homoharringtonine and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

Chronic myeloid leukemia (CML) is a malignant disease of the hematopoietic system with crucial pathogenic protein named BCR-ABL, which endangers the life of patients severely. As a milestone of targeted drug, Imatinib has achieved great success in the treatment of CML. Nevertheless, inevitable drug resistance of Imatinib has occurred frequently in clinical due to the several mutations in the BCR-ABL kinase. Subsequently, the second-generation of tyrosine kinase inhibitors (TKIs) against BCR-ABL was developed to address the mutants of Imatinib resistance, except T315I. To date, the third-generation of TKIs targeting T315I has been developed for improving the selectivity and safety. Notably, the first allosteric inhibitor has been in market which could overcome the mutations in ATP binding site effectively. Meanwhile, some advanced technology, such as proteolysis-targeting chimeras (PROTAC) based on different E3 ligand, are highly expected to overcome the drug resistance by selectively degrading the targeted proteins. In this review, we summarized the current research progress of inhibitors and degraders targeting BCR-ABL for the treatment of CML.

Topics: Antineoplastic Agents; Benzamides; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Piperazines; Protein Kinase Inhibitors; Pyrimidines

Chronic myeloid leukemia (CML) is driven by the BCR-ABL1 fusion protein, formed by a translocation between chromosomes 9 and 22 that creates the Philadelphia chromosome. The BCR-ABL1 fusion protein is an optimal target for tyrosine kinase inhibitors (TKIs) that aim for the adenosine triphosphate (ATP) binding site of ABL1. While these drugs have greatly improved the prognosis for CML, many patients ultimately fail treatment, some requiring multiple lines of TKI therapy. Mutations can occur in the ATP binding site of ABL1, causing resistance by preventing the binding of many of these drugs and leaving patients with limited treatment options. The approved TKIs are also associated with adverse effects that may lead to treatment discontinuation in some patients. Efficacy decreases with each progressive line of therapy; data suggest little clinical benefit of treatment with a third-line (3L), second-generation tyrosine kinase inhibitor (2GTKI) after failure of a first-generation TKI and a 2GTKI. Novel treatment options are needed for the patient population that requires treatment in the 3L setting and beyond. This review highlights the need for clear guidelines and new therapies for patients requiring 3L treatment and beyond.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Clinical Trials as Topic; Fusion Proteins, bcr-abl; Homoharringtonine; Humans; Imidazoles; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Molecular Targeted Therapy; Niacinamide; Nitriles; Protein Kinase Inhibitors; Pyrazoles; Pyridazines; Quinolines

The tyrosine kinase inhibitors (TKIs) have revolutionized the management of chronic myeloid leukemia (CML) and BCR-ABL1 inhibitors form the mainstay of CML treatment. Although patients with CML generally do well under TKI therapy, there is a subgroup of patients who are resistant and/or intolerant to TKIs. In these group of patients, there is the need of additional treatment strategies. In this review, we provide an update on the current knowledge of these novel treatment approaches that can be used alone and/or in combination with TKIs.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Drug Resistance, Neoplasm; Everolimus; Fusion Proteins, bcr-abl; Gene Expression; Histone Deacetylase Inhibitors; Homoharringtonine; Humans; Immunotherapy; Interferon-alpha; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Molecular Targeted Therapy; Niacinamide; Piperidines; Polyethylene Glycols; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Quinolones; Recombinant Proteins

Homoharringtonine(HHT) is an alkaloid with anti-tumor activity, having a good therapeutic effect on chronic myeloid leukemia(CML), and its toxicity is much lower than other anti-cancer drugs. However, the remarkable therapeutic efficacy of imatinib on CML treatment made HHT to be forgotten gradually. Today, the omacetaxine mepesuccinate, a semisynthetic form of HHT, display a good clinical response to TKI-resistant CML patients. Therefore, the HHT again attracts more attention from the medical field. Here, the clinical effects of HHT on IM-resistant CML patients and its mechanism are briefly reviewed.

Topics: Antineoplastic Agents, Phytogenic; Harringtonines; Homoharringtonine; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive

The advent of targeted oncolytic agents has created a revolution in the treatment of malignancies. Perhaps best exemplified in myeloproliferative neoplasms (MPN), the tyrosine kinase inhibitors, including inhibitors of BCR-ABL tyrosine kinase and JAK2, have dramatically changed outcomes in persons with MPN. However, clinically relevant dosing of these adenosine triphosphate-mimetic agents in humans leads to inhibition of numerous tyrosine kinases beyond those touted by drug manufacturers and studied in landmark clinical trials. These so-called off-target effects have been linked to both clinical efficacy and toxicity. Rational drug development and serendipitous discovery of drug molecules allows the clinician to select targeted oncolytic agents to treat a specific clinical diagnosis and/or avoid exacerbation of concomitant disease states due to effects upon signaling pathways. Understanding the off-target binding and effects upon signaling pathway of the agents approved for the treatment of MPN will empower the clinician to adroitly select pharmacotherapy, predict toxicities, and utilize these agents in clinical practice for indications beyond MPN.

Topics: Aniline Compounds; Antineoplastic Agents; Carbazoles; Dasatinib; Drug-Related Side Effects and Adverse Reactions; Eosinophilia; Furans; Fusion Proteins, bcr-abl; Gastrointestinal Stromal Tumors; Graft vs Host Disease; Harringtonines; Homoharringtonine; Humans; Hypertension, Pulmonary; Imatinib Mesylate; Imidazoles; Janus Kinase 2; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mastocytosis; Myeloproliferative Disorders; Nitriles; Polycythemia Vera; Primary Myelofibrosis; Protein Kinase Inhibitors; Pulmonary Fibrosis; Pyrazoles; Pyridazines; Pyrimidines; Quinolines; Scleroderma, Systemic; Smallpox; Thrombocythemia, Essential; Tuberculosis, Multidrug-Resistant

Omacetaxine mepesuccinate is approved by the Food and Drug Administration in the United States for the treatment of chronic myeloid leukemia in chronic or accelerated phase resistant to two or more tyrosine kinase inhibitors. This review summarizes the mode of action, pharmacokinetics, efficacy and safety of omacetaxine mepesuccinate. Omacetaxine mepesuccinate has activity in chronic myeloid leukemia, especially in the chronic phase, regardless of the presence of ABL1 kinase domain mutations. Omacetaxine mepesuccinate has distinct but manageable adverse events profile. Omacetaxine mepesuccinate is a treatment option for a subset of patients with refractory chronic myeloid leukemia.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Phytogenic; Blast Crisis; Codon; Fusion Proteins, bcr-abl; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Accelerated Phase; Leukemia, Myeloid, Chronic-Phase; Mutation; Treatment Outcome

Omacetaxine mepesuccinate is a drug approved in 2014 by FDA for the use in CML therapy in patients resistant to at least two thymidine kinase inhibitors (TKIs). It possesses unique mechanism of anticancer activity that is principally different from mechanism of activity of TKIs. Omacetaxine mepesuccinate inhibits protein translation through prevention of the initial elongation step of protein synthesis and its use benefits CML patients possessing the BCR-ABL oncogene. Because of the superior activity of Omacetaxine in patients who became resistant to therapy with TKIs, FDA decided on the accelerated approval of this drug taking its consideration not only its activity as such but also a favorable benefit-to-risk profile in patients included into clinical studies.

Topics: Antineoplastic Agents, Phytogenic; Drug Resistance, Neoplasm; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Kinase Inhibitors; Protein Synthesis Inhibitors

Therapy of chronic myeloid leukemia (CML) has been completely transformed by the development of tyrosine kinase inhibitors (TKIs). However, a subset of patients will fail TKI therapy due to resistance or intolerance. Omacetaxine mepesuccinate (OM), a protein translation inhibitor, is currently the only approved therapy that does not directly target the kinase domain. It has activity for CML patients irrespective of the phase or underlying kinase domain mutation status.. We searched the MEDLINE database for articles published in English on homoharringtonine or omacetaxine from 1970 to present. This article reviews the pharmacokinetics of OM and its clinical evolution for the treatment of CML pre- and post TKI development. Toxicity profile, drug administration and future directions are also discussed.. OM represents a unique addition to the CML therapeutic armamentarium with its distinct mechanism of action and activity. The adverse event profile is manageable and with subcutaneous administration at the approved dose, cardiac toxicity is no longer a concern. The recent approval of home administration will facilitate access to this therapy and increase patient compliance. We conclude with specific scenarios where OM use should be considered in CP and AP-CML patients in the era of TKI therapy.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Drug Resistance, Neoplasm; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Kinase Inhibitors

Homoharringtonine (HHT), a plant alkaloid with antitumor properties originally identified nearly 40 years ago, has a unique mechanism of action by preventing the initial elongation step of protein synthesis. HHT has been used widely in China for the treatment of chronic myeloid leukemia (CML), acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Omacetaxine, a semisynthetic form of HHT, with excellent bioavailability by the subcutaneous route, has recently been approved by FDA of the United States for the treatment of CML refractory to tyrosine kinase inhibitors. This review summarized preclinical and clinical development of HHT and omacetaxine for myeloid hematological malignancies.

