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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 -
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 -
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 -
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 -
Annals of Translational Medicine Jul 2022Multiple myeloma (MM) with t (11;14) has a unique biology. New combinations of novel agents are needed to improve the prognosis of patients with t (11;14) MM. As a...
BACKGROUND
Multiple myeloma (MM) with t (11;14) has a unique biology. New combinations of novel agents are needed to improve the prognosis of patients with t (11;14) MM. As a selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), palbociclib (PAL) has been used to treat various malignancies, including breast cancer, ovarian cancer, and so on. However, the effects of PAL on MM remain unclear, and thus, further investigations are warranted.
METHODS
Two t (11;14) MM cell lines, U266 and KMS27, were used in this study. The cell viability and cell cycle were detected to evaluate the anti-myeloma effect of the combination of pralatrexate (PTX) and methotrexate (MTX) with PAL. Three-dimensional (3D) spheroid and mouse models were built to verify the effect of the combination treatment. Western blot was used to detect the expressions of Minichromosome Maintenance Complex Component 2 (MCM2), Minichromosome Maintenance Complex Component 3 (MCM3), and dihydrofolate reductase (DHFR).
RESULTS
It was observed that PAL had obvious anticancer effects on U266 and KMS27 cells, which had synergistic effects together with PTX and MTX. Importantly, it was found that PAL could promote cell cycle genes including MCM2 and MCM3, and increase the number of MM cells in the G1 phase. Moreover, PAL reduced the expression level of DHFR and exerted its anticancer effects on MM cells by targeting DHFR. It was also determined that PAL exerted anticancer effects on MM in the spheroid and mouse models.
CONCLUSIONS
PAL exerted obvious anticancer effects on t (11;14) MM cells, which had synergistic effects together with PTX and MTX. PAL could promote cell cycle genes and the G1 phase of MM cells. Moreover, PAL reduced the expression level of DHFR and exerted its anticancer effects on t (11;14) MM cells by targeting DHFR.
PubMed: 35957711
DOI: 10.21037/atm-22-2830 -
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 -
Anti-cancer Agents in Medicinal... 2023Due to their primary effects on DNA synthesis, antimetabolites are most effective against actively dividing cells and are significantly specific to the cell cycle phase.... (Review)
Review
BACKGROUND
Due to their primary effects on DNA synthesis, antimetabolites are most effective against actively dividing cells and are significantly specific to the cell cycle phase. Pralatrexate (PDX), an antifolate metabolite designed to accumulate in cancer cells, was the first new agent approved by the US Food and Drug Administration for the treatment of resistant/recurrent peripheral T-cell lymphomas. PDX was a drug that is frequently used not only for PTCL, but also for cutaneous T-cell lymphoma (CTCL), extranodal natural killer (NK) / T-cell lymphoma.
OBJECTIVE
This article reviews Pralatrexate's history, pharmacokinetics, clinical phase studies including phases I, II and III, types of cancers it is effective on, drug side effects, inhibition mechanism and even its use in the treatment of other cancers with innovative methods, including its antiviral effect against SARS-CoV-2 infection.
METHODS
A comprehensive internet-based research was planned, covering all published and unpublished studies on the subject. We conducted this review in accordance with Preferred Reporting Items for systematic reviews and metaanalysis (PRISMA-P), and Cochrane Collaboration reporting items for systematic reviews and meta-analysis. The results of the studies in the articles were recorded to include all phase studies.
RESULTS
Pralatrexate was structurally designed to have enhanced cellular transport via RFC (reduced folate carrier type) and be subject to more polyglutamation compared to methotrexate. The enhanced polyglutamylation ability of pralatrexate is associated with increased tumor cell death and ultimately improved anticancer activity. Pralatrexate is considered a promising drug for patients with recurrent and treatment-resistant PTCL with a good survival advantage. At the same time, it is an antifolate agent with a significant advantage over methotrexate as it does not cause myelosuppression.
CONCLUSION
While there are manageable side effects such as thrombocytopenia, neutropenia, and mucositis, it is critical to explore new approaches, targeted agents, novel cellular therapies, and immunotherapies to determine optimal pretreatment in the rare but heterogeneous disease PTCL, and future studies and experienced haematologists are needed.
