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Cytotherapy Dec 2023Medium-dose etoposide (ETP), cyclophosphamide (CY) and total body irradiation (TBI) is a beneficial conditioning regimen for allogeneic hematopoietic cell... (Review)
Review
Medium-dose etoposide, cyclophosphamide and total body irradiation conditioning potentiates anti-leukemia immunity in adults with acute lymphoblastic leukemia without aggravating graft-versus-host disease.
Medium-dose etoposide (ETP), cyclophosphamide (CY) and total body irradiation (TBI) is a beneficial conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT) in adults with acute lymphoblastic leukemia (ALL), especially with high-risk ALL, as compared with CY and TBI conditioning. ETP may enhance immunogenicity of leukemia-associated antigens through increased expression of major histocompatibility antigen complex class I, leading to cross-priming of T cells by dendritic cells and generating leukemia-specific cytotoxic T cells. Furthermore, ETP can eliminate activated effector T cells, sparing naïve and memory T cells, accompanied with depletion of regulatory T cells. These mechanisms are supposed to lead to inhibit immune escape of leukemia cells and enhance anti-leukemia immunity in addition to direct cytotoxicity of ETP, followed by an efficient eradication of leukemia cells. According to the findings of pharmacokinetics studies, spreading the administration of low-dose ETP may be more efficacious than non-spreading administration, to induce a potent anti-leukemia immunity without aggravating graft-versus-host disease and transplant-related toxicity. In the present review, I discuss the immunological aspects elicited by the addition of medium-dose ETP to the CY/TBI conditioning and the possible positioning of allo-HCT with this conditioning in adults with ALL, considering recent progress in non-HCT treatment including bispecific antibody-based therapy.
Topics: Adult; Humans; Etoposide; Whole-Body Irradiation; Graft vs Host Disease; Cyclophosphamide; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 37665303
DOI: 10.1016/j.jcyt.2023.07.008 -
Nucleic Acids Research Apr 2024RNA-binding proteins emerge as effectors of the DNA damage response (DDR). The multifunctional non-POU domain-containing octamer-binding protein NONO/p54nrb marks...
RNA-binding proteins emerge as effectors of the DNA damage response (DDR). The multifunctional non-POU domain-containing octamer-binding protein NONO/p54nrb marks nuclear paraspeckles in unperturbed cells, but also undergoes re-localization to the nucleolus upon induction of DNA double-strand breaks (DSBs). However, NONO nucleolar re-localization is poorly understood. Here we show that the topoisomerase II inhibitor etoposide stimulates the production of RNA polymerase II-dependent, DNA damage-inducible antisense intergenic non-coding RNA (asincRNA) in human cancer cells. Such transcripts originate from distinct nucleolar intergenic spacer regions and form DNA-RNA hybrids to tether NONO to the nucleolus in an RNA recognition motif 1 domain-dependent manner. NONO occupancy at protein-coding gene promoters is reduced by etoposide, which attenuates pre-mRNA synthesis, enhances NONO binding to pre-mRNA transcripts and is accompanied by nucleolar detention of a subset of such transcripts. The depletion or mutation of NONO interferes with detention and prolongs DSB signalling. Together, we describe a nucleolar DDR pathway that shields NONO and aberrant transcripts from DSBs to promote DNA repair.
Topics: Humans; DNA Breaks, Double-Stranded; DNA-Binding Proteins; Etoposide; RNA Precursors; Transcription Factors; DNA; RNA-Binding Proteins
PubMed: 38224452
DOI: 10.1093/nar/gkae022 -
Cancer Nov 2023Immune checkpoint inhibitor combined with platinum-etoposide is the standard first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC). The...
BACKGROUND
Immune checkpoint inhibitor combined with platinum-etoposide is the standard first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC). The phase 3 clinical trials that led to the approval of chemoimmunotherapy in ES-SCLC excluded patients who had an Eastern Cooperative Group (ECOG) performance status (PS) of 2-3. Therefore, data on the efficacy of chemoimmunotherapy in patients with an ECOG PS of 2-3 are limited.
