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Pediatric Blood & Cancer May 2023Temsirolimus has shown in vivo activity against rhabdomyosarcoma (RMS). We aimed to determine the feasibility of incorporating temsirolimus within the standard...
Feasibility of combining temsirolimus to vincristine, dactinomycin, cyclophosphamide, and vincristine and irinotecan chemotherapy for children with intermediate-risk rhabdomyosarcoma: A report from Children's Oncology Group.
BACKGROUND
Temsirolimus has shown in vivo activity against rhabdomyosarcoma (RMS). We aimed to determine the feasibility of incorporating temsirolimus within the standard Children's Oncology Group (COG) chemotherapy backbone of vincristine, actinomycin-D, and cyclophosphamide (VAC) alternating with vincristine and irinotecan (VI) in children with intermediate-risk (IR) RMS.
METHODS
The feasibility phase of the COG IR-RMS trial, ARST1431 (NCT02567435), assigned 10 patients to receive 15 mg/m /dose (dose level 1) of temsirolimus on days 1, 8, and 15 of each of three weekly VAC and VI cycles for the first 12 weeks of induction chemotherapy. The primary endpoint of the feasibility phase was to establish the safe dose and safety of combining temsirolimus with VAC/VI. The combination regimen was deemed feasible if less than 40% of patients developed a priori defined nonhematological dose-limiting toxicities (DLTs).
RESULTS
Ten patients (seven males and three females; median age = 4.5 years [range: 0.2-14.4 years]) with IR-RMS were enrolled and received dose level 1 of temsirolimus. Eight patients had FOXO1-negative disease, while two had FOXO1-positive disease. Two patients had metastatic disease. Of 10 patients, two developed DLTs: grade 3 oral mucositis and pneumonitis. Four patients (40%) had grade 4 neutropenia. No treatment-related mortality occurred. The median duration of the completion of the feasibility phase was 12.1 weeks (range: 11.7-15 weeks).
CONCLUSIONS
Weekly temsirolimus at 15 mg/m /dose during VAC/VI chemotherapy was feasible and well tolerated. The efficacy of this regimen is currently being tested in a phase III randomized trial against VAC/VI chemotherapy alone in the ARST1431 trial.
PubMed: 37243336
DOI: 10.1002/pbc.30436 -
International Journal of Molecular... Mar 2023Actinomycin is a family of chromogenic lactone peptides that differ in their peptide portions of the molecule. An antimicrobial peptide, actinomycin X2 (Ac.X2), was...
Actinomycin is a family of chromogenic lactone peptides that differ in their peptide portions of the molecule. An antimicrobial peptide, actinomycin X2 (Ac.X2), was produced through the fermentation of a strain. Immobilization of Ac.X2 onto a prepared silk fibroin (SF) film was done through a carbodiimide reaction. The physical properties of immobilized Ac.X2 (antimicrobial films, AMFs) were analyzed by ATR-FTIR, SEM, AFM, and WCA. The findings from an in vitro study showed that AMFs had a more broad-spectrum antibacterial activity against both and compared with free Ac.X2, which showed no apparent strong effect against These AMFs showed a suitable degradation rate, good hemocompatibility, and reduced cytotoxicity in the biocompatibility assay. The results of in vivo bacterially infected wound healing experiments indicated that wound inflammation was prevented by AMFs, which promoted wound repair and improved the wound microenvironment. This study revealed that Ac.X2 transformation is a potential candidate for skin wound healing.
Topics: Dactinomycin; Fibroins; Immobilized Proteins; Wound Healing; Antimicrobial Peptides; Streptomyces; Escherichia coli; Staphylococcus aureus; Spectroscopy, Fourier Transform Infrared; Microscopy, Atomic Force; Fermentation; Materials Testing; Biocompatible Materials; Animals; Rats; Male; Rats, Sprague-Dawley
PubMed: 37047243
DOI: 10.3390/ijms24076269 -
Life Sciences May 2023Actinomycin (Act) D, a polypeptide antibiotic, is used clinically to inhibit the growth of malignant tumors. Act D binds to DNA at the transcription initiation complex...
