Octadecyloxyethyl Adefovir Exhibits Potent in vitro and in vivo Cytotoxic Activity and Has Synergistic Effects with Ara-C in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) continues to be a deadly disease, with only 50 –70% of patients achieving complete remission and less than 30% of adults having sustained long-term remissions. In order to address these unmet medical needs, we carried out a high-throughput screen of an in-house library of on- and off-patent drugs with the OCI/AML-2 cell line. Through this scre en, we discovered adefovir dipi­voxil (adefovir-DP) as being active against human AML. In addition to adefovir-DP, there are second-generation formulations of adefovir, including octadecyloxyethyl adefovir (ODE-adefovir) and hexadecyloxypropyl adefovir (HDP-adefovir), which were designed to overcom e the pharmacokinetic problems of the parent compound adefovir. Given the known clinical benefit of nucleoside analogs for the treatment of AML, we undertook studies to evaluate the potential benefit of adefovir-based molecules. In AML cell lines and patient samples, adefovir-DP and ODE-adefovir wer e highly potent, whereas HDP-adefovir was significantly less active. Interestingly, ODE-adefovir was remarkably less toxic than adefovir-DP towards normal hematopoietic cells. In addition, ODE-adefovir at a dose of 15 mg/kg/day showed potent activity against human AML in a NOD/SCID mouse model, with a reduction of human leukemia in mouse bone marrow of #x3e; 40% in all mice tested within 20 days of treatment. Based on its chemical structure, we hypothesized that the cytotoxicity of ODE-adefovir toward AML was...
Source: Chemotherapy - Category: Cancer & Oncology Source Type: research

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or Clinical Trials in Oncology Abstract Leukemia stem cells are more resistant to standard chemotherapy and their persistence during remission can cause relapse which is still one of the major clinical challenges in the treatment of acute myeloid leukemia. A better understanding of the mutational patterns and the prognostic impact of molecular markers associated with stemness could lead to better clinical management and improve patients' outcomes. We generated a previously described 17-gene expression score comprising genes differently expressed between leukemia stem cells and leukemic bulk blasts, for 934 adult p...
Source: Haematologica - Category: Hematology Authors: Tags: Haematologica Source Type: research
Publication date: Available online 7 August 2019Source: The Lancet HaematologyAuthor(s): Farhad Ravandi, Rita Assi, Naval Daver, Christopher B Benton, Tapan Kadia, Philip A Thompson, Gautam Borthakur, Yesid Alvarado, Elias J Jabbour, Marina Konopleva, Koichi Takahashi, Steven Kornblau, Courtney D DiNardo, Zeev Estrov, Wilmer Flores, Sreyashi Basu, James Allison, Padmanee Sharma, Sherry Pierce, Allison PikeSummaryBackgroundOutcomes for younger patients with acute myeloid leukaemia have moderately improved over the past two decades owing to better supportive care and recent introduction of novel targeted agents. Blocking PD-...
Source: The Lancet Haematology - Category: Hematology Source Type: research
Publication date: Available online 6 August 2019Source: Cancer GeneticsAuthor(s): Prasad Koduru, Weina Chen, Barbara Haley, Kevin Ho, Dwight Oliver, Kathleen WilsonAbstractBreast cancer patients treated with adjuvant chemotherapy regimens containing alkylating agents and anthracyclines are at an increased risk for secondary myeloid malignancies, either acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Complex genomic changes (karyotypes and/or gene amplification) accompany the development of the secondary neoplasms. Here we present a unique case of a breast cancer patient who developed secondary AML within 18...
