-
Molecules (Basel, Switzerland) Jan 2021Amsacrine, an anticancer drug first synthesised in 1970 by Professor Cain and colleagues, showed excellent preclinical activity and underwent clinical trial in 1978... (Review)
Review
Amsacrine, an anticancer drug first synthesised in 1970 by Professor Cain and colleagues, showed excellent preclinical activity and underwent clinical trial in 1978 under the auspices of the US National Cancer Institute, showing activity against acute lymphoblastic leukaemia. In 1984, the enzyme DNA topoisomerase II was identified as a molecular target for amsacrine, acting to poison this enzyme and to induce DNA double-strand breaks. One of the main challenges in the 1980s was to determine whether amsacrine analogues could be developed with activity against solid tumours. A multidisciplinary team was assembled in Auckland, and Professor Denny played a leading role in this approach. Among a large number of drugs developed in the programme, -[2-(dimethylamino)-ethyl]-acridine-4-carboxamide (DACA), first synthesised by Professor Denny, showed excellent activity against a mouse lung adenocarcinoma. It underwent clinical trial, but dose escalation was prevented by ion channel toxicity. Subsequent work led to the DACA derivative SN 28049, which had increased potency and reduced ion channel toxicity. Mode of action studies suggested that both amsacrine and DACA target the enzyme DNA topoisomerase II but with a different balance of cellular consequences. As primarily a topoisomerase II poison, amsacrine acts to turn the enzyme into a DNA-damaging agent. As primarily topoisomerase II catalytic inhibitors, DACA and SN 28049 act to inhibit the segregation of daughter chromatids during anaphase. The balance between these two actions, one cell cycle phase specific and the other nonspecific, together with pharmacokinetic, cytokinetic and immunogenic considerations, provides links between the actions of acridine derivatives and anthracyclines such as doxorubicin. They also provide insights into the action of cytotoxic DNA-binding drugs.
Topics: Adenocarcinoma of Lung; Amsacrine; Anaphase; Animals; Antineoplastic Agents; Chromatids; Chromosome Segregation; DNA Topoisomerases, Type II; DNA, Neoplasm; History, 20th Century; History, 21st Century; Humans; Lung Neoplasms; Mice; Naphthyridines; Neoplasm Proteins; Topoisomerase II Inhibitors
PubMed: 33494466
DOI: 10.3390/molecules26030552 -
RSC Medicinal Chemistry Mar 2020A series of eleven 9-acridinyl amino acid derivatives were synthesized using a two-step procedure. Cytotoxicity was tested on the K562 and A549 cancer cell lines and...
A series of eleven 9-acridinyl amino acid derivatives were synthesized using a two-step procedure. Cytotoxicity was tested on the K562 and A549 cancer cell lines and normal diploid cell line MRC5 using the MTT assay. Compounds , , and were the most active, with IC values comparable to or lower than that of chemotherapeutic agent amsacrine. and were especially effective in the A549 cell line (IC ≈ 6 μM), which is of special interest since amsacrine is not sufficiently active in lung cancer patients. Cell cycle analysis revealed that and caused G2/M block, amsacrine caused arrest in the S phase, while and induced apoptotic cell death independently of the cell cycle regulation. In comparison to amsacrine, , , , and showed similar inhibitory potential towards topoisomerase II, whereas only showed DNA intercalation properties. In contrast to amsacrine, , , and showed a lack of toxicity towards unstimulated normal human leucocytes.
PubMed: 33479643
DOI: 10.1039/c9md00597h -
Pharmaceuticals (Basel, Switzerland) Sep 2022In this study, we report the synthesis of twenty new acridine-thiosemicarbazone derivatives and their antiproliferative activities. Mechanisms of action such as the...
Synthesis and Evaluation of Antiproliferative Activity, Topoisomerase IIα Inhibition, DNA Binding and Non-Clinical Toxicity of New Acridine-Thiosemicarbazone Derivatives.