AIMS
Actinomycin (Act) D, a polypeptide antibiotic, is used clinically to inhibit the growth of malignant tumors. Act D binds to DNA at the transcription initiation complex to prevent the elongation of RNA. Act D causes DNA damage, growth inhibition, and cell death. Myeloid cell leukemia (Mcl-1) is an anti-apoptotic Bcl-2 family member protein, and the present study explored the effects and molecular mechanism of Act D-induced Mcl-1 downregulation.
MAIN METHODS
Human adenocarcinoma A549 cells were used to check the cytotoxic signaling pathways of Act D, particularly in apoptotic mechanism, in a cell-based study approach. Specific blockers targeting the apoptotic factors were examined for their possible roles.
KEY FINDINGS
We found that Act D caused cell growth inhibition and apoptosis. Propidium iodide-based flow cytometric analysis and immunostaining confirmed cell apoptosis. Treatment with Act D caused DNA damage, followed by p53-independent cell death. Western blotting showed a significant decrease in Mcl-1 expression, mitochondrial transmembrane potential loss, and caspase-9/caspase-3 cascade activation. The proteasome inhibitor MG132 reversed Act D-induced Mcl-1 downregulation. However, pharmacological inhibition of glycogen synthase kinase-3, p53 expression, ER stress, autophagy, and vesicle acidification, which are Mcl-1-regulating signaling pathways, did not rescue these effects. Notably, Cullin-Ring E3 ligase partially mediated Mcl-1 downregulation. Administration of transforming growth factor-β induced mesenchymal cell differentiation, but Act D still decreased Mcl-1 and caused cell apoptosis.
SIGNIFICANCE
All of these data show a potential pro-apoptotic effect for Act D by facilitating Mcl-1 uncanonical downregulation.
Topics: Humans; Dactinomycin; Down-Regulation; Myeloid Cell Leukemia Sequence 1 Protein; Anti-Bacterial Agents; Tumor Suppressor Protein p53; Cell Line, Tumor; Lung Neoplasms; Apoptosis; Leukemia; Myeloid Cells; Proto-Oncogene Proteins c-bcl-2
PubMed: 37001403
DOI: 10.1016/j.lfs.2023.121615 -
PeerJ 2023Multidrug-resistant tuberculosis (MDR-TB) is one of the world's most devastating contagious diseases and is caused by the MDR- (MDR-Mtb) bacteria. It is therefore...
BACKGROUND
Multidrug-resistant tuberculosis (MDR-TB) is one of the world's most devastating contagious diseases and is caused by the MDR- (MDR-Mtb) bacteria. It is therefore essential to identify novel anti-TB drug candidates and target proteins to treat MDR-TB. Here, and studies were used to investigate the anti-TB potential of two newly sourced actinomycins, actinomycin-X (act-X) and actinomycin-D (act-D), from the strain UKAQ_23 (isolated from the Jubail industrial city of Saudi Arabia).
METHODS
The anti-TB activity of the isolated actinomycins was assessed using the Mtb H37Ra, (BCG), and Mtb H37Rv bacterial strains, using the Microplate Alamar Blue Assay (MABA) method. molecular docking studies were conducted using sixteen anti-TB drug target proteins using the AutoDock Vina 1.1.2 tool. The molecular dynamics (MD) simulations for both actinomycins were then performed with the most suitable target proteins, using the GROningen MAchine For Chemical Simulations (GROMACS) simulation software (GROMACS 2020.4), with the Chemistry at HARvard Macromolecular Mechanics 36m (CHARMM36m) forcefield for proteins and the CHARMM General Force Field (CGenFF) for ligands.
RESULTS
results for the Mtb H37Ra, BCG, and Mtb H37Rv strains showed that act-X had minimum inhibitory concentration (MIC) values of 1.56 ± 0.0, 1.56 ± 0.0, and 2.64 ± 0.07 µg/mL and act-D had MIC values of 1.56 ± 0.0, 1.56 ± 0.0, and 1.80 ± 0.24 µg/mL respectively. The molecular docking results showed that protein kinase PknB was the preferred target for both actinomycins, while KasA and pantothenate synthetase were the least preferred targets for act-Xand act-D respectively. The molecular dynamics (MD) results demonstrated that act-X and act-D remained stable inside the binding region of PknB throughout the simulation period. The MM/GBSA (Molecular Mechanics/Generalized Born Surface Area) binding energy calculations showed that act-X was more potent than act-D.