Topics: Acute Disease; Antineoplastic Agents, Phytogenic; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Myelodysplastic Syndromes; Treatment Outcome

The pharmacology, pharmacokinetics, clinical efficacy, and safety of a first-in-class protein synthesis inhibitor for use in treatment-resistant chronic myeloid leukemia (CML) are reviewed.. Omacetaxine mepesuccinate (Synribo, Teva Pharmaceuticals) is a potent plant alkaloid isolated from Cephalotaxus (Chinese yew tree) species. It has a mechanism of action distinct from that of the standard first-line therapy for CML, tyrosine kinase inhibitors (TKIs), and has demonstrated efficacy in adult patients with chronic- or accelerated-phase CML who develop intolerance to two or more TKIs or experience multiple TKI treatment failures. Two open-label Phase II trials (combined n = 108) demonstrated that omacetaxine produced a major cytogenetic response in 18.4% of patients with chronic-phase CML and a major hematologic response in 14.3% of patients with accelerated-phase CML (median duration of reponse, 12.5 and 4.7 months, respectively). Symptom improvement or improved overall survival in omacetaxine-treated patients has not been demonstrated. In clinical trials to date, the most common grade 1-4 adverse reactions included thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, and asthenia. The drug is administered subcutaneously on an intermittent schedule (14 days on, 14 days off during induction; 7 days on, 21 days off during maintenance). Research to better delineate omacetaxine's optimal role in the management of CML and other hematologic malignancies (e.g., acute myelogenic leukemia) is ongoing.. Omacetaxine, a novel protein synthesis inhibitor, provides an alternative therapy for patients with CML who have experienced TKI treatment failures or are intolerant of two or more TKIs.

Topics: Adult; Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Cephalotaxus; Clinical Trials as Topic; Drug Resistance, Neoplasm; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Survival Rate; Treatment Outcome

The treatment of chronic myelogenous leukemia (CML) has been revolutionized by the introduction of tyrosine kinase inhibitors (TKI), however, with the exception of ponatinib, none of the existing licensed agents seem to eradicate the reservoir of Philadelphia positive stem cells, thus sustaining the disease over time, and retaining activity in cells and patients harboring an ABL T315I mutation. Omacetaxine mepesuccinate (OMA), formerly known as homoharringtonine, is a cephalotaxus alkaloid derivative and an inhibitor of protein synthesis without tyrosine kinase activity developed 35 years ago by Chinese investigators in the treatment of leukemia. This compound demonstrates specific activity in CML and has been recently commercialized in the U.S. for the treatment of patients in chronic or accelerated phase CML with resistance and/or intolerance to two or more tyrosine kinase inhibitors or harboring a T315I ABL mutation. CML patients with a T315I mutation experienced poor overall survival rates in the pre-ponatinib era (median for CP CML 24 months). Recent studies demonstrate the activity of OMA even in such a poor prognosis population. We hereby detail the development of OMA as an effective agent in CML in these patients.

Topics: Animals; Antineoplastic Agents, Phytogenic; Drug Resistance, Neoplasm; Harringtonines; Homoharringtonine; Humans; Infusions, Subcutaneous; Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Homoharringtonine (HHT) and other alkaloid esters were originally isolated from the Cephalotaxus evergreen tree and have been used in traditional Chinese medicine since the 1970s to treat a variety of malignancies. Although HHT was investigated for the treatment of chronic myeloid leukemia (CML) in the 1990s with good results, the advent of BCR-ABL1 tyrosine kinase inhibitors (TKIs) at that time rapidly established a new standard of care for CML. Omacetaxine mepesuccinate is a semisynthetic derivative of HHT with known clinical activity in relapsed or refractory CML following TKI therapy.. In this review, we summarize the biologic effects of HHT and its derivative, omacetaxine, in CML. Additionally, we analyze the concepts learned from the early trials using these drugs. Data from clinical trials resulting in drug approval are also reviewed.. Omacetaxine has a clear role in the CML armamentarium for patients in chronic and accelerated phase who have failed or were intolerant to two or more TKIs.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Neoplastic Stem Cells

Omacetaxine mepesuccinate (formerly known as homoharringtonine [HHT]) is a natural alkaloid with significant anticancer activity partly through inhibition of protein synthesis and induction of apoptosis. Prior to the development of tyrosine kinase inhibitors (TKIs), HHT was the most active therapy in chronic myeloid leukemia (CML) after interferon failure. Subsequent trials showed that HHT and omacetaxine are active in patients failing several TKIs or carrying the T315I mutation.. This review will discuss the preclinical development of HHT and omacetaxine mepesuccinate in CML and the clinical studies leading to its approval by the Food and Drug Administration (FDA).. A sizable number of patients with CML will develop TKI resistance, frequently through the acquisition of BCR-ABL1 kinase domain mutations. Omacetaxine is active in patients with CML after failure to multiple TKIs and in those carrying the T315I mutation, which is highly resistant to all FDA-approved TKIs except for ponatinib. Both ponatinib and omacetaxine have been recently approved by the FDA and represent useful treatment options for patients with CML who failed several TKIs and/or acquired the T315I mutation. The development of an oral formulation of omacetaxine would greatly facilitate its use and provide an attractive option for TKI-based combinatorial strategies.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Omacetaxine mepesuccinate is a protein synthesis inhibitor that causes apoptosis of chronic myeloid leukemia cells without binding to the BCR-ABL tyrosine kinase that is implicated in the pathogenesis of this disease. It has been approved for the treatment of chronic myeloid leukemia in patients with resistance to two or more tyrosine kinase inhibitors and is emerging as an important agent in countering the highly resistant T315I mutation. This review will focus on the preclinical pharmacology, pharmacokinetics and clinical utility of omacetaxine mepesuccinate in the current milieu of tyrosine kinase inhibitor-dominant therapy of chronic myeloid leukemia.

Topics: Clinical Trials as Topic; Drug Interactions; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Omacetaxine mepesuccinate was originally identified more than 35 years ago and initial studies in chronic myeloid leukemia (CML) showed promising activity. It has also been studied in other hematologic and solid tumors as both a single agent and in combination with other treatments. However, the introduction of imatinib and related tyrosine kinase inhibitors (TKIs) abated the clinical development of omacetaxine as a treatment for CML. The advent of resistance to imatinib and other TKIs in CML patients (often due to the presence of an ABL mutation at position 315) has led to a revived clinical interest in omacetaxine in CML patients who failed TKIs. Here we review omacetaxine's mechanism of action (MOA) as a protein translation inhibitor, how its MOA may translate into activity in treatment of cancers, its potential to eradicate leukemia initiating cells and other cancer stem cells and the potential significance of this activity in clinical practice.

Topics: Antineoplastic Agents, Phytogenic; Gene Expression Regulation, Leukemic; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Models, Genetic; Neoplastic Stem Cells; Protein Synthesis Inhibitors

Chronic myeloid leukemia (CML) is induced by the BCR-ABL oncogene, a product of Philadelphia (Ph) chromosome. The BCR-ABL kinase inhibitor imatinib is a standard treatment for Ph+ leukemia, and has been shown to induce a complete hematologic and cytogenetic response in most chronic phrase CML patients. However, imatinib does not cure CML, and one of the reasons is that imatinib does not kill leukemia stem cells (LSCs) in CML both in vitro and in vivo. Recently, several new targets or drugs have been reported to inhibit LSCs in cultured human CD34+ CML cells or in mouse model of BCR-ABL induced CML, including an Alox5 pathway inhibitor, Hsp90 inhibitors, omacetaxine, hedgehog inhibitor and BMS-214662. Specific targeting of LSCs but not normal stem cell is a correct strategy for developing new anti-cancer therapies in the future.

Topics: Animals; Antineoplastic Agents; Arachidonate 15-Lipoxygenase; Benzodiazepines; Harringtonines; Hedgehog Proteins; Homoharringtonine; HSP90 Heat-Shock Proteins; Humans; Imidazoles; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lipoxygenase Inhibitors; Medical Oncology; Mice; Models, Biological; Neoplastic Stem Cells; Signal Transduction

Homoharringtonine (HHT) is a natural alkaloid that is obtained from various Cephalotaxus species. The mechanism of action by which HHT exerts its antitumor activity is through inhibition of protein synthesis and promotion of apoptosis. In the 1990s, HHT proved to be significantly active as salvage therapy for patients with chronic myeloid leukemia (CML) after failure on interferon-alpha therapy. However, the remarkable success of imatinib mesylate in the treatment of CML relegated HHT to oblivion. The development of omacetaxine mepesuccinate, a subcutaneously bioavailable semisynthetic form of HHT, and its activity in imatinib-resistant CML has established this agent for the second time as a valuable option in the management of this disease. Preliminary results appear to support the use of this agent for patients who have imatinib-resistant CML, including those who carry the tyrosine kinase inhibitor-insensitive mutation that exchanges the amino acids threonine and isoleucine at position 315 (the T315I mutation). In this article, the authors discuss the current data on omacetaxine and the prospects of this agent to be integrated into the state-of-the-art treatment algorithms for CML.

Topics: Algorithms; Antineoplastic Agents, Phytogenic; Benzamides; Clinical Trials as Topic; Drug Discovery; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Harringtonines; Homoharringtonine; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Piperazines; Pyrimidines

The emergence of resistance to imatinib has become a significant problem despite the remarkable clinical results achieved with this tyrosine kinase inhibitor in the treatment of chronic myeloid leukaemia. The most common cause of imatinib resistance is the selection of leukemic clones with point mutations in the Abl kinase domain. These mutations lead to amino acid substitutions and prevent the appropriate binding of imatinib. Genomic amplification of BCR-ABL, modulation of drug efflux or influx transporters, and Bcr-Abl-independent mechanisms also play important roles in the development of resistance. Persistent disease is another therapeutic challenge and may in part, be due to the inability of imatinib to eradicate primitive stem cell progenitors. A multitude of novel agents have been developed and have shown in vitro and in vivo efficacy in overcoming imatinib resistance. In this review, we will discuss the current status of the ATP-competitive and non-ATP-competitive Bcr-Abl tyrosine kinase inhibitors. We will also describe inhibitors acting on targets found in signaling pathways downstream of Bcr-Abl, such as the Ras-Raf-mitogen-activated protein kinase and phosphatidylinositol-3 kinase-Akt-mammalian target of rapamycin pathways, and targets without established links with Bcr-Abl.

