platinum drugs, antimetabolites and EGFR inhibitors. Dose- and time-dependent cytotoxicity of pralatrexate correlated with high mRNA expression of FPGS. Acquired resistance to pralatrexate was associated with decreased RFC-1 expression, whereas methotrexate resistance correlated with increased DHFR expression, suggesting different mechanisms of acquired resistance.
CONCLUSION
Pralatrexate was more potent than methotrexate in a panel of solid tumour lines. Our findings support the further clinical development of pralatrexate in combination with certain cytotoxics and targeted therapies, and suggest that RFC-1, FPGS and DHFR may be potential biomarkers of outcome.
Topics: Aminopterin; Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Folic Acid Antagonists; Humans; Methotrexate; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 21179031
DOI: 10.1038/sj.bjc.6606063 -
Biomolecules & Therapeutics May 2021Novel coronavirus (SARS-CoV-2) has caused more than 100 million confirmed cases of human infectious disease (COVID-19) since December 2019 to paralyze our global...
Novel coronavirus (SARS-CoV-2) has caused more than 100 million confirmed cases of human infectious disease (COVID-19) since December 2019 to paralyze our global community. However, only limited access has been allowed to COVID-19 vaccines and antiviral treatment options. Here, we report the efficacy of the anticancer drug pralatrexate against SARS-CoV-2. In Vero and human lung epithelial Calu-3 cells, pralatrexate reduced viral RNA copies of SARS-CoV-2 without detectable cytotoxicity, and viral replication was successfully inhibited in a dose-dependent manner. In a time-to-addition assay, pralatrexate treatment at almost half a day after infection also exhibited inhibitory effects on the replication of SARS-CoV-2 in Calu-3 cells. Taken together, these results suggest the potential of pralatrexate as a drug repurposing COVID-19 remedy.
PubMed: 33731494
DOI: 10.4062/biomolther.2021.032 -
Heliyon Dec 2022Gemcitabine is the first-line chemotherapeutic agent for pancreatic cancer. However, gemcitabine-resistance frequently leads to poor prognosis. Exploring new...
Gemcitabine is the first-line chemotherapeutic agent for pancreatic cancer. However, gemcitabine-resistance frequently leads to poor prognosis. Exploring new chemotherapeutic agents is important for patients with gemcitabine-resistant pancreatic cancer. In this study, we established a new acquired gemcitabine-resistant pancreatic cancer cell line BxPC-GEM-20 from parental BxPC-3. We found that pralatrexate significantly inhibited the growth of BxPC-GEM-20. The half-maximal inhibitory concentration of pralatrexate on BxPC-GEM-20 cell was about 3.43 ± 0.25 nM. Pralatrexate was found to effectively inhibit the clonal growth of BxPC-GEM-20 cell. Additionally, pralatrexate at 20 mg/kg had an excellent tumor inhibitory effect with an inhibitory rate of 76.92% . This pralatrexate therapy showed good safety profile that with little to no additional influence on the hepatic, renal function as well as body weight changes in nude mice. Pralatrexate was confirmed to prevent cells from entering the G2/M phase, leading to the promotion of apoptosis and autophagy. Further analysis demonstrated that the reduced phosphorylation of mTOR played a significant role in the tumor cell damage caused by pralatrexate. Pralatrexate effectively inhibited the mTOR/4E-BP1 pathway. Activation of mTOR pathway can further obstruct the repressive effect of pralatrexate on gemcitabine-resistant pancreatic cancer. In summary, pralatrexate induces effective inhibition of gemcitabine-resistant pancreatic cancer. This may lead to the expansion of pralatrexate's application and offer benefit to gemcitabine-resistant pancreatic cancer patients in the future.
PubMed: 36544829
DOI: 10.1016/j.heliyon.2022.e12064 -
Cancer Chemotherapy and Pharmacology Sep 2013To characterize, directly and for the first time, the membrane transport and metabolism of pralatrexate, a new-generation dihydrofolate reductase inhibitor approved for... (Comparative Study)
Comparative Study
PURPOSE
To characterize, directly and for the first time, the membrane transport and metabolism of pralatrexate, a new-generation dihydrofolate reductase inhibitor approved for the treatment for peripheral T-cell lymphoma.