CONCLUSION
In conclusion, our results suggest that both actinomycins X and D are highly potent anti-TB drug candidates. We show that act-Xis better able to antagonistically interact with the protein kinase PknB target than act-D, and thus has more potential as a new anti-TB drug candidate.
Topics: Humans; Antitubercular Agents; BCG Vaccine; Dactinomycin; Molecular Docking Simulation; Protein Kinases; Tuberculosis, Multidrug-Resistant
PubMed: 36935926
DOI: 10.7717/peerj.14502 -
Gynecologic Oncology May 2023Gestational Trophoblastic Neoplasia (GTN) is a rare group of malignant placental-related tumours requiring systemic anti-cancer treatment. Leptomeningeal disease (LMD)... (Review)
Review
OBJECTIVES
Gestational Trophoblastic Neoplasia (GTN) is a rare group of malignant placental-related tumours requiring systemic anti-cancer treatment. Leptomeningeal disease (LMD) related to GTN is not well reported with no consensus in optimal treatment. We offer recommendations for management of these patients.
METHODS
We discuss five patients with GTN who presented with features of LMD and were diagnosed with gadolinium-enhanced MRI brain, all of whom received low dose induction etoposide-cisplatin (EP) followed by either EP-etoposide, methotrexate (CNS) and actinomycin-D (EMA) or EMA(CNS)-cyclophosphamide and vincristine (CO).
RESULTS
Four out of the five patients additionally received intrathecal methotrexate. Four patients had complete hCG response to first line multi-agent chemotherapy, one patient required second line paclitaxel, cisplatin alternating with paclitaxel, etoposide (TP/TE), where paclitaxel was substituted with nab-paclitaxel due to anaphylaxis, followed by hysterectomy. One of the four initial complete hCG responders relapsed in the lung requiring further systemic treatment with subsequent lobectomy. Patient reported outcomes indicate persistent neurological symptoms are mild and do not affect functionality and quality of life.
CONCLUSION
With a follow-up range of 2-6 years, all five patients remain cured demonstrating excellent survival outcomes with the avoidance of whole-brain radiotherapy in all cases.
Topics: Pregnancy; Humans; Female; Etoposide; Cisplatin; Methotrexate; Quality of Life; Placenta; Gestational Trophoblastic Disease; Dactinomycin; Cyclophosphamide; Vincristine; Paclitaxel; Antineoplastic Combined Chemotherapy Protocols; Retrospective Studies
PubMed: 36934478
DOI: 10.1016/j.ygyno.2023.03.007 -
Nucleic Acids Research May 2023Combination cancer chemotherapy is one of the most useful treatment methods to achieve a synergistic effect and reduce the toxicity of dosing with a single drug. Here,...
Combination cancer chemotherapy is one of the most useful treatment methods to achieve a synergistic effect and reduce the toxicity of dosing with a single drug. Here, we use a combination of two well-established anticancer DNA intercalators, actinomycin D (ActD) and echinomycin (Echi), to screen their binding capabilities with DNA duplexes containing different mismatches embedded within Watson-Crick base-pairs. We have found that combining ActD and Echi preferentially stabilised thymine-related T:T mismatches. The enhanced stability of the DNA duplex-drug complexes is mainly due to the cooperative binding of the two drugs to the mismatch duplex, with many stacking interactions between the two different drug molecules. Since the repair of thymine-related mismatches is less efficient in mismatch repair (MMR)-deficient cancer cells, we have also demonstrated that the combination of ActD and Echi exhibits enhanced synergistic effects against MMR-deficient HCT116 cells and synergy is maintained in a MMR-related MLH1 gene knockdown in SW620 cells. We further accessed the clinical potential of the two-drug combination approach with a xenograft mouse model of a colorectal MMR-deficient cancer, which has resulted in a significant synergistic anti-tumour effect. The current study provides a novel approach for the development of combination chemotherapy for the treatment of cancers related to DNA-mismatches.