Topics: Aniline Compounds; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Benzamides; Clinical Trials as Topic; Dasatinib; Drug Resistance, Neoplasm; Enzyme Inhibitors; Fusion Proteins, bcr-abl; Gene Amplification; Harringtonines; Histone Deacetylase Inhibitors; Homoharringtonine; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Nitriles; Oxides; Piperazines; Protein-Tyrosine Kinases; Pyrimidines; Quinolines; Thiazoles

The anticancer activity of the natural alkaloid homoharringtonine (HHT) was first recognized by Chinese investigators. HHT exerts its activity through inhibition of protein synthesis and promotion of apoptosis.. The authors reviewed the most relevant preclinical and clinical studies involving patients with chronic myelogenous leukemia (CML) receiving therapy with either natural HHT or omacetaxine mepesuccinate (Ceflatonin, Myelostat, CGX-653), a semisynthetic subcutaneously bioavailable form of HHT presently under development for the treatment of CML.. Prior to the advent of the tyrosine kinase inhibitor (TKI) imatinib mesilate, controlled clinical studies established HHT as the most active therapy in CML after failure of IFN-a for patients who were not candidates for allogeneic stem cell transplantation. Preliminary results from Phase II studies suggest that omacetaxine mepesuccinate is active in patients with imatinib-resistant CML, including those carrying the T315I mutation, which renders imatinib and second-generation TKIs ineffective.. These encouraging results have propelled the development of several Phase II/III trials both in Europe and in the US to further delineate the activity of omacetaxine mepesuccinate in patients with CML who are resistant to TKI therapy.

Topics: Animals; Antineoplastic Agents, Phytogenic; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drugs, Chinese Herbal; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Targeted therapy with the Abl kinase inhibitor imatinib has markedly improved the outlook for patients with chronic myeloid leukemia (CML). Breakpoint cluster region (Bcr)-Abl signaling is reactivated at the time of resistance, predominantly due to mutations in the kinase domain of Bcr-Abl that interfere with drug binding. This discovery prompted the development of new Abl kinase inhibitors, among which nilotinib and dasatinib have gained regulatory approval. Despite excellent results in patients with imatinib-resistant or imatinib-intolerant CML treated with nilotinib or dasatinib, early indications suggest that: the cross-resistant Bcr-Abl(T315I) mutant is disproportionately represented among patients who relapse on these therapies; each Abl inhibitor exhibits vulnerabilities to certain kinase domain mutations. We review new inhibitors of Bcr-Abl, including preliminary information on inhibitors of Bcr-Abl(T315I) and discuss the potential of combined Abl kinase inhibitor therapy to preempt resistance. Improved Abl inhibitor therapies will be useful in achieving maximum disease control but a clinical T315I inhibitor remains a high priority.

Topics: Administration, Oral; Antineoplastic Agents; Benzamides; Biological Availability; Clinical Trials as Topic; Drug Design; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Fusion Proteins, bcr-abl; Genes, abl; Harringtonines; Homoharringtonine; HSP90 Heat-Shock Proteins; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mutation, Missense; Neoplasm Proteins; Piperazines; Point Mutation; Protein Conformation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-abl; Pyrimidines; Tumor Cells, Cultured

Most patients with chronic myeloid leukemia (CML) achieve clinically relevant hematologic and cytogenetic responses to imatinib. Patients who show resistance to imatinib need new therapeutic options. A range of options are being developed to treat imatinib-resistant patients who have CML. Promising results of early-phase clinical trials have been reported for new tyrosine kinase inhibitors, farnesyl transferase inhibitors, decitabine, homoharringtonine, and vaccines. Further clinical trials are needed to characterize the efficacy and safety profile of these new agents and to determine which agents improve the long-term prognosis for patients with CML who have shown resistance to imatinib.

Topics: Angiogenesis Inhibitors; Azacitidine; Benzamides; Cancer Vaccines; Clinical Trials as Topic; Decitabine; Drug Resistance, Neoplasm; Farnesyl-Diphosphate Farnesyltransferase; Female; Harringtonines; Homoharringtonine; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Piperazines; Prognosis; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Time Factors

Imatinib is the cornerstone of therapy in chronic myelogenous leukemia (CML) and a model for the development of novel agents directed at specific targets. The results of imatinib therapy continue to improve with approaches such as higher doses of imatinib and, possibly, with combinations of imatinib and interferon-alpha with or without cytarabine. There are multiple targets with agents directed to them that may prove to be synergistic with imatinib. These approaches are attractive, particularly when dealing with imatinib resistant CML, to prevent resistance and improve the probability of cure. The continued understanding of the biology of CML and mechanisms of resistance to imatinib and the ability to develop target-specific therapies should lead to the increased probability of cure for most patients who have CML.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Benzamides; Cancer Vaccines; DNA Methylation; Enzyme Inhibitors; Harringtonines; Homoharringtonine; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Oxides; Piperazines; Pyrimidines; Research; Treatment Outcome

HHT, one of the alkaloids from a Chinese natural plant, Cephalotaxus, has shown its potential in leukemia treatment. This compound demonstrated strong growth-inhibiting activities in vitro and in animal experiments, and obtained encouraging results in some clonal proliferative disease such as in chronic myeloid leukemia (CML) and in polycythemia vera. Evidences also confirmed HHT as an apoptosis inducer in tumor cell lines and fresh cells from cancer patients. The CR rate reported with HHT-based regimen in acute nonlymphocytic leukemia showed no statistic differences from that with DNR-based regimen, although the case number was limited. While used in clinical trial, the drug often cause noticeably cardiovascular disturbances if be given rapidly by intravenous infusion. Myelosuppression is the common complication in HHT-based chemotherapy. Although with the anti-growth activity in vitro and praisable achievement in acute and chronic myeloid leukemia treatment, the drug shows no beneficial effect in lymphocytic leukemia and solid tumors. The underlying mechanism for the discrepancy of efficacy keeps unknown. This review will present with the preclinical research data including the action mechanism, pharmacokinetics and drug resistance of HHT as well as the result from the clinical trial with HHT in China and the United States.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cardiovascular Diseases; Cell Proliferation; Cephalotaxus; Clinical Trials as Topic; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Polycythemia

Multiple new agents are currently being developed in chronic myelogenous leukemia (CML). Most of these agents are now being investigated in patients who have developed resistance to imatinib. Their mechanisms of action are diverse and many may be synergistic with imatinib. These agents will be used soon in different combinations, most likely including imatinib, with the hope of obtaining a complete blockade of the intracellular pathways that are triggered by Bcr-Abl. If this is successful, complete eradication of disease may become a reality for the majority of patients with CML.

Topics: Angiogenesis Inhibitors; Arsenic Trioxide; Arsenicals; Cytosine; Dioxolanes; Farnesyltranstransferase; Harringtonines; Histone Deacetylase Inhibitors; Homoharringtonine; Humans; Interferon-alpha; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Oxides; Vaccination

Topics: Antineoplastic Agents; Bone Marrow Transplantation; Cytarabine; Harringtonines; Hematopoietic Stem Cell Transplantation; Homoharringtonine; Humans; Immunologic Factors; Interferon-alpha; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Prognosis; Randomized Controlled Trials as Topic; Remission Induction; Risk Factors; Salvage Therapy; Treatment Outcome

Chronic myelogenous leukemia (CML) is a chronic myeloproliferative disorder with an initially chronic course lasting for 3-5 years. It eventually transforms into accelerated and blastic phases, which are generally fatal. CML was one of the first diseases in which a specific chromosomal abnormality was identified, a t(9;22)(q34;q11) or Philadelphia chromosome. CML had been traditionally treated with conventional chemotherapy with hydroxyurea or busulfan. Although these agents can achieve hematologic remissions in most patients, no evidence of sustained disappearance of the chromosomal abnormality was evident. Interferon alpha (IFN-alpha) has been able to achieve hematologic and cytogenic remissions in a significant number of patients, and recent studies show a survival advantage for patients treated with IFN-alpha compared with those treated with conventional chemotherapy. The results of these studies are discussed, and the reasons for discordance among different investigators analyzed in this review. Allogeneic bone marrow transplantation (BMT) may be curative in some patients with CML. The benefits and limitations of this approach in the treatment of CML are also discussed and the results of different alternatives compared. Other alternatives of therapy, including newer chemotherapeutic agents, combinations of IFN-alpha with other agents, and autologous BMT, are presented. The availability of very sensitive techniques for detection of the Philadelphia chromosome at the molecular level has allowed the detection of minimal residual disease. The information available on these measurements is also analyzed. Finally, we discuss the alternatives for patients with accelerated and blastic phase CML, as well as the clinical characteristics and prognosis for patients with Philadelphia-chromosome-negative CML.