In this study, we report the synthesis of twenty new acridine-thiosemicarbazone derivatives and their antiproliferative activities. Mechanisms of action such as the inhibition of topoisomerase IIα and the interaction with DNA have been studied for some of the most active derivatives by means of both in silico and in vitro methods, and evaluations of the non-clinical toxicities (in vivo) in mice. In general, the compounds showed greater cytotoxicity against B16-F10 cells, with the highest potency for DL-08 (IC = 14.79 µM). Derivatives DL-01 (77%), DL-07 (74%) and DL-08 (79%) showed interesting inhibition of topoisomerase IIα when compared to amsacrine, at 100 µM. In silico studies proposed the way of bonding of these compounds and a possible stereoelectronic reason for the absence of enzymatic activity for CL-07 and DL-06. Interactions with DNA presented different spectroscopic effects and indicate that the compound CL-07 has higher affinity for DNA (Kb = 4.75 × 10 M; Ksv = 2.6 × 10 M). In addition, compounds selected for non-clinical toxicity testing did not show serious signs of toxicity at the dose of 2000 mg/kg in mice; cytotoxic tests performed on leukemic cells (K-562) and its resistant form (K-562 Lucena 1) identified moderate potency for DL-01 and DL-08, with IC between 11.45 and 17.32 µM.
PubMed: 36145320
DOI: 10.3390/ph15091098 -
Annals of Hematology Jun 2022Reduced intensity conditioning (RIC) and reduced toxicity conditioning (RTC) regimens enable allogeneic hematopoietic stem cell transplantation (alloSCT) to more...
Conditioning with fludarabine and treosulfan compared to FLAMSA-RIC in allogeneic stem cell transplantation for myeloid malignancies: a retrospective single-center analysis.
Reduced intensity conditioning (RIC) and reduced toxicity conditioning (RTC) regimens enable allogeneic hematopoietic stem cell transplantation (alloSCT) to more patients due to reduction in transplant-related mortality (TRM). The conditioning regimens with fludarabine and treosulfan (Flu/Treo) or fludarabine, amsacrine, cytarabine (FLAMSA)-RIC have shown their efficacy and tolerability in various malignancies. So far, no prospective study comparing the two regimens is available. Two studies compared the regimens retrospectively, in which both provided similar outcome. In this retrospective, single-center analysis, these two regimens were compared with regard to outcome, rate of acute and chronic graft versus host disease (GvHD), and engraftment. 113 consecutive patients with myeloid malignancies who received Flu/Treo or FLAMSA-RIC conditioning prior to alloSCT between 2007 and 2019 were included. Except for age, previous therapies, and remission status before alloSCT, patient characteristics were well balanced. The median follow-up time within this analysis was 44 months. There was no significant difference in absolute neutrophil count (ANC) or platelet engraftment between the two conditioning regimens. Overall survival (OS), the relapse-free survival (RFS), and the TRM were not significantly different between the two cohorts. The rate of GvHD did not differ between the two groups. In summary, this retrospective analysis shows that there is no major difference regarding tolerability and survival between the Flu/Treo and FLAMSA-RIC regimens. Despite several limitations due to uneven distribution concerning age and remission status, we demonstrate that Flu/Treo and FLAMSA-RIC provide similar outcomes and are feasible in older and intensively pre-treated patients.
Topics: Aged; Busulfan; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Myeloproliferative Disorders; Neoplasm Recurrence, Local; Retrospective Studies; Transplantation Conditioning; Vidarabine
PubMed: 35364726
DOI: 10.1007/s00277-022-04822-x -
Briefings in Bioinformatics Sep 2021Current coronavirus disease-2019 (COVID-19) pandemic has caused massive loss of lives. Clinical trials of vaccines and drugs are currently being conducted around the...