Topics: Humans; Animals; Mice; Dactinomycin; Echinomycin; Thymine; Base Sequence; Binding Sites; Nucleic Acid Conformation; DNA; Colorectal Neoplasms
PubMed: 36919604
DOI: 10.1093/nar/gkad156 -
Journal of Biomolecular Structure &... 2023The failure of chemotherapy in the treatment of carcinoma is mainly due to the development of multidrug resistance (MDR), which is largely caused by the overexpression...
The failure of chemotherapy in the treatment of carcinoma is mainly due to the development of multidrug resistance (MDR), which is largely caused by the overexpression of P-glycoprotein (P-gp/ABCB1/MDR1). Until recently, the 3D structure of the P-gp transporter has not been experimentally resolved, which restricted the discovery of prospective P-gp inhibitors utilizing techniques. In this study, the binding energies of 512 drug candidates in clinical or investigational stages were assessed as potential P-gp inhibitors employing methods. On the basis of the available experimental data, the performance of the AutoDock4.2.6 software to predict the drug-P-gp binding mode was initially validated. Molecular docking and molecular dynamics (MD) simulations combined with molecular mechanics-generalized Born surface area (MM-GBSA) binding energy computations were subsequently conducted to screen the investigated drug candidates. Based on the current results, five promising drug candidates, namely valspodar, dactinomycin, elbasvir, temsirolimus, and sirolimus, showed promising binding energies against P-gp transporter with Δ values of -126.7, -112.1, -111.9, -102.9, and -101.4 kcal/mol, respectively. The post-MD analyses revealed the energetical and structural stabilities of the identified drug candidates in complex with the P-gp transporter. Furthermore, in order to mimic the physiological conditions, the potent drugs complexed with the P-gp were subjected to 100 ns MD simulations in an explicit membrane-water environment. The pharmacokinetic properties of the identified drugs were predicted and demonstrated good ADMET characteristics. Overall, these results indicated that valspodar, dactinomycin, elbasvir, temsirolimus, and sirolimus hold promise as prospective P-gp inhibitors and warrant further / investigations.
Topics: Humans; Molecular Docking Simulation; Dactinomycin; Prospective Studies; Drug Resistance, Multiple; Neoplasms; ATP Binding Cassette Transporter, Subfamily B; Sirolimus; Drug Discovery; Drug Resistance, Neoplasm
PubMed: 36883864
DOI: 10.1080/07391102.2023.2176360 -
The Journal of International Medical... Mar 2023To date, only 34 cases of primary pulmonary rhabdomyosarcoma (PPRMS) in the middle-aged and elderly population have been published. However, analyses of the... (Review)
Review
To date, only 34 cases of primary pulmonary rhabdomyosarcoma (PPRMS) in the middle-aged and elderly population have been published. However, analyses of the clinicopathological characteristics and prognosis of PPRMS in this population have not been performed. A 75-year-old man visited our hospital because of abdominal pain and discomfort. His serum lactate dehydrogenase, neuron specific enolase, and progastrin-releasing peptide levels were elevated. Positron emission tomography-computed tomography revealed a lobulated mass of 7.6 × 5.5 cm in the lower lobe of the left lung with abnormally high fluoro-2-deoxy-d-glucose metabolism. Histologically, the tumor cells were small with little cytoplasm, deep nuclear staining, and heavily stained nuclear chromatin. Immunohistochemically, the tumor cells were positive for desmin, MyoD1 myogenin, synaptophysin, and CD56. Cytogenetic analysis for FOXO1A translocation was negative. Finally, the patient was diagnosed with PPRMS. He received combined chemotherapy with vincristine 1 mg, actinomycin 0.4 mg, cyclophosphamide 0.8 mg; however, only one course of chemotherapy was completed, and the patient died 2 months after diagnosis. PPRMS in middle-aged and elderly people is a highly malignant soft tissue tumor with significant clinicopathological characteristics.