Topics: Adult; Antimetabolites, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Busulfan; Cytarabine; Drug Therapy, Combination; Harringtonines; Homoharringtonine; Humans; Hydroxyurea; Immunosuppressive Agents; Interferon-alpha; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Middle Aged; Prognosis; Time Factors

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Female; Harringtonines; Homoharringtonine; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Accelerated Phase; Leukemia, Myeloid, Chronic-Phase; Male; Middle Aged; Neoplasm Staging; Retreatment; Treatment Outcome; Young Adult

Omacetaxine mepesuccinate promotes apoptosis by inhibiting the production of short-lived oncoproteins. The efficacy and safety of omacetaxine in patients with advanced chronic myeloid leukemia (CML) previously treated with tyrosine kinase inhibitors were assessed in two phase II trials (CML-202 and CML-203). Fifty-one patients in accelerated phase (AP-CML) and 44 in myeloid blast phase (BP-CML) received subcutaneous omacetaxine 1.25 mg/m(2) twice daily days 1-14 every 28 days until hematologic response/improvement or any cytogenetic response, then days 1-7 every 28 days until disease progression. The primary endpoint was maintenance or attainment of a major hematologic response (MHR). Cytogenetic responses were also evaluated. MHR was 37% in patients with AP-CML and 9% with BP-CML (22% and 5% in those with a history of T315I). Most grade 3/4 adverse events were related to myelosuppression, and were generally manageable. Omacetaxine demonstrates activity and an acceptable safety profile in pretreated patients with advanced CML, irrespective of mutational status.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Disease Progression; Drug Resistance, Neoplasm; Female; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Neoplasm Staging; Protein Kinase Inhibitors; Survival Analysis; Treatment Outcome; Young Adult

This study investigated the effect of homoharringtonine (HHT) on bone marrow CD34 + CD117 + cells in patients with chronic myelogenous leukemia (CML). Fifty-seven patients with CML who could not receive either imatinib or interferon-α were treated with HHT (n = 31) or hydroxycarbamide (HU) (n = 26) to induce and maintain remission, and bone marrow CD34 + CD117 + cells were assayed with flow cytometry. The proportion of CD34 + CD117 + cells was higher in untreated patients (24.7 ± 6.4%) than in donors (4.4 ± 1.1%) and decreased remarkably in patients who had hematological remission (11.2 ± 3.1%) and cytogenetic response (8.9 ± 3.1%) as compared with those without (27.8 ± 7.3% and 18.5 ± 5.3%, respectively) at 12 months after therapy. The hematological remission rate for patients with proportion of CD34 + CD117 + cells ≥ 20% prior to treatment was lower (41.7%) than in patients with CD34 + CD117 + cells < 20% (78.9%; p < 0.05). However, there was no such difference of CD34 + CD117 + cell percentage in the HU group. It can be concluded that high expression of CD117 on CD34 + cells is a marker of poor prognosis and is also a target for the anti-CML effect of HHT.

Topics: Adolescent; Adult; Antineoplastic Agents, Phytogenic; Bone Marrow Cells; CD4 Antigens; Cell Count; Female; Flow Cytometry; Harringtonines; Homoharringtonine; Humans; Hydroxyurea; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Prognosis; Proto-Oncogene Proteins c-kit; Remission Induction; Young Adult

We investigated the efficacy of the induction therapy involving granulocyte colony-stimulating factor (G-CSF) and low-dose homoharringtonine as well as standard-dose imatinib, which we called the G-CSF + homoharringtonine + imatinib (GHI) regimen, in patients with chronic myelogenous leukemia (CML) in blast crisis who have failed prior single-agent therapy with imatinib. Twelve patients were enrolled. The GHI regimen consisted in a unique induction course where imatinib was administered at 400 mg day(-1) until remission, together with homoharringtonine (1 mg/m(2) s.c. twice daily for 14 days every 28 days), and G-CSF, which was administered 1 day before chemotherapy (5 µg/kg s.c. daily). Patients who failed to obtain at least a partial hematologic response (PHR) after three courses were taken off study. Patients who responded to induction treatment and who had a matched donor received allogeneic hematopoietic stem cell transplantation (allo-HSCT). The results demonstrates that the GHI regimen re-induce hematologic responses or improve the cytogenetic responses in all evaluable patients. Furthermore, eligible patients have benefited from allo-HSCT after response to this induction treatment. We conclude that the GHI regimen may overcome disease-poor response to conventional doses of imatinib and this approach deserves further evaluation as frontline therapy for newly diagnosed CML.

Topics: Adolescent; Adult; Antineoplastic Agents; Benzamides; Blast Crisis; Drug Therapy, Combination; Female; Granulocyte Colony-Stimulating Factor; Harringtonines; Homoharringtonine; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Piperazines; Pyrimidines; Treatment Failure; Treatment Outcome; Young Adult

Both homoharringtonine (HHT), an alkaloid derivative from the Chinese yew tree that inhibits protein synthesis, and low-dose cytarabine have independent activity in CML and have been used in combination after failure of interferon therapy.. The CALGB performed a phase II trial of HHT (2.5 mg/m(2) per day) plus cytarabine (7.5 mg/m(2) per day), given together via continuous intravenous infusion for 7 days in previously untreated patients with Ph chromosome positive chronic phase CML. HHT/cytarabine cycles were repeated every 28 days if the blood counts were adequate. The primary endpoint was the major cytogenetic response rate after 9 months.. Forty of the 44 enrolled patients required reduction in the infusion duration during at least one cycle. Myelosuppression was common; 66% developed neutrophil count <500/microl, but grade 3 infections occurred in only 7%. Thirty-six of 44 patients (82%) achieved a complete hematologic remission; the median duration has not been reached. Only 4 of the 23 patients (17%) having adequate cytogenetic response assessment achieved a major response within nine cycles.. Although HHT/cytarabine was generally well tolerated, the cytogenetic response rate did not exceed the level previously seen in patients with interferon-refractory CML and was not nearly as high as associated with imatinib in newly diagnosed patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Female; Harringtonines; Homoharringtonine; Humans; Infusions, Intravenous; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Male; Middle Aged; Neoplasm Staging; Palliative Care; Prognosis; Prospective Studies; Risk Factors; Survival Rate; Time Factors; Treatment Outcome

Homoharringtonine (HHT) is effective in treating late stage chronic myelogenous leukaemia (CML), but little is known about long term maintenance during complete cytogenetic response. Long term efficacy and toxicity profiles of low dose HHT were evaluated in this study.. One hundred and six patients with CML received 1.5 mg/m(2) of HHT alone by continuous daily infusion for seven to nine days every four weeks. Of 79 patients in the control group, 31 were treated with interferon alpha (IFN-alpha) and 48 with hydroxycarbamide. For 17 patients who failed to achieve cytogenetic response within 12 months' treatment of IFN-alpha, HHT was administered. Quantitative RT-PCR was used to detect the BCR-ABL mRNA expression in 36 Philadelphia positive CML patients enrolled after 2007. Haematological and cytogenetic responses were evaluated in all patients at the 12th month of follow-up. Long term efficacy was assessed in a follow-up with a median time of 54 months (12 months-98 months).. After 12 months of therapy, cytogenetic response rate of the HHT, IFN-alpha and hydroxycarbamide groups were 39/106, 14/31 and 3/48, and corresponding molecular cytogenetic response rates 6/18, 3/8 and 0. Of the 17 patients who received HHT as salvage treatment, 6 achieved cytogenetic response (3 major). At the 48 months' follow-up, cytogenetic response was maintained in 32/39 patients treated with HHT. Patients who had cytogenetic response in HHT group or treated with IFN-alpha also showed longer median chronic durations, which were 45 months (12 months-98 months) and 49 months (12 months-92 months) respectively, indicating a longer survival time.. Low dose HHT alone showed considerable short term and long term efficacy in the treatment of late stage CML. It may also be a good choice for patients who have failed imatinib, IFN-alpha treatment or haematopoietic stem cell transplantation or cannot afford these treatments.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Phytogenic; Female; Fusion Proteins, bcr-abl; Harringtonines; Homoharringtonine; Humans; Interferon-alpha; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Treatment Outcome; Young Adult

Homoharringtonine (HHT) is a cephalotaxus alkaloid that inhibits the synthesis of proteins leading to apoptosis. Intravenous HHT has demonstrated activity in patients with chronic myeloid leukemia (CML) after failure with interferon.. A Phase I study was completed of subcutaneous (s.c.) HHT in patients with CML in accelerated or blast phases and demonstrated efficacy and good tolerance at the same doses used by intravenous (i.v.) administration. The maximal tolerated dose (MTD) was 1.25 mg/m(2) s.c. twice daily. The cohort was then expanded to treated at the MTD to include patients in late chronic phase CML after imatinib failure. Therapy consisted of an i.v. loading dose of HHT 2.5 mg/m(2) over 24 hours, followed by 1.25 mg/m(2) s.c. twice daily for 14 days every 28 days until remission, then for 7 days every 28 days. Six patients (median age, 53 years) who had failed imatinib were treated and 5 were evaluable. Patients received a median of 4.5 courses of s.c. HHT.. Complete hematologic remission was obtained in all 5 evaluable patients and 3 had cytogenetic (CG) responses: 1 complete and 2 minor. The 2 patients with BCR-ABL kinase domain mutations at the start of therapy with HHT had a CG response and in both instances the mutations became undetectable. All patients developed myelosuppression and 3 had their HHT dose reduced due to prolonged neutropenia. Nonhematologic toxicity was mild and manageable.. Subcutaneous HHT is well tolerated and may have clinical activity in patients with CML after imatinib failure.