Current coronavirus disease-2019 (COVID-19) pandemic has caused massive loss of lives. Clinical trials of vaccines and drugs are currently being conducted around the world; however, till now no effective drug is available for COVID-19. Identification of key genes and perturbed pathways in COVID-19 may uncover potential drug targets and biomarkers. We aimed to identify key gene modules and hub targets involved in COVID-19. We have analyzed SARS-CoV-2 infected peripheral blood mononuclear cell (PBMC) transcriptomic data through gene coexpression analysis. We identified 1520 and 1733 differentially expressed genes (DEGs) from the GSE152418 and CRA002390 PBMC datasets, respectively (FDR < 0.05). We found four key gene modules and hub gene signature based on module membership (MMhub) statistics and protein-protein interaction (PPI) networks (PPIhub). Functional annotation by enrichment analysis of the genes of these modules demonstrated immune and inflammatory response biological processes enriched by the DEGs. The pathway analysis revealed the hub genes were enriched with the IL-17 signaling pathway, cytokine-cytokine receptor interaction pathways. Then, we demonstrated the classification performance of hub genes (PLK1, AURKB, AURKA, CDK1, CDC20, KIF11, CCNB1, KIF2C, DTL and CDC6) with accuracy >0.90 suggesting the biomarker potential of the hub genes. The regulatory network analysis showed transcription factors and microRNAs that target these hub genes. Finally, drug-gene interactions analysis suggests amsacrine, BRD-K68548958, naproxol, palbociclib and teniposide as the top-scored repurposed drugs. The identified biomarkers and pathways might be therapeutic targets to the COVID-19.
Topics: Algorithms; Brain Neoplasms; Central Nervous System Diseases; Computational Biology; Disease Progression; Glioblastoma; Humans; Machine Learning
PubMed: 33839760
DOI: 10.1093/bib/bbab120 -
Journal of Clinical Medicine Sep 2019Reduced-intensity conditioning (RIC) regimens are established options for hematopoietic stem cell transplantation (HSCT) for patients with acute myeloid leukemia (AML)... (Review)
Review
Reduced-intensity conditioning (RIC) regimens are established options for hematopoietic stem cell transplantation (HSCT) for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, the efficacy of RIC regimens for patients with high-risk disease is limited. The addition of a fludarabine, amsacrine, and cytarabine (FLAMSA)-sequential conditioning regimen was introduced for patients with high-risk MDS and AML to combine a high anti-leukemic activity with the advantages of RIC. The current systematic literature review and meta-analysis was conducted with the aim of identifying all cohort studies of patients with AML and/or MDS who received FLAMSA-RIC to determine its efficacy and toxicity. Out of 3044 retrieved articles, 12 published studies with 2395 overall patients (18.1-76.0 years; 96.8% AML and 3.2% MDS; follow-up duration of 0.7-145 months; 50.3% had active AML disease before HSCT) met the eligibility criteria and were included in the meta-analysis. In the pooled analysis, the 1- and 3-year overall survival (OS) rates were 59.6% (95% confidence interval (CI), 47.9-70.2%) and 40.2% (95% CI, 28.0-53.7%), respectively. The pooled 3-year OS rate of the patients who achieved CR1 or CR2 prior to HSCT was 60.1% (95% CI, 55.1-64.8%) and the percentage of those with relapse or refractory disease was 27.8% (95% CI, 23.3-32.8%). The pooled 3-year leukemia-free survival (LFS) rate was 39.3% (95% CI, 26.4-53.9%). Approximately 29% of the patients suffered from grades 2-4 acute graft-versus-host disease (GVHD), while 35.6% had chronic GVHD. The pooled 1- and 3-year non-relapse mortality (NRM) rates were 17.9% (95% CI, 16.1-19.8%) and 21.1% (95% CI, 18.8-23.7%), respectively. Our data indicates that the FLAMSA-RIC regimen is an effective and well-tolerated regimen for HSCT in patients with high-risk AML and MDS.
PubMed: 31514339
DOI: 10.3390/jcm8091437 -
Viruses Jul 2023The Venezuelan equine encephalitis virus (VEEV) nonstructural protein 2 (nsP2) cysteine protease (EC 3.4.22.B79) is essential for viral replication. High throughput in...