Topics: United States; Humans; Folic Acid Antagonists; Lymphoma, T-Cell, Peripheral; Methotrexate; Neoplasm Recurrence, Local; COVID-19; SARS-CoV-2; Systematic Reviews as Topic; Meta-Analysis as Topic; Lymphoma, T-Cell, Cutaneous; Skin Neoplasms
PubMed: 35692151
DOI: 10.2174/1871520622666220610151603 -
Oncology (Williston Park, N.Y.) May 2022The peripheral T-cell lymphomas (PTCLs) are a notoriously diverse family of non-Hodgkin lymphomas with generally aggressive biology. Clinical management is challenging...
The peripheral T-cell lymphomas (PTCLs) are a notoriously diverse family of non-Hodgkin lymphomas with generally aggressive biology. Clinical management is challenging given a largely inadequate literature base comprised of few randomized trials and heterogeneous observational reports. Herein, we provide an account of our practice in the treatment of the 3 most common nodal PTCLs: PTCL, not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic large cell lymphoma (ALCL). In the up-front setting, we employ anthracycline-based induction, with the incorporation of brentuximab vedotin for all those with ALCL and consideration in those with other CD30-expressing PTCLs based on improved progression-free and overall survival in the absence of additional toxicity in the ECHELON-2 trial. We strongly consider high-dose therapy with autologous stem cell rescue in first complete remission. In the relapsed or refractory (R/R) setting, we often look to clinical trials or choose from 4 FDA-approved single agents-belinostat, brentuximab vedotin, romidepsin, and pralatrexate-based on tumor phenotype and side-effect profiles. Our goal in the R/R setting is achievement of complete remission followed by allogeneic transplant with curative intent in appropriate candidates or long-term disease control in others. Numerous investigational agents are advancing through trials and have potential to alter standards of care in the near future.
Topics: Antineoplastic Combined Chemotherapy Protocols; Brentuximab Vedotin; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, T-Cell, Peripheral; Transplantation, Autologous
PubMed: 35576176
DOI: 10.46883/2022.25920960 -
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 -
ACS Applied Materials & Interfaces Jan 2022Folic acid was reported to significantly improve chondrogenic differentiation of mesenchymal stem cells. In a similar mechanism of action, we investigated clinically...
Folic acid was reported to significantly improve chondrogenic differentiation of mesenchymal stem cells. In a similar mechanism of action, we investigated clinically approved antifolates by the U.S. Food and Drug Administration as chondrogenic-promoting compounds for tonsil-derived mesenchymal stem cells. A poly(ethylene glycol)-poly(l-alanine) thermogelling system was used as a three-dimensional cell culture matrix, where stem cells and antifolates could be incorporated simultaneously during a heat-induced in situ sol-to-gel transition. The antifolates could be supplied over several days by the sustained release of the drug from the thermogel. Initially, seven antifolates were prescreened based on cell viability and expression of a typical chondrogenic biomarker of type II collagen (COL II) at the mRNA level. Then, dapsone, pralatrexate, and trimethoprim were selected as candidate compounds in the second round screening, and detailed studies were carried out on the mRNA and protein expression of various chondrogenic biomarkers including COL II, SRY box transcription factor 9, and aggrecan. Three-dimensional cultures of stem cells in the thermogel in the absence of a chondrogenic promoter compound and in the presence of kartogenin (KGN) were performed as a negative control and positive control, respectively. The chondrogenic biomarkers were significantly increased in the selected antifolate-incorporating systems compared to the negative control system, without an increase in type I collagen (an osteogenic biomarker) expression. Pralatrexate was the best compound for inducing chondrogenic differentiation of the stem cells, even better than the positive control (KGN). Nuclear translocation of the core-binding factor β subunit (CBFβ) and enhanced nuclear runt-related transcription factor 1 (RUNX1) by antifolate treatment suggested that the chondrogenesis-enhancing mechanism is mediated by CBFβ and RUNX1. An in silico modeling study confirmed the mechanism by proving the high binding affinity of pralatrexate to a target protein of filamin A compared with other antifolate candidates. To conclude, pralatrexate was rediscovered as a lead compound, and the polypeptide thermogel incorporating pralatrexate and mesenchymal stem cells can be a very effective system in promoting chondrogenic differentiation of stem cells and might be used in injectable tissue engineering for cartilage repair.
Topics: Aminopterin; Biocompatible Materials; Cell Differentiation; Chondrogenesis; Gels; Humans; Materials Testing; Mesenchymal Stem Cells; Peptides; Temperature
PubMed: 35014790
DOI: 10.1021/acsami.1c20585