Topics: Adult; Aged; Anemia; Antineoplastic Agents, Phytogenic; Benzamides; Blast Crisis; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue; Female; Harringtonines; Homoharringtonine; Humans; Imatinib Mesylate; Injections, Intravenous; Injections, Subcutaneous; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Nausea; Piperazines; Protein Kinase Inhibitors; Pyrimidines; Treatment Failure; Treatment Outcome

A Phase I/II study was designed to show whether the addition of semisynthetic homoharringtonine (sHHT) would reduce the level of residual disease in patients with Ph-positive chronic myeloid leukemia who appeared to have achieved a suboptimal response to imatinib alone.. Patients with CML who had achieved >/= 35% Ph-negativity on imatinib were included. All patients had been treated with imatinib at >/= 400 mg/day for at least 2 years and had achieved a plateau in BCR-ABL transcripts defined by measuring BCR-ABL transcripts on at least 4 occasions over a minimum period of 1 year with the latest value not lower than the previous minimum value. Initially sHHT was given subcutaneously at a dose of 1.25 mg/m(2) twice daily for 1 day. Courses were repeated every 28 days. The dosage of sHHT was escalated by adding one day of treatment every two days. Efficacy was assessed by serial monitoring of blood levels of BCR-ABL transcripts.. Of 10 evaluable patients, 7 had an appreciable decline in BCR-ABL transcript levels; in 5 cases the reduction was greater than 1 log. Asthenia (n = 10) and cytopenias (n = 3) were prominent side-effects, but the drug was generally well tolerated. Mutations in the P-loop of the BCR-ABL kinase domain were found in 2 of the patients who responded to the addition of sHHT.. The addition of sHHT should be considered for patients on imatinib who fail to obtain low levels of minimal residual disease.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Cytogenetic Analysis; Drug Resistance, Neoplasm; Female; Fusion Proteins, bcr-abl; Harringtonines; Homoharringtonine; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Mutation; Neoplasm, Residual; Piperazines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines

Before the discovery of imatinib mesylate, a Bcr-Abl selective tyrosine kinase inhibitor, three agents, interferon-alpha (IFN-alpha), cytarabine (ara-C), and homoharringtonine (HHT), had demonstrated activity against Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) as single agents and in couplet combinations. The goals of the current study were to evaluate the efficacy of the triple combination regimen with IFN-alpha, ara-C, and HHT in newly diagnosed Ph-positive CML and to assess the impact of the added sequential therapy with imatinib on overall prognosis.. Ninety patients with Ph-positive CML in early chronic phase received the triple regimen. Therapy consisted of 5 million units (MU)/m(2) IFN-alpha subcutaneously (s.c. daily, ara-C 10 mg s.c. daily, and HHT 2.5 mg/m(2) by continuous infusion over 24 hours daily x 5 every month. After a median duration of 16.5 months of therapy, 78 patients had their therapy changed to 400 mg orally administered imatinib daily.. With the triple regimen, 85 patients (94%) achieved complete hematologic response and 67 patients (74%) had a cytogenetic response (Ph suppression to < or = 90%) which was complete (Ph 0%) in 20 patients (22%) and major in 42 patients (46%). Myelosuppression was significant, resulting in considerable reductions in the dose schedules. After 12 months of therapy, the median IFN-alpha dose was 1.6 MU/m(2) daily, the median ara-C dose was 1.85 mg daily, and the median number of HHT days was 2 every month. Only three patients developed blastic phase while receiving the triple regimen. With the change to imatinib therapy, currently 57 patients (63%) are in complete cytogenetic response and 69 patients (76%) in major cytogenetic response. With a median follow-up time of 46 months for the total study group, the estimated 5-year survival rate was 88%, and only 8 patients (9%) to date have developed blastic phase.. The sequence of IFN-alpha, ara-C, and HHT followed by imatinib (imposed by the discovery of the latter drug) resulted in an estimated 5-year survival rate of 88%. This finding suggests that imatinib combination regimens may improve the prognosis in CML.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Cytarabine; Drug Administration Schedule; Female; Harringtonines; Homoharringtonine; Humans; Imatinib Mesylate; Infusions, Intravenous; Injections, Subcutaneous; Interferon-alpha; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Piperazines; Pyrimidines; Survival Analysis; Treatment Outcome

Homoharringtonine (HHT) is a cephalotaxine alkaloid with reported efficacy in acute myelogenous leukemia (AML). In a phase II trial, we evaluated HHT 5 mg/m2 by continuous infusion daily for 9 days in patients with relapsed or refractory acute leukemia and blastic phase of chronic myelogenous leukemia (BLCML). Sixty-six patients were entered. There were 40 males and 26 females with a median age of 41 years (range 15-81). Of 43 patients with relapsed AML, seven achieved a complete remission (16%, 95% confidence interval 5%-27%). Although 11 patients with AML primarily resistant to an anthracycline/cytarabine combination did not respond, two of three patients primarily resistant to low-dose cytarabine achieved complete remission. No patients with acute lymphoblastic leukemia, biphenotypic leukemia, or BLCML responded. Hypotension during the administration of HHT was the most difficult toxicity encountered, requiring multiple interruptions of therapy in several patients and the administration of intravenous saline. Fluid retention and weight gain occurred in 29% of patients. Transient asymptomatic hyperglycemia was observed in 63% of patients. Other toxicity was mild and included nausea and vomiting, diarrhea, mucositis, hepatic dysfunction, and cardiac arrhythmias. As expected, severe myelosuppression occurred in all patients. HHT is well tolerated, but with unique problems associated with administration. It has demonstrable efficacy in pre-treated patients with AML, but its role in the treatment of this disease remains to be defined.

Topics: Antineoplastic Agents, Phytogenic; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence

Chronic myeloid leukemia (CML) is a hematologic malignancy predominantly driven by the BCR-ABL fusion gene. One of the significant challenges in treating CML lies in the emergence of resistance to tyrosine kinase inhibitors (TKIs), especially those associated with the T315I mutation. Homoharringtonine (HHT) is an FDA-approved, naturally-derived drug with known anti-leukemic properties, but its precise mechanisms of action remain incompletely understood. In this study, we rigorously evaluated the anti-CML activity of HHT through both in vitro and in vivo assays, observing substantial anti-CML effects. To elucidate the molecular mechanisms underpinning these effects, we performed proteomic analysis on BCR-ABL T315I mutation-bearing cells treated with HHT. Comprehensive pathway enrichment analysis identified oxidative phosphorylation (OXPHOS) as the most significantly disrupted, suggesting a key role in the mechanism of action of HHT. Further bioinformatics exploration revealed a substantial downregulation of proteins localized within mitochondrial complex I (MCI), a critical OXPHOS component. These results were validated through Western blot analysis and were supplemented by marked reductions in MCI activity, ATP level, and oxygen consumption rate (OCR) upon HHT exposure. Collectively, our results shed light on the potent anti-CML properties of HHT, particularly its effectiveness against T315I mutant cells through MCI inhibition. Our study underscores a novel therapeutic strategy to overcome BCR-ABL T315I mutation resistance, illuminating a previously uncharted mechanism of action for HHT.

Topics: Cell Proliferation; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mutation; Protein Kinase Inhibitors; Proteomics

Drug resistance to tyrosine kinase inhibitors (TKIs) is currently a clinical problem in patients with chronic myelogenous leukemia (CML). Homoharringtonine (HHT) is an approved treatment for adult patients with chronic‑ or accelerated‑phase CML who are resistant to TKIs and other therapies; however, the underlying mechanisms remain unclear. In the present study, HHT treatment demonstrated induction of apoptosis in imatinib‑resistant K562G cells by using MTS assay and western blotting, and BCR‑ABL protein was reduced. CHX chase assay revealed that HHT induced degradation of the BCR‑ABL protein, which could be reversed by autophagy lysosome inhibitors Baf‑A1 and CQ. Next, HHT treatment confirmed the induction of autophagy in K562G cells, and silencing the key autophagic proteins ATG5 and Beclin‑1 inhibited the degradation of the BCR‑ABL protein and cytotoxicity. In addition, autophagic receptor p62/SQSTM1(p62) participated during the autophagic degradation of BCR‑ABL induced by HHT, and this was confirmed by co‑immunoprecipitation, in which HHT enhanced the ubiquitination of the BCR‑ABL protein and promoted its binding to p62. In conclusion, HHT induced p62‑mediated autophagy in imatinib‑resistant CML K562G cells, thus promoting autophagic degradation of the BCR‑ABL protein and providing a novel strategy for the treatment of TKI‑resistant CML.

Topics: Antineoplastic Agents, Phytogenic; Autophagy; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Gene Expression Regulation, Neoplastic; Homoharringtonine; Humans; Imatinib Mesylate; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Proteolysis; RNA-Binding Proteins; Signal Transduction

Homoharringtonine (HHT) and imatinib have a synergistic effect in the clinical treatment of chronic myeloid leukemia (CML). The purpose of the present study was to explore the underlying mechanisms by which HHT enhanced imatinib sensitivity. K562 CML cells were treated with HHT and imatinib separately or in combination. Cell viability was detected by Cell Counting Kit‑8 assay; apoptotic rates and protein expression levels of phosphorylated‑tyrosine (p‑Tyr) and p‑CRK like proto‑oncogene, adaptor protein (p‑Crkl) were analyzed by flow cytometry; zinc‑finger protein, X‑linked (ZFX) overexpression plasmid was transfected to cells using electroporation; western blotting was used to detect the protein expression levels of PI3K, AKT, p‑AKT and ZFX; and reverse transcription‑quantitative PCR was used to measure ZFX mRNA expression levels. The results demonstrated that HHT and imatinib co‑treatment had significant effects of proliferation inhibition and apoptosis induction on K562 CML cells compared with imatinib alone. Co‑treatment also significantly downregulated the expression levels of p‑Tyr, p‑Crkl, PI3K and p‑Akt compared with imatinib or HHT treatment. In addition, HHT downregulated ZFX mRNA and protein expression. ZFX overexpression reversed cell sensitivity to imatinib and HHT and also reduced the HHT‑induced imatinib sensitization by increasing p‑Akt expression. In conclusion, HHT may enhance the effect of imatinib on CML cells by downregulating ZFX.