EXPERIMENTAL DESIGN
[(3)H]pralatrexate transport was studied in unique HeLa cell lines that express either the reduced folate carrier (RFC) or the proton-coupled folate transporter (PCFT). Metabolism to active polyglutamate derivatives was assessed by liquid chromatography. These properties were compared to those of methotrexate (MTX).
RESULTS
The pralatrexate influx K t, mediated by RFC, the major route of folate/antifolate transport at systemic pH, was 0.52 μΜ, 1/10th the MTX influx K i. The electrochemical potential of pralatrexate within HeLa cells far exceeded the extracellular level and was greater than for MTX. In contrast, MTX transport mediated by PCFT, the mechanism of folate/antifolate absorption in the small intestine, exceeded that for pralatrexate. After a 6 h exposure of HeLa cells to 0.5 μM pralatrexate, 80 % of intracellular drug was its active polyglutamate forms, predominantly the tetraglutamate, and was suppressed when cells were loaded with natural folates. There was negligible formation of MTX polyglutamates. The difference in pralatrexate and MTX growth inhibition was far greater after transient exposures (375-fold) than continuous exposure (25-fold) to the drugs.
CONCLUSIONS
Pralatrexate's enhanced activity relative to MTX is due to its much more rapid rate of transport and polyglutamation, the former less important when the carrier is saturated. The low affinity of pralatrexate for PCFT predicts a lower level of enterohepatic circulation and increased fecal excretion of the drug relative to MTX.
Topics: Aminopterin; Biological Transport; Chromatography, Liquid; Electrochemistry; Folic Acid Antagonists; HeLa Cells; Humans; Methotrexate; Polyglutamic Acid; Proton-Coupled Folate Transporter; Reduced Folate Carrier Protein; Time Factors
PubMed: 23881211
DOI: 10.1007/s00280-013-2231-9 -
Blood Advances Jun 2024Patients with relapsed or refractory (R/R) mature natural killer cell and T-cell lymphoma have limited treatment options. To evaluate pralatrexate's performance and...
Patients with relapsed or refractory (R/R) mature natural killer cell and T-cell lymphoma have limited treatment options. To evaluate pralatrexate's performance and factors influencing its safety and efficacy in R/R peripheral T-cell lymphoma (PTCL), we performed a pooled analysis of data from 4 similarly designed, regulatory-mandated prospective clinical trials. Of 221 patients (median age, 59 years; 67.0% male) in the study population, 48.9% had PTCL not otherwise specified (PTCL-NOS), 21.3% angioimmunoblastic T-cell lymphoma, and 11.8% ALK-negative anaplastic large cell lymphoma (ALCL). Patients received pralatrexate for a median of 2.56 months (range, 0.03-24.18) and had a 40.7% objective response rate with a median duration of response of 9.1 months, progression-free survival 4.6 months, and overall survival 16.3 months. The most common treatment-related all-grade adverse events were stomatitis, thrombocytopenia, white blood cell count decrease, pyrexia, and vomiting. Subgroup exploratory analyses suggest improved efficacy with 1 prior line of chemotherapy vs 2 or ≥4 prior lines; PTCL-NOS or ALCL vs transformed mycosis fungoides; chemotherapy and transplant before pralatrexate vs chemotherapy alone or chemotherapy with other nontransplant treatments. In conclusion, these pooled analysis results further support using pralatrexate in patients with R/R PTCL. Prospective studies are needed to confirm the findings of subgroups analyses.
Topics: Humans; Aminopterin; Lymphoma, T-Cell, Peripheral; Middle Aged; Male; Female; Aged; Adult; Aged, 80 and over; Treatment Outcome; Recurrence; Young Adult
PubMed: 38429077
DOI: 10.1182/bloodadvances.2023010441