METHODS
A retrospective analysis was performed on patients diagnosed with ES-SCLC who received chemoimmunotherapy (atezolizumab or durvalumab) within the Mayo Clinic Health System between January 2016 and January 2021. The objective of this study was to compare the overall survival (OS), progression-free survival (PFS), and best clinical response to therapy in patients with an ECOG PS of 0-1 vs. patients with an ECOG PS of 2-3 who received chemoimmunotherapy for newly diagnosed ES-SCLC.
RESULTS
In total, 82 patients were included in the study. The mean ± standard deviation age was 68.1 ± 8.3 years. Of these, 56 patients were identified with an ECOG PS of 0-1, and 26 patients were identified with an ECOG PS of 2-3. The median PFS was similar regardless of ECOG PS (5.8 months [95% CI, 4.3-6.0 months] in the ECOG PS 0-1 group vs. 4.1 months [95% CI, 3.8-6.9 months] in the ECOG PS 2-3; p = .2994). The median OS was also similar regardless of ECOG PS (10.6 months [95% CI, 8.4-13.4 months] in the ECOG PS 0-1 group vs. 9.3 months [95% CI, 4.9-12.8 months]; p = .2718) in the ECOG PS 2-3 group.
CONCLUSIONS
The study results demonstrated no significant difference in PFS or OS among the ECOG PS 2-3 and ECOG PS 0-1 groups. Therefore, chemoimmunotherapy should be considered for patients who have ES-SCLC with an ECOG PS of 2-3.
Topics: Humans; Middle Aged; Aged; Small Cell Lung Carcinoma; Lung Neoplasms; Retrospective Studies; Etoposide; Progression-Free Survival
PubMed: 37548029
DOI: 10.1002/cncr.34966 -
Molecules (Basel, Switzerland) Oct 2023and sp. resistance to antiparasitic drugs has become a major concern in malaria and leishmaniasis control. These diseases are public health problems with significant...
and sp. resistance to antiparasitic drugs has become a major concern in malaria and leishmaniasis control. These diseases are public health problems with significant socioeconomic impacts, and mostly affect disadvantaged populations living in remote tropical areas. This challenge emphasizes the need to search for new chemical scaffolds that preferably possess novel modes of action to contribute to antimalarial and antileishmanial research programs. This study aimed to investigate the antimalarial and antileishmanial properties of a methanol extract (-) of the stem bark of the Cameroonian medicinal plant and its isolated compounds. The purification of - led to the isolation of a new ordered limonoid derivative, 21-hydroxybourjotinolone A (), together with 15 known compounds (-) using a repeated column chromatography. Compound was obtained in an epimeric mixture of 21-melianodiol () and 21-melianodiol (). Structural characterization of the isolated compounds was achieved with HRMS, and 1D- and 2D-NMR analyses. The extracts and compounds were screened using pre-established in vitro methods against synchronized ring stage cultures of the multidrug-resistant Dd2 and chloroquine-sensitive/sulfadoxine-resistant 3D7 strains of and the promastigote form of (1S(MHOM/SD/62/1S). In addition, the samples were tested for cytotoxicity against RAW 264.7 macrophages. Positive controls consisted of artemisinin and chloroquine for , amphotericin B for , and podophyllotoxin for cytotoxicity against RAW 264.7 cells. The extract and fractions exhibited moderate to potent antileishmanial activity with 50% inhibitory concentrations (IC) ranging from 5.99 ± 0.77 to 2.68 ± 0.42 μg/mL, while compounds displayed IC values ranging from 81.73 ± 0.12 to 6.43 ± 0.06 μg/mL. They were weakly active against the chloroquine-sensitive/sulfadoxine-resistant 3D7 strain but highly potent toward the multidrug-resistant Dd2 (extracts, IC 2.50 ± 0.12 to 4.78 ± 0.36 μg/mL; compounds IC 2.93 ± 0.02 to 50.97 ± 0.37 μg/mL) with selectivity indices greater than 10 (SI > 10) for the extract and fractions and most of the derived compounds. Of note, the limonoid mixture [21-hydroxylbourjotinolone A () + 21-melianodiol () + 21-melianodiol ()] exhibited moderate activity against and This novel antiplasmodial and antileishmanial chemical scaffold qualifies as a promising starting point for further medicinal chemistry-driven development of a dually active agent against two major infectious diseases affecting humans in Africa.