Topics: Apoptosis; Down-Regulation; Gene Expression Regulation, Leukemic; Homoharringtonine; Humans; Imatinib Mesylate; K562 Cells; Kruppel-Like Transcription Factors; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Neoplasm Proteins

We synthetized and investigated the anti-leukemic potential of the novel cytostatic bis(4-hydroxycoumarin) derivative OT-55 which complied with the Lipinski's rule of 5 and induced differential toxicity in various chronic myeloid leukemia (CML) cell models. OT-55 triggered ER stress leading to canonical, caspase-dependent apoptosis and release of danger associated molecular patterns. Consequently, OT-55 promoted phagocytosis of OT-55-treated CML cells by both murine and human monocyte-derived macrophages. Moreover, OT-55 inhibited tumor necrosis factor α-induced activation of nuclear factor-кB and produced synergistic effects when used in combination with imatinib to inhibit colony formation in vitro and Bcr-Abl

Topics: Alarmins; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Survival; Drug Synergism; Endoplasmic Reticulum Stress; Homoharringtonine; Humans; Imatinib Mesylate; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Macrophages; Mice; Phagocytosis; Xenograft Model Antitumor Assays; Zebrafish

The anti-leukemic mechanism of homoharringtonine (HHT) differs from that of IM, and HHT is one of the most useful agents for use in patients with IM resistance or intolerance. The Bcl-6/p53 pathway has been shown to regulate the sensitivity of tumor cells to antitumor drugs. We tested whether HHT blocked the Bcl-6/p53 pathway in order to promote the apoptosis of IM-resistant cells in vitro and in vivo.. Ph+ acute lymphoblastic leukemia (ALL) cells and IM-resistant chronic myeloid leukemia (CML) cells showed high expression of Bcl-6 protein. Bcl-6 mediated the upregulation of p53, and and Bcl-6 induced growth inhibition of IM-resistant cells as well as its apoptosis by targeting p53. In addition, Bcl-6 was downregulated moderately after HHT treatment in different cells. The Bcl-6 expression was significantly increased in patients with CML when compared with healthy subjects. Furthermore, the expression of Bcl-6 was higher in patients with CML-blastic phase (CML-BP) than in those with CML-chronic phase (CML-CP).. The inhibitory effect of drugs on cell growth was detected by Cell Counting Kit-8 (CCK-8), The apoptosis rate and the cell cycle were investigated by flow cytometry. The expression of Bcl-6, p53, Bcl-2, caspase9, and caspase3 proteins was assayed by western blot, Real- Time PCR (qPCR) detect Bcl-6 and p53 mRNA.. HHT can suppress the growth and induce apoptosis of IM-resistant cells, the mechanism of which is associated with blocking of the Bcl-6/p53 pathway. Our results could offer a theoretical explanation for HHT use in patients with IM resistance or intolerance.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Cycle Checkpoints; Cell Survival; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Leukemic; Harringtonines; Homoharringtonine; Humans; Imatinib Mesylate; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Proto-Oncogene Proteins c-bcl-6; RNA Interference; Signal Transduction; Tumor Suppressor Protein p53; Young Adult

The objective of this study was to determine the changes in protein profiles of K562 chronic myeloid leukemia (CML) cells in response to Homoharringtonine (HHT). HHT treatment significantly increased apoptosis of K562 cells. Proteomic analyses indicated 32 differentially expressed proteins, 13 of which were identified by mass spectrometry (nine down-regulated and four up-regulated). Aside from alterations in apoptotic proteins and proteins associated with transcription and translation, our data also revealed changes in oxidative stress response and redox reaction-related proteins, such as heat shock proteins (Hsps), DJ-1 and thioredoxin. Specifically, these proteins were validated to decrease after HHT treatment in K562 cells and in primary CML cells by immunoblot analysis. Additionally, Hsps, DJ-1 and thioredoxin, which were also shown to decrease in primary cells from imatinib-resistant patients, may be promising potential targets for mechanistic research and new clinical treatments.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Biomarkers, Tumor; Blotting, Western; Electrophoresis, Gel, Two-Dimensional; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Proteomics; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tumor Cells, Cultured

Topics: Adult; Antineoplastic Agents, Phytogenic; Drug Approval; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Treatment Outcome; United States; United States Food and Drug Administration

Topics: Antineoplastic Agents, Phytogenic; Drug Resistance, Neoplasm; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Regression Analysis; Survival Analysis

The therapeutic armamentarium of chronic myeloid leukemia (CML) has been considerably improved after the introduction of first- and second-generation tyrosine-kinase inhibitors (TKIs). Accordingly, the natural history of the diseases has changed, and patients in complete molecular response now have the same life expectancy of their healthy coetaneous. Notwithstanding these results, ∼ 20 - 30% of patients do not respond optimally to TKIs therapy, and most of these patients are potential candidates to progress toward the accelerated or blastic phase of the disease. Unfortunately, patients who become resistant to both first- and second-generation TKIs develop BCR-ABL kinase domain mutations, against which TKIs have extremely low cross-activity. In particular, none of the TKIs, with the exception of ponatinib, has significant activity against T315 mutation, which is estimated to be present in ∼ 15 - 20% of patients carrying BCR-ABL mutations. The use of omacetaxine mepesuccinate/homoharringtonine for the treatment of TKI-resistant CML patients regained interest due to its mechanism of action independent of binding to the ATP-binding pocket. Therefore, the activity of this compound is independent from the presence of BCR-ABL1 mutations, which makes it an attractive option for the treatment of CML patients after TKI failure.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Phytogenic; Drug Resistance, Neoplasm; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Kinase Inhibitors; Protein-Tyrosine Kinases

On October 26, 2012, the U.S. Food and Drug Administration (FDA) granted accelerated approval to omacetaxine mepesuccinate (Synribo; Teva Pharmaceuticals USA, Inc., North Wales, PA, http://www.tevausa.com) for the treatment of adult patients with chronic phase (CP) or accelerated phase (AP) chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKIs). The approval was based on the FDA review of data from 111 patients with CML in CP or in AP who had received two or more prior TKIs, including imatinib. Major cytogenetic response was achieved in 18% of patients with CP, with a median response duration of 12.5 months. Major hematologic response was achieved in 14% of patients with AP, with a median response duration of 4.7 months. The FDA safety evaluation was based on submitted data from 163 patients with CP or AP CML who had received at least one dose of omacetaxine mepesuccinate. The safety evaluation was limited by the single-arm design of the clinical trials as conducted in a small number of previously treated patients. The most common (≥20%) adverse reactions of any grade in enrolled patients included thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection site reaction, pyrexia, and infection. The FDA concluded that omacetaxine mepesuccinate has shown activity and a favorable benefit-to-risk profile for the studied population of adult patients with CML (CP or AP) with resistance and/or intolerance to two or more TKIs. Further evidence of response durability to verify clinical benefit is pending.

Topics: Aged; Angiogenesis Inhibitors; Clinical Trials, Phase II as Topic; Drug Approval; Female; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; United States; United States Food and Drug Administration

The purpose was to investigate the role of EphB4 in imatinib (IM) resistance and the mechanism responsible for homoharringtonine (HHT) contributing to imatinib sensitivity for a chronic myeloid leukemia (CML) cell lines. We established cell lines from a patient with CML at the time of first diagnosis and relapsed phase and designated them as NPhA1 and NPhA2, respectively. Stable underexpressing EphB4 cells (NPhA2-sh) were obtained. The activated signal proteins in cells were tested by Western blot. The EphB4 was overexpressed in IM-resistant NPhA2 in comparison with the NPhA1 cell line, but the expression of EphB4 mRNA and protein significantly decreased in knockdown NPhA2-EphB4-sh cells compared with NPhA2 and NPhA1 (P < 0.001) cell lines. NPhA2-EphB4-sh cells were sensitive to IM (IC50 0.93 mg/L), and NPhA2 showed IM resistance (IC50 5.45 mg/L) (P < 0.001). Meanwhile, phospho-Rac1/cdc42 was significantly increased in NPhA2 cells compared to NPhA2-EphB4-sh (P < 0.001). The apoptosis rate reached 58.71 ± 2.39 % with NPhA2 cells incubated with HHT + IM, which was higher than NPhA2 cells incubated with IM alone (P = 0.002). IC50 of NPhA2 cells incubated with IM was 5.45 mg/L. However, co-stimulation with HHT + IM decreased the IC50 of NPhA2 cells from 5.45 to 1.17 mg/L (P < 0.001). Furthermore, HHT blocked the expressions of EphB4/RhoA, but did not down-regulate the phospho-MEK/ERK in NPhA2 cells. The overexpression of EphB4 contributed to IM resistance in CML line cells. EphB4/RhoA may be a new marker of IM resistance. HHT + IM gained more treatment advantages than IM alone by blocking EphB4/RhoA pathways in CML cell lines.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzamides; Blotting, Western; Cell Proliferation; Drug Resistance, Neoplasm; Drug Synergism; Harringtonines; Homoharringtonine; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Neoplasm Recurrence, Local; Piperazines; Pyrimidines; Real-Time Polymerase Chain Reaction; Receptor, EphB4; Reverse Transcriptase Polymerase Chain Reaction; rhoA GTP-Binding Protein; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Tumor Cells, Cultured

Post-transplant lymphoproliferative disorders originating from T lymphocytes are a rare complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT) that are not usually associated with Epstein-Barr virus infection. A male patient diagnosed at the age of 15 years with chronic myeloid leukaemia (in the chronic phase) was initially treated with oral hydroxyurea. The disease entered an accelerated phase when the patient was 22 years old. Complete remission was achieved after one course of homoharringtonine and cytarabine. The patient then underwent human leucocyte antigen-matched sibling donor allo-HSCT. Just over 6.5 years after the allo-HSCT, a second primary tumour was located in the distal femur and diagnosed as T-cell non-Hodgkin's lymphoma (stage IV, group B). This was treated with various chemotherapy and radiotherapy regimens, but the outcomes were poor and the disease progressed. The T-cell lymphoma invaded many sites, including the skeleton, spleen and skin, and the patient died within 8 months of the diagnosis. This current case report highlights the need for the early detection and prevention of subsequent primary malignancies after allo-HSCT.