The Venezuelan equine encephalitis virus (VEEV) nonstructural protein 2 (nsP2) cysteine protease (EC 3.4.22.B79) is essential for viral replication. High throughput in silico/in vitro screening using a focused set of known cysteine protease inhibitors identified two epoxysuccinyl prodrugs, E64d and CA074 methyl ester (CA074me) and a reversible oxindole inhibitor. Here, we determined the X-ray crystal structure of the CA074-inhibited nsP2 protease and compared it with our E64d-inhibited structure. We found that the two inhibitors occupy different locations in the protease. We designed hybrid inhibitors with improved potency. Virus yield reduction assays confirmed that the viral titer was reduced by >5 logs with CA074me. Cell-based assays showed reductions in viral replication for CHIKV, VEEV, and WEEV, and weaker inhibition of EEEV by the hybrid inhibitors. The most potent was NCGC00488909-01 which had an EC of 1.76 µM in VEEV-Trd-infected cells; the second most potent was NCGC00484087 with an EC = 7.90 µM. Other compounds from the NCATS libraries such as the H1 antihistamine oxatomide (>5-log reduction), emetine, amsacrine an intercalator (NCGC0015113), MLS003116111-01, NCGC00247785-13, and MLS00699295-01 were found to effectively reduce VEEV viral replication in plaque assays. Kinetic methods demonstrated time-dependent inhibition by the hybrid inhibitors of the protease with NCGC00488909-01 (K = 3 µM) and NCGC00484087 (K = 5 µM). Rates of inactivation by CA074 in the presence of 6 mM CaCl, MnCl, or MgCl were measured with varying concentrations of inhibitor, Mg and Mn slightly enhanced inhibitor binding (3 to 6-fold). CA074 inhibited not only the VEEV nsP2 protease but also that of CHIKV and WEEV.
Topics: Animals; Horses; Encephalitis Virus, Venezuelan Equine; Cysteine Proteases; Virus Replication; Cysteine Proteinase Inhibitors
PubMed: 37515189
DOI: 10.3390/v15071503 -
Clinical Lymphoma, Myeloma & Leukemia Jan 2022Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) remains the best curative option for high-risk myelodysplastic syndrome . We retrospectively compared...
On Behalf of the SFGM-TC: Retrospective Comparison of Reduced and Higher Intensity Conditioning for High-Risk Myelodysplastic Syndrome Treated With Allogeneic Stem-Cell Transplantation.
BACKGROUND
Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) remains the best curative option for high-risk myelodysplastic syndrome . We retrospectively compared patient outcomes after allo-HSCT according to the intensity of the conditioning regimen.
PATIENTS AND METHODS
Three conditioning regimens were compared in 427 patients allografted for high-risk myelodysplastic syndrome: reduced-intensity conditioning (RIC), fludarabine (150-160 mg/m) and busulfan (6.4 mg/kg); sequential FLAMSA-RIC, fludarabine, amsacrine, and aracytine followed by RIC; and myeloablative with reduced toxicity (RTC), fludarabine and busulfan (9.6 mg/kg or 12.8 mg/kg).
RESULTS
The patients in the 3 conditioning groups were different in regards to the number of treatment lines (P< .001), percentage of blasts in bone marrow (P< .001), and disease status at transplantation (P< .001). No significant differences in outcomes (overall survival, progression-free survival, nonrelapse mortality, relapse incidence, and graft versus host disease relapse-free survival) were observed between the 3 groups. Using propensity score analysis to overcome baseline imbalances, we compared 70 patients receiving FLAMSA-RIC to 260 patients receiving RIC, and compared 83 patients receiving RTC to 252 patients receiving RIC. The only factor influencing overall and progression-free survival was cytogenetic risk at transplantation. After the covariate adjustment using propensity score to reduce baseline imbalances, the only factor influencing overall and progression-free survival was still cytogenetic risk at transplantation.
CONCLUSION
Overall survival appears to be similar with the 3 conditioning regimens. The only factor influencing survival is cytogenetic risk at transplantation, suggesting that new promising drugs in the conditioning and/or early interventions after transplantation are needed to improve outcomes in these patients.