Source: Cancer Genetics - Category: Cancer & Oncology Source Type: research
va Notarbartolo Drug resistance is a major obstacle in antibiotic and antitumor chemotherapy. In response to the necessity to find new therapeutic strategies, plant secondary metabolites including essential oils (EOs) may represent one of the best sources. EOs in plants act as constitutive defenses against biotic and abiotic stress, and they play an important role in the pharmacology for their low toxicity, good pharmacokinetic and multitarget activity. In this context, natural products such as EOs are one of the most important sources of drugs used in pharmaceutical therapeutics. The aim of this paper was to identi...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research
AbstractPatients with hematological malignancies are severely immunocompromised and are at high risk of invasive fungal infection (IFI), particularly those undergoing remission-induction chemotherapy for acute myeloid leukemia (AML). IFIs are a major cause of morbidity and mortality in such patients. We planned to study the incidence of IFI in patients with AML undergoing intensive chemotherapy and receiving antifungal prophylaxis. We retrospectively reviewed consecutive 46 patients with non-M3 AML, who received induction chemotherapy and systemic antifungal prophylaxis. None of the patients had IFI at the time of initiati...
Source: Indian Journal of Hematology and Blood Transfusion - Category: Hematology Source Type: research
Rationale: Atopic dermatitis (AD) is a chronic recurrent dermatitis with profound itching, which could be the first manifestation of acute myeloid leukemia (AML). Patient concerns: A 53-year-old Chinese man suffered a 6-month history of systemic symmetrical dermatitis, accompanied with profound itching. The patient was diagnosed as “eczema” in several hospitals, and the effects of antihistamine and topical steroid creams were poor. Nocturnal sleep was seriously affected by aggravating pruritus. Laboratorial examination was compatible with AML-M4. Diagnoses: AML-M4 with AD as first manifestation. Interv...
Source: Medicine - Category: Internal Medicine Tags: Research Article: Clinical Case Report Source Type: research
In this study, we investigated the effect of EDO-S101 in combination with cytarabine in treating AML cells. The synergic activity against AML was identified by remarkable reduction of cell viability, significant apoptosis enhancement and the upregulation of the cleaved PARP, Casepase-3 and -7 proteins compared with monotherapy. To explain the drivers, we detected the DNA damage pathway including DNA double-strand breaks marker γ-H2AX and DNA damage checkpoint proteins, which was supposed to be responsible for the enhanced apoptosis activity. In summary, our data demonstrated that EDO-S101 in combination with cytarabi...
Source: Medical Oncology - Category: Cancer & Oncology Source Type: research
Conclusion: The results indicate that oral candidiasis is a prevalent fungal infection in the patients with hematologic malignancies with C. albicans being the main etiological agent. However, other species of Candida cause similar infections in these patients. PMID: 31341565 [PubMed]
Source: Iranian Journal of Microbiology - Category: Microbiology Tags: Iran J Microbiol Source Type: research
Authors: Khodashahi R, Hakemi-Vala M, Mardani M, Abolghasemi S, Lotfali E, Arab-Mazar Z, Omidi N, Ghasemshahi S Abstract Background and Objectives: The aim of this study was to determine the drug susceptibility pattern of the pathogens causing bacteraemia and fungemia in patients who have developed febrile neutropenia after chemotherapy. Materials and Methods: A total of 95 patients with suspected or proven malignancy (50 patients) were admitted to the adult haematology ward at Taleghani Hospital in Tehran. Blood samples were inoculated into the bottles of Bact/Alert blood culture system and sent to Payvand's c...
Source: Iranian Journal of Microbiology - Category: Microbiology Tags: Iran J Microbiol Source Type: research
Systemic mastocytosis (SM) is a disorder characterized by abnormal proliferation of mast cells with KIT mutations, especially in codon 816. The prognosis of patients developing acute myeloid leukemia (AML) from SM is extremely poor, and hematopoietic cell transplantation is recommended. Herein, we describe a case of an 8-year-old female diagnosed with SM developing AML. A KIT M541L variant in SM was identified in leukemic cells, normal hematopoietic cells, and buccal mucosal cells, suggesting a germline polymorphism. The patient has remained in complete remission for 39 months after completion of chemotherapy. SM developin...
Source: Journal of Pediatric Hematology Oncology - Category: Hematology Tags: Online Articles: Clinical and Laboratory Observations Source Type: research
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