Topics: Adult; Angiogenesis Inhibitors; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cytarabine; Dexamethasone; Harringtonines; Hematopoietic Stem Cell Transplantation; Homoharringtonine; Humans; Hydroxyurea; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lymphoma, T-Cell; Male; Neoplasm Invasiveness; Transplantation, Homologous

Chronic myelogenous leukemia (CML) is driven by the Bcr-Abl fusion protein, which is a result of a (9;22) chromosomal translocation. Imatinib, dasatinib, and nilotinib (tyrosine kinase inhibitors, TKI) have revolutionized how CML is treated. Although the majority of patients respond to these kinase inhibitors, a subset becomes resistant to these therapeutics. Synribo (omacetaxine mepesuccinate) was recently approved by the U.S. Food and Drug Administration for Philadelphia-positive CML either in the chronic or the accelerated phase whose disease failed two prior TKIs. With omacetaxine 1.25 mg/m(2) twice daily for 14 days during induction and for 7 days during maintenance, a major cytogenetic response occurred in 20% of patients in the chronic phase and major hematologic response in 27% of patients in the accelerated phase. Laboratory investigations unraveled the mechanism of action and effectiveness of this agent. Bcr-Abl protein is intrinsically programmed to turn over with a short half-life that makes it susceptible to protein translation inhibitors. Omacetaxine (homoharringtonine) inhibits total protein biosynthesis by binding to A-site cleft of ribosomes. As a corollary to this action, there is a diminution of short-lived proteins, such as Bcr-Abl, followed by cell death. Approval of this first-in-class protein translation inhibitor opens up new avenues for its use in other diseases as well as mechanism-based combinations.

Topics: Drug Approval; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Biosynthesis; United States; United States Food and Drug Administration

Harringtonine (HT) and homoharringtonine (HHT) are Cephalotaxus alkaloids with considerable antileukaemic activity. The objectives of this research were to (1) determine the content of HT and HHT present in Cephalotaxus griffithii needles alkaloid fraction (CGAF) and (2) compare the antiproliferative activity of CGAF, with that of HT and HHT on chronic myelogenous leukaemia K562 cell. The concentration of HT and HHT was found to be 122.14 and 16.79 mg/g of CGAF, respectively. Treatment of K562 cells with CGAF, HT and HHT decreased the viable cells in a dose- and time-dependent manner. Interestingly, the maximum cell death was found in CGAF, with IC50 value which was 3- to 4.6-fold lower than those of HT and HHT. Our results indicate that HT content in the needles of C. griffithii is higher than HHT, and alkaloids other than HT and HHT in CGAF are predominantly responsible for K562 cell death.

Topics: Alkaloids; Antineoplastic Agents, Phytogenic; Apoptosis; Cephalotaxus; Chromatography, High Pressure Liquid; Drug Screening Assays, Antitumor; Harringtonines; Homoharringtonine; Humans; Inhibitory Concentration 50; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Homoharringtonine (HHT) is a kind of cephalotaxus alkaloid used in traditional Chinese medicine. Although HHT has been successfully used as a therapeutic agent for leukemia, the drug resistance and toxicity are major concerns. MicroRNAs (miRNAs) have been identified to modulate cellular sensitivity to anticancer drugs. We examined the synergistic action between miR-370 and HHT in vitro and in vivo.. The synergistic action between miR-370 and HHT was examined by flow cytometry. The effect of HHT on miR-370 expression was determined by quantitative RT-PCR (qRT-PCR). The expression of miR-370 and Forkhead box M1 (FoxM1) in 23 patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) and 10 patients with blast-crisis CML (CML-BP) as well as miR-370-targeted FoxM1 was determined by qRT-PCR and western blot analysis.. Ectopic expression of miR-370 sensitized the CML K562 cell line to HHT by targeting FoxM1, the major regulator in cell proliferation and apoptosis. miR-370 significantly promoted HHT-mediated cell apoptosis and miR-370 and HHT cooperated in affecting FoxM1 expression. As well, miR-370 was moderately upregulated after HHT treatment in K562 cells. In addition, the expression of miR-370 was significantly reduced in CML patients as compared with healthy controls. Furthermore, the expression of miR-370 was lower in CML-BP than CML-CP patients.. MiR-370 sensitized K562 cells to HHT by inducing apoptosis in part by downregulation of FoxM1 expression. These findings may provide further information for CML treatment with HHT.

Topics: Antineoplastic Agents, Phytogenic; Base Sequence; Blotting, Western; DNA Primers; Down-Regulation; Flow Cytometry; Forkhead Box Protein M1; Forkhead Transcription Factors; Harringtonines; Homoharringtonine; Humans; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; MicroRNAs; Polymerase Chain Reaction; Up-Regulation

Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Gene Expression Regulation, Leukemic; Harringtonines; Homoharringtonine; HSP90 Heat-Shock Proteins; Humans; Imidazoles; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Primary Cell Culture; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Pyridazines; Signal Transduction

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Drug Resistance; Female; Harringtonines; Homoharringtonine; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mutation; Neoplasm, Residual; Piperazines; Pyrimidines

Overcoming resistance against BCR-ABL-inhibitors in chronic myeloid leukemia (CML) is central to prevent progression to advanced phase disease. Kinase mutations of BCR-ABL and cytokine-mediated modulation of response to tyrosine kinase inhibitors (TKIs) are key mechanisms governing clinical response to imatinib and second generation TKIs. Omacetaxine mepesuccinate is effective in imatinib-resistant CML with reported stem cell activity. We specifically thought to explore omacetaxine in the context of the pan-resistant mutant T315I, and in its potential to modify cytokine-dependent resistance. Omacetaxine was investigated in cell lines and primary CD34+ enriched progenitor cells from patients with CML. Addition of cytokines, shown to revert the efficacy of TKIs in BCR-ABL-positive cells, does not affect omacetaxine mediated antiproliferative activity, neither in cell lines nor in primary CML CD34+ progenitor cells. Looking at potential mechanisms, we found marked downregulation of the common β-subunit c of the cytokine-receptors (cCRβc) for IL3, IL5 and GM-CSF by omacetaxine in cell lines and primary progenitor cultures. The observed cytokine-independent in-vitro cytotoxicity of omacetaxine may be explained by downregulation of cCRβc. Whether this can be used clinically as a means to optimize the stem cell activity of TKIs merits further evaluation.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Benzamides; Blotting, Western; Cell Proliferation; Cells, Cultured; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Harringtonines; Homoharringtonine; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice; Neoplastic Stem Cells; Piperazines; Precursor Cells, B-Lymphoid; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Real-Time Polymerase Chain Reaction; Receptors, Cytokine; RNA, Messenger

Topics: Antineoplastic Agents, Phytogenic; Clinical Trials as Topic; Drug Approval; Drug Discovery; Harringtonines; Homoharringtonine; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; United States; United States Food and Drug Administration

Chronic myeloid leukaemia (CML) is maintained by a rare population of tyrosine kinase inhibitor (TKI)-insensitive malignant stem cells. Our long-term aim is to find a BcrAbl-independent drug that can be combined with a TKI to improve overall disease response in chronic-phase CML. Omacetaxine mepesuccinate, a first in class cetaxine, has been evaluated by clinical trials in TKI-insensitive/resistant CML. Omacetaxine inhibits synthesis of anti-apoptotic proteins of the Bcl-2 family, including (myeloid cell leukaemia) Mcl-1, leading to cell death. Omacetaxine effectively induced apoptosis in primary CML stem cells (CD34(+)38(lo)) by downregulation of Mcl-1 protein. In contrast to our previous findings with TKIs, omacetaxine did not accumulate undivided cells in vitro. Furthermore, the functionality of surviving stem cells following omacetaxine exposure was significantly reduced in a dose-dependant manner, as determined by colony forming cell and the more stringent long-term culture initiating cell colony assays. This stem cell-directed activity was not limited to CML stem cells as both normal and non-CML CD34(+) cells were sensitive to inhibition. Thus, although omacetaxine is not leukaemia stem cell specific, its ability to induce apoptosis of leukaemic stem cells distinguishes it from TKIs and creates the potential for a curative strategy for persistent disease.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Phytogenic; Apoptosis; Down-Regulation; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Myeloid Cell Leukemia Sequence 1 Protein; Neoplastic Stem Cells; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Tumor Cells, Cultured

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzamides; Child; Cytarabine; Daunorubicin; Female; Harringtonines; Homoharringtonine; Humans; Imatinib Mesylate; Induction Chemotherapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Maintenance Chemotherapy; Piperazines; Pyrimidines

Omacetaxine mepesuccinate, formerly known as homoharringtonine, is a first-in-class cephalotaxine that has experienced phases of increasing and waning interest since its first use in traditional Chinese medicine. With activity being reported in patients with chronic myeloid leukemia (CML) resistant to currently available tyrosine kinase inhibitors, renewed interest has recently been generated.. The development of omacetaxine mepesuccinate, with emphasis on synthesis and mode of administration, is addressed. An overview on current clinical results as a single agent or within combination regimens in patients with acute myeloid leukemia (AML) and CML is given.. Omacetaxine mepesuccinate has a unique mode of action and appreciable activity in AML and CML with generally mild nonhematologic toxicity. In patients with AML, results indicate a role within combination regimens in selected, possibly elderly patient populations. In CML, patients with resistance to tyrosine kinase inhibitors, especially due to the T315I mutation, are the most intensively studied. Despite successful results in some patients, single-agent therapy with omacetaxine mepesuccinate has resulted in modest results. However, upfront combination with tyrosine kinase inhibitor represents an attractive option due their differing mechanisms of action.