Topics: Humans; Antimalarials; Limonins; Plant Extracts; Sulfadoxine; Plant Bark; Antiprotozoal Agents; Chloroquine; Malaria, Falciparum; Meliaceae; Plasmodium falciparum
PubMed: 37894704
DOI: 10.3390/molecules28207227 -
Cell Death & Disease Jul 2023Mammalian oocytes spend most of their life in a unique state of cell cycle arrest at meiotic prophase I, during which time they are exposed to countless DNA-damaging...
Mammalian oocytes spend most of their life in a unique state of cell cycle arrest at meiotic prophase I, during which time they are exposed to countless DNA-damaging events. Recent studies have shown that DNA double-strand break repair occurs predominantly via the homologous recombination (HR) pathway in small non-growing meiotically arrested oocytes (primordial follicle stage). However, the DNA repair mechanisms employed by fully grown meiotically arrested oocytes (GV-stage) have not been studied in detail. Here we established a conditional knockout mouse model to explore the role of Ku80, a critical component of the nonhomologous end joining (NHEJ) pathway, in the repair of DNA damage in GV oocytes. GV oocytes lacking Ku80 failed to repair etoposide-induced DNA damage, even when only low levels of damage were sustained. This indicates Ku80 is needed to resolve DSBs and that HR cannot compensate for a compromised NHEJ pathway in fully-grown oocytes. When higher levels of DNA damage were induced, a severe delay in M-phase entry was observed in oocytes lacking XRCC5 compared to wild-type oocytes, suggesting that Ku80-dependent repair of DNA damage is important for the timely release of oocytes from prophase I and resumption of meiosis. Ku80 was also found to be critical for chromosome integrity during meiotic maturation following etoposide exposure. These data demonstrate that Ku80, and NHEJ, are vital for quality control in mammalian GV stage oocytes and reveal that DNA repair pathway choice differs in meiotically arrested oocytes according to growth status.
Topics: Animals; Mice; DNA Damage; DNA End-Joining Repair; DNA Repair; Etoposide; Mammals; Meiosis; Oocytes
PubMed: 37407587
DOI: 10.1038/s41419-023-05886-x -
International Journal of Molecular... Dec 2023Four copper(II) complexes, -, derived from 1-(isoquinolin-3-yl)heteroalkyl-2-one ligands - were synthesized and characterized using an elemental analysis, IR...
Four copper(II) complexes, -, derived from 1-(isoquinolin-3-yl)heteroalkyl-2-one ligands - were synthesized and characterized using an elemental analysis, IR spectroscopic data as well as single crystal X-ray diffraction data for complex . The stability of complexes - under conditions mimicking the physiological environment was estimated using UV-Vis spectrophotometry. The antiproliferative activity of both ligands - and copper(II) compounds - were evaluated using an MTT assay on four human cancer cell lines, A375 (melanoma), HepG2 (hepatoma), LS-180 (colon cancer) and T98G (glioblastoma), and a non-cancerous cell line, CCD-1059Sk (human normal skin fibroblasts). Complexes - showed greater potency against HepG2, LS180 and T98G cancer cell lines than (IC = 5.04-14.89 μg/mL vs. IC = 43.21->100 μg/mL), while free ligands - remained inactive in all cell lines. The prominent copper(II) compound appeared to be more selective towards cancer cells compared with normal cells than compounds , and . The treatment of HepG2 and T98G cells with complex resulted in sub-G1 and G2/M cell cycle arrest, respectively, which was accompanied by DNA degradation. Moreover, the non-cytotoxic doses of synergistically enhanced the cytotoxic effects of chemotherapeutic drugs, including , and , in HepG2 and T98G cells. The antimicrobial activities of ligands - and their copper(II) complexes - were evaluated using different types of Gram-positive bacteria, Gram-negative bacteria and yeast species. No correlation was found between the results of the antiproliferative and antimicrobial experiments. The antioxidant activities of all compounds were determined using the DPPH and ABTS radical scavenging methods. Antiradical tests revealed that among the investigated compounds, copper(II) complex possessed the strongest antioxidant properties. Finally, the ADME technique was used to determine the physicochemical and drug-likeness properties of the obtained complexes.