Topics: Adult; Aged; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Retrospective Studies; Risk Factors; Survival Analysis; Transplantation Conditioning; Transplantation, Homologous
PubMed: 34456160
DOI: 10.1016/j.clml.2021.07.027 -
Annals of Hematology Apr 2023Intensive chemotherapy is the backbone of induction treatment in patients with acute myeloid leukemia (AML). However, AML patients with concomitant cardiac disease may...
Intensive chemotherapy is the backbone of induction treatment in patients with acute myeloid leukemia (AML). However, AML patients with concomitant cardiac disease may not be eligible for anthracycline-based therapies. In a small cohort of patients, we have previously shown that anthracycline-free, amsacrine-based chemotherapy TAA (thioguanine, cytarabine, amsacrine) may be as effective as cytarabine/daunorubicin for induction therapy in these patients. In this systematic retrospective single-center analysis, we documented the outcome of 31 patients with significant cardiac comorbidities including coronary heart disease or cardiomyopathy receiving TAA as induction chemotherapy. Median (range) ejection fraction (EF) was 48% (30-67%) in this cohort. Patients with EF below 30% were considered unfit for intensive induction therapy. Event-free survival (EFS), overall survival (OS), and relapse-free survival (RFS) were 1.61, 5.46, and 13.6 months respectively. Poor outcome was primarily related to a high early mortality rate within the first 30 days of therapy, mainly caused by infectious complications. TAA cannot be recommended as a substitute of standard induction for AML patients with significant concomitant cardiac disease. In the era of novel agents, alternative strategies (e.g., hypomethylating agents plus venetoclax) should be considered when anthracycline-based regimens are not suitable.
Topics: Humans; Amsacrine; Induction Chemotherapy; Retrospective Studies; Antineoplastic Combined Chemotherapy Protocols; Leukemia, Myeloid, Acute; Remission Induction; Heart Diseases; Anthracyclines; Cytarabine
PubMed: 36749402
DOI: 10.1007/s00277-023-05111-x -
Scientific Reports Dec 2019Treatments for refractory glaucoma include trabeculectomy, in which a filtering bleb is created to reduce aqueous pressure. Mitomycin C (MMC) is often used as an...
Treatments for refractory glaucoma include trabeculectomy, in which a filtering bleb is created to reduce aqueous pressure. Mitomycin C (MMC) is often used as an adjuvant to reduce post-trabeculectomy bleb scarring and consequent failure. However, scarring sometimes still occurs. Thus, we searched for more effective trabeculectomy adjuvants with high-throughput screening (HTS) of a library of 1,165 off-patent drug compounds. This revealed that amsacrine (AMSA), a DNA topoisomerase II (TOP2) inhibitor, was the top candidate. Compared to MMC, rabbits that underwent trabeculectomy with 10% AMSA had lower IOP at 42, 56, and 70 days (P < 0.01 at all measurement points) and a higher bleb score at 28, 42, 56, and 70 days (P = < 0.01, 0.04, 0.04, and < 0.01, respectively). Compared to saline, rabbits that received 1% AMSA also had lower IOP and better bleb score at all time points, without a sharp drop in IOP just after surgery (all P < 0.01). Both effects were milder than MMC at 7 days (P = 0.02 and <0.01, respectively). Thus, this study showed that HTS may help identify new, promising uses for off-patent drugs. Furthermore, trabeculectomy with AMSA at a suitable concentration may improve the prognosis after trabeculectomy compared to MMC.
Topics: Animals; Humans; Amsacrine; Callithrix; Cicatrix; Conjunctiva; Disease Models, Animal; DNA Topoisomerases, Type II; Filtering Surgery; Glaucoma; Glaucoma Drainage Implants; Intraocular Pressure; Primary Cell Culture; Topoisomerase II Inhibitors; Trabeculectomy
PubMed: 31848363
DOI: 10.1038/s41598-019-55365-7