Topics: Aged; Humans; Male; Middle Aged; Cyclophosphamide; Lung Neoplasms; Prognosis; Rhabdomyosarcoma; Vincristine; Dactinomycin; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36883437
DOI: 10.1177/03000605231159782 -
Journal of Clinical Oncology : Official... May 2023JCO The RMS2005 study included two phase III randomized trials for high-risk (HR) and observational trials for low (LR), standard (SR), and very high-risk (VHR)... (Clinical Trial)
Clinical Trial
JCO The RMS2005 study included two phase III randomized trials for high-risk (HR) and observational trials for low (LR), standard (SR), and very high-risk (VHR) patients who have been partially reported. Herein, we present a comprehensive report of results achieved for the complete unselected nonmetastatic cohort and analyze the evolution of treatment in comparison with previous European protocols. After a median follow-up of 73.1 months, the 5-year event-free survival (EFS) and overall survival (OS) of the 1,733 patients enrolled were 70.7% (95% CI, 68.5 to 72.8) and 80.4% (95% CI, 78.4 to 82.3), respectively. The results by subgroup: LR (80 patients) EFS 93.7% (95% CI, 85.5 to 97.3), OS 96.7% (95% CI, 87.2 to 99.2); SR (652 patients) EFS 77.4% (95% CI, 73.9 to 80.5), OS 90.6% (95% CI, 87.9 to 92.7); HR (851 patients) EFS 67.3% (95% CI, 64.0 to 70.4), OS 76.7% (95% CI, 73.6 to 79.4); and VHR (150 patients) EFS 48.8% (95% CI, 40.4 to 56.7), OS 49.7% (95% CI, 40.8 to 57.9). The RMS2005 study demonstrated that 80% of children with localized rhabdomyosarcoma could be long-term survivors. The study has established the standard of care across the European Soft tissue sarcoma Study Group countries with the confirmation of a 22-week vincristine/actinomycin D regimen for LR patients, the reduction of the cumulative ifosfamide dose in the SR group, and for HR disease, the omission of doxorubicin and the addition of maintenance chemotherapy.
Topics: Adolescent; Child; Humans; Antineoplastic Combined Chemotherapy Protocols; Dactinomycin; Disease-Free Survival; Rhabdomyosarcoma; Sarcoma
PubMed: 36848614
DOI: 10.1200/JCO.22.02093 -
BMC Women's Health Feb 2023Gestational trophoblastic neoplasia (GTN) is rare, and it is even rarer for GTN to merge with primary malignant tumors in other organs. Herein is described a rare... (Review)
Review
BACKGROUND
Gestational trophoblastic neoplasia (GTN) is rare, and it is even rarer for GTN to merge with primary malignant tumors in other organs. Herein is described a rare clinical case of GTN combined with primary lung cancer and mesenchymal tumor of the sigmoid colon, followed with literature review.
CASE PRESENTATION
The patient was hospitalized due to diagnosis of GTN with primary lung cancer. Firstly, two cycles of chemotherapy including 5-fluorouracil (5-FU) and actinomycin-D(Act-D) was given. Laparoscopic total hysterectomy and right salpingo-oophorectomy was performed during the third chemotherapy. During the operation, a 3*2 cm nodule was removed which was protruded from the serous surface of the sigmoid colon, and the nodule was confirmed mesenchymal tumor pathologically, in accord with gastrointestinal stromal tumor. During the treatment of GTN, Icotinib tablets were taken orally to control the progression of lung cancer. After 2 cycles of consolidation chemotherapy of GTN, she received thoracoscopic lower lobe of right lung lobectomy and the mediastinum lymph nodes removal. She undertook gastroscopy and colonoscopy and the tubular adenoma of the descending colon was removed. At present, the regular follow-up is taken and she remains free of tumors.
CONCLUSIONS
GTN combined with primary malignant tumors in other organs are extremely rare in clinical practice. When imaging examination reveals a mass in other organs, clinicians should be aware of the possibility of a second primary tumor. It will increase the difficulty of GTN staging and treatment. We emphasis the importance of the collaboration of multidisciplinary teams. Clinicians should choose a reasonable treatment plan according to the priorities of different tumors.
Topics: Pregnancy; Female; Humans; Colon, Sigmoid; Retrospective Studies; Gestational Trophoblastic Disease; Dactinomycin; Lung Neoplasms
PubMed: 36803691
DOI: 10.1186/s12905-023-02204-7