Topics: Humans; Etoposide; Antioxidants; Copper; Anti-Infective Agents; Carcinoma, Hepatocellular
PubMed: 38203181
DOI: 10.3390/ijms25010008 -
Anti-cancer Drugs Nov 2023The purpose is to compare the clinical efficacy and toxicity of etoposide plus lobaplatin (EL) or etoposide plus cisplatin (EP) with concurrent thoracic radiotherapy... (Randomized Controlled Trial)
Randomized Controlled Trial
Preliminary results of randomized phase II study of etoposide plus lobaplatin or etoposide plus cisplatin with concurrent thoracic radiotherapy in the treatment of limited-stage small cell lung cancer.
The purpose is to compare the clinical efficacy and toxicity of etoposide plus lobaplatin (EL) or etoposide plus cisplatin (EP) with concurrent thoracic radiotherapy during the treatment of limited-stage small cell lung cancer (LS-SCLC). Forty-two patients with LS-SCLC were randomly divided into EL ( n = 19) or EP ( n = 23) regimens combined with thoracic intensity-modulated radiotherapy. The primary endpoint was 1-year progression-free survival (PFS) rate. The 1-, 2-, and 3-year PFS rates in the EL and EP cohorts were 50.8, 38.1, and 12.7%; and 56.5, 43.5, and 29.0%, respectively ( P = 0.527), whereas the 1-, 2-, and 3-year overall survival (OS) rates were 72.2, 52.5, and 43.8%; and 73.9, 48.4, and 48.4%, respectively ( P = 0.923). The hematological toxicities were similar in two cohorts. However, gastrointestinal reactions were more severe in the EP group. The incidence of nausea and vomiting in EL and EP cohorts were 31.6% vs. 73.9% ( P = 0.006) and 20.1% vs. 60.9% ( P = 0.009), respectively. The two cohorts did not show ≥grade 4 radiation esophagitis and ≥grade 3 radiation pneumonitis. The incidence of acute radiation esophagitis in EL group was lower ( P = 0.038), both groups showed a similar incidence of radiation pneumonitis ( P = 1.000). EL or EP chemotherapy with concurrent thoracic radiotherapy showed similar PFS and OS. The EL group showed milder gastrointestinal toxicity and radiation esophagitis. Radiation pneumonitis and hematological toxicity were similar in the two regimens, which can be tolerated by patients.
Topics: Humans; Small Cell Lung Carcinoma; Cisplatin; Etoposide; Lung Neoplasms; Radiation Pneumonitis; Antineoplastic Combined Chemotherapy Protocols; Esophagitis
PubMed: 36727741
DOI: 10.1097/CAD.0000000000001501 -
Digestive Diseases and Sciences Aug 2023Adult hemophagocytic lymphohistiocytosis is a lifethreatenning disease which has hepatic manifestations mimicking acute hepatitis or can present with fulminant hepatic...
Adult hemophagocytic lymphohistiocytosis is a lifethreatenning disease which has hepatic manifestations mimicking acute hepatitis or can present with fulminant hepatic failure. The undelying pathophysiology is immune dysregulation causing a hyperinflammatory state. Clues to diagnosis include extremely high ferritin levels, whereas definitive diagnosis is usually made by bone marrow, as opposed to liver biopsy. Even with early and appropriate treatment with weekly dexamethasone and etoposide, mortality remains high.
Topics: Humans; Adult; Hepatitis, Viral, Human; Lymphohistiocytosis, Hemophagocytic; Ferritins; Bone Marrow; Dexamethasone; Anti-Inflammatory Agents; Etoposide; Diagnosis, Differential; Anorexia; Muscle Weakness; Weight Loss; Treatment Outcome
PubMed: 37286930
DOI: 10.1007/s10620-023-07985-3 -
Advanced Materials (Deerfield Beach,... May 2024The application of nanomedicines for glioblastoma (GBM) therapy is hampered by the blood-brain barrier (BBB) and the dense glioblastoma tissue. To achieve efficient BBB...
The application of nanomedicines for glioblastoma (GBM) therapy is hampered by the blood-brain barrier (BBB) and the dense glioblastoma tissue. To achieve efficient BBB crossing and deep GBM penetration, this work demonstrates a strategy of active transcellular transport of a mitochondrion-disturbing nanomedicine, pGBEMA-b-pSSPPT (GBEPPT), in the GBM tissue through mitocytosis. GBEPPT is computer-aided designed and prepared by self-assembling a conjugate of an amphiphilic block polymer and a drug podophyllotoxin (PPT). When GBEPPT is delivered to the tumor site, overexpressed γ-glutamyl transpeptidase (GGT) on the brain-blood endothelial cell, or the GBM cell triggered enzymatic hydrolysis of γ-glutamylamide on GBEPPT to reverse its negative charge to positive. Positively charged GBEPPT rapidly enter into the cell and target the mitochondria. These GBEPPT disturb the homeostasis of mitochondria, inducing mitocytosis-mediated extracellular transport of GBEPPT to the neighboring cells via mitosomes. This intracellular-to-intercellular delivery cycle allows GBEPPT to penetrate deeply into the GBM parenchyma, and exert sustainable action of PPT released from GBEPPT on the tumor cells along its penetration path at the tumor site, thus improving the anti-GBM effect. The process of mitocytosis mediated by the mitochondrion-disturbing nanomedicine may offer great potential in enhancing drug penetration through malignant tissues, especially poorly permeable solid tumors.
Topics: Mitochondria; Glioblastoma; Humans; Cell Line, Tumor; Polymers; Animals; Blood-Brain Barrier; Podophyllotoxin; Mice; Brain Neoplasms; Antineoplastic Agents; gamma-Glutamyltransferase; Drug Carriers
PubMed: 38299748
DOI: 10.1002/adma.202311500 -
Annals of Hematology May 2024Indolent lymphoma, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma (FL), can undergo histological transformation into...
Venetoclax plus dose-adjusted R-EPOCH (VR-DA-EPOCH) or G-EPOCH bridging to subsequent cellular therapy for the patients with transformed lymphoma a single center clinical experience.
Indolent lymphoma, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma (FL), can undergo histological transformation into an aggressive subtype, typically diffuse large B-cell lymphoma (DLBCL). The prognosis of transformed lymphoma is poor. In this study, we reported the efficacy and toxicity of a combination of venetoclax, dose-adjusted rituximab or obinutuzumab, etoposide, prednisone, vincristine, doxorubicin, and cyclophosphamide (VR-DA-EPOCH or VG-DA-EPOCH) in 11 patients with biopsy-proven histology transformation into DLBCL, including 8 patients with RT and 3 with transformed FL (tFL). The study was conducted between October 2019 and March 2023 at our single center. The median age of participants at enrolment was 53 years. Six patients (85.7%, 6/7) achieved complete remission (CR) at the end of treatment. The best overall response rate (ORR) and CR rate were both 72.7%, respectively. Two patients received autologous hemopoietic stem cell transplant (ASCT) while two patients received ASCT concurrently with CAR-T therapy for consolidation. With a median follow-up of 13.5 (range, 2.4-29.8) months after enrollment, the median event-free survival, progression-free survival, and overall survival were 9.4, 11.5, and 17.5 months, respectively. Hematologic toxicities of grade ≥3 consisted of neutropenia (90.9%, 10/11), thrombocytopenia (63.6%, 7/11), and febrile neutropenia (54.5%, 6/11). In conclusion, VR-DA-EPOCH or VG-DA-EPOCH was a promising strategy to achieve an early remission, bridging to cellular therapy within this population.
Topics: Humans; Middle Aged; Prednisone; Vincristine; Etoposide; Antibodies, Monoclonal, Murine-Derived; Cyclophosphamide; Rituximab; Lymphoma, Non-Hodgkin; Doxorubicin; Lymphoma, Large B-Cell, Diffuse; Antineoplastic Combined Chemotherapy Protocols; Virtual Reality; Sulfonamides; Bridged Bicyclo Compounds, Heterocyclic
PubMed: 38246951
DOI: 10.1007/s00277-024-05618-x