Topics: Antineoplastic Agents, Phytogenic; Clinical Trials as Topic; Drug Resistance, Neoplasm; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Topics: Adult; Antineoplastic Agents, Phytogenic; Female; Fusion Proteins, bcr-abl; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Treatment Outcome; Young Adult

The onset of a BCR-ABLT315I mutation during the course of chronic myelogenous leukemia (CML) on tyrosine kinase inhibitors (TKIs) usually results in poor survival, and therapeutic options remain few in the absence of any allogeneic donor.. We have investigated the affect of subcutaneous omacetaxine (OMA, or homo-harringtonine) cycles on unmutated and T315I-mutated BCR-ABL transcripts in a series of 8 TKI-resistant chronic-phase CML patients and we have addressed the question of whether the administration of OMA could resensitize patients to TKIs. Patients were regularly monitored for total disease burden and for BCR-ABLT315I transcripts using a new quantitative sensitive technique (sensitivity threshold, 0.05%), for up to 27 cycles of OMA.. Overall, patients demonstrated hematologic, cytogenetic, or molecular improvement. An initial rapid decline and a sustained disappearance of T315I-mutated transcripts were observed in 50% of patients, after a median of 10.5 cycles (range, 3-27 cycles) of OMA. As the unmutated leukemic burden reduction was modest, 2 patients were submitted to nilotinib after 9 months of sustained BCR-ABLT315I transcripts negativity on OMA and mutated transcripts remained undetectable after a median follow-up of 12 months on nilotinib challenge.. We suggest that OMA (ie, a non-targeted therapy) might provide a better disease control allowing the disappearance of the mutated clone probably elicited by the clone deselection after TKI release, and/or a preferential activity of OMA on the T315I-mutated cells through unknown mechanisms. These observations suggest that OMA could allow a safe TKI rechallenge in patients with resistant chronic-phase CML.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Drug Resistance, Neoplasm; Female; Fusion Proteins, bcr-abl; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines

Topics: Aged; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Benzamides; Dasatinib; Drug Resistance, Neoplasm; Female; Fusion Proteins, bcr-abl; Harringtonines; Homoharringtonine; Humans; Hydroxyurea; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Mutagenesis; Mutation, Missense; Piperazines; Point Mutation; Protein Kinase Inhibitors; Protein Structure, Tertiary; Pyrimidines; Thiazoles; Treatment Failure

Omacetaxine mepesuccinate (formerly homoharringtonine) is a molecule with a mechanism of action that is different from tyrosine kinase inhibitors, and its activity in chronic myeloid leukemia (CML) seems to be independent of the BCR-ABL mutation status. Using BCR-ABL-expressing myelogenous and lymphoid cell lines and mouse models of CML and B-cell acute lymphoblastic leukemia (B-ALL) induced by wild-type BCR-ABL or T315I mutant-BCR-ABL, we evaluated the inhibitory effects of omacetaxine on CML and B-ALL. We showed that more than 90% of the leukemic stem cells were killed after treatment with omacetaxine in vitro. In contrast, less than 9 or 25% of the leukemic stem cells were killed after treating with imatinib or dasatinib, respectively. After 4 days of treatment of CML mice with omacetaxine, Gr-1(+)myeloid leukemia cells decreased in the peripheral blood of the treated CML mice. In the omacetaxine-treated B-ALL mice, only 0.8% of the B220(+)leukemia cells were found in peripheral blood, compared with 34% of the B220(+)leukemia cells in the placebo group. Treatment with omacetaxine decreased the number of leukemia stem cells and prolonged the survival of mice with BCR-ABL-induced CML or B-ALL.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Fusion Proteins, bcr-abl; Gene Expression Regulation, Leukemic; Harringtonines; Homoharringtonine; HSP90 Heat-Shock Proteins; Humans; K562 Cells; Leukemia, B-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplastic Stem Cells; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Radiation Chimera; Recombinant Fusion Proteins; Transduction, Genetic

Topics: Adolescent; Adult; Antineoplastic Agents, Phytogenic; Benzamides; Drug Resistance, Neoplasm; Drug Therapy, Combination; Harringtonines; Homoharringtonine; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Middle Aged; Piperazines; Protein Kinase Inhibitors; Pyrimidines; Remission Induction; Young Adult

Hypoxia-inducible factor-1alpha (HIF-1alpha) is a key transcription factor under anoxic circumstances. Little is known about changes in biological characters of hematological malignancies, especially leukemia. This study was to explore the influence of RNA interference (RNAi) targeting HIF-1alpha on sensitivity of human chronic myelogeneous leukemia (CML) K562 cells towards homoharringtonine (HHT).. HIF-1alpha short hairpin RNA (shRNA) was constructed using pSilencer 2.1-U6 hygro vector and transfected into K562 cells. Positive clones were screened using hygromycin. After inhibition of HIF-1alpha, expressions of its target genes such as vascular endothelial growth factor (VEGF), glucose transporter-1 (Glut-1), phosphoglycerate kinase (PGK), and P-glycoprotein (P-gp) were detected by real-time reverse transcriptase polymerase chain reaction (RT-PCR). Sensitivity of K562 cells to HHT was detected by MTT assay.. HIF-1alpha expression was inhibited at both mRNA and protein levels after transfection of RNAi HIF-1alpha, which subsequently caused a dramatic decrease in VEGF, Glut-1, PGK, and P-gp under hypoxic conditions. In addition, HIF-1alpha inhibition was found to increase drug sensitivity of K562 cells to HHT.. HIF-1alpha inhibition may result in a decrease of genes related to angiogenesis and glycolysis metabolism and an increase of drug sensitivity to HHT in K562 cells.

Topics: Antineoplastic Agents, Phytogenic; Base Sequence; Glucose Transporter Type 1; Harringtonines; Homoharringtonine; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Molecular Sequence Data; RNA Interference; Vascular Endothelial Growth Factor A

The effect of ABT-737, a BH3-mimicking inhibitor for anti-apoptotic Bcl-2 and Bcl-X(L), but not Mcl-1, against Bcr-Abl-positive (Bcr-Abl(+)) leukaemic cells was examined. ABT-737 potently induced apoptosis in Bcr-Abl(+) chronic myeloid leukaemia (CML) cell lines and primary CML samples in vitro and prolonged the survival of mice xenografted with BV173 cells, a CML cell line. Higher expression of anti-apoptotic Bcl-2 proteins reduced cell killing by ABT-737 in each cell line, but there was no correlation between the sensitivities to ABT-737 and the specific expression patterns of Bcl-2 family proteins among cell lines. Thus, the cell killing effect of ABT-737 must be determined not only by the expression patterns of Bcl-2 family proteins but also by other mechanisms, such as high expression of Bcr-Abl, or a drug-efflux pump, in CML cells. ABT-737 augmented the cell killing effect of imatinib in Bcr-Abl(+) cells with diverse drug-resistance mechanisms unless leukaemic cells harboured imatinib-insensitive Abl kinase domain mutations, such as T315I. The combination of homoharringtonine that reduces Mcl-1 enhanced the killing by ABT-737 strongly in Bcr-Abl(+) cells even with T315I mutation. These results suggest that ABT-737 is a useful component of chemotherapies for CML with diverse drug-resistance mechanisms.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biphenyl Compounds; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Transplantation; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Survival Analysis; Transplantation, Heterologous; Tumor Cells, Cultured

Homoharringtonine (HHT), a natural alkaloid extracted from various Cephalotaxus species, exerts its antitumoral and anti-angiogenic activity through an inhibition of protein synthesis and the promotion of apoptosis. ChemGenex Pharmaceuticals Ltd, in collaboration with Stragen Group, is developing omacetaxine mepesuccinate, a semisynthetic formulation of HHT, as a potential treatment for chronic myelocytic leukemia (CML), myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). In preclinical studies, omacetaxine mepesuccinate induced apoptosis in leukemia cell lines. Results from phase II clinical trials revealed omacetaxine mepesuccinate to be active in patients with CML that was resistant to tyrosine kinase inhibitor (TKI) therapy, including those patients who carry the BCR-ABL1T315I mutation, which is highly insensitive to the TKIs imatinib, nilotinib and dasatinib; the therapeutic was also generally well tolerated. Phase II and III clinical trials are underway to assess the activity of omacetaxine mepesuccinate, either alone or in combination with TKIs or other cytotoxic drugs, in patients with CML that is resistant to TKI therapy. Phase I and II clinical trials for omacetaxine mepesuccinate in the treatment of AML and MDS are also ongoing; intravenous, subcutaneous and oral formulations of the drug are being developed. Omacetaxine mepesuccinate appears to hold potential for the treatment of CML and, in particular, imatinib-resistant CML; the development of alternative formulations of the therapeutic further expands the potential for success in drug development.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Clinical Trials as Topic; Drug Evaluation, Preclinical; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Myelodysplastic Syndromes; Patents as Topic; Structure-Activity Relationship; Treatment Outcome

Topics: Antineoplastic Agents; Benzamides; Bone Marrow; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Gene Expression Regulation, Leukemic; Harringtonines; Homoharringtonine; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Mutation; Piperazines; Pyrimidines; Time Factors; Treatment Outcome

Topics: Aged; Fusion Proteins, bcr-abl; Harringtonines; Homoharringtonine; Humans; Interferon-alpha; Isoleucine; Kinetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Mutation; Salvage Therapy; Tyrosine

Topics: Adult; Antineoplastic Agents, Phytogenic; Harringtonines; Homoharringtonine; Humans; India; Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Molecular monitoring of the BCR-ABL transcript in chronic myelogenous leukemia (CML) using quantitative RT-PCR provides clinicians with important diagnostic and prognostic information. To determine whether molecular detection and monitoring of CML is comparable using peripheral blood (PB) and bone marrow (BM) aspirate samples, we performed a prospective study using quantitative real-time RT-PCR (QRT-PCR) of paired PB and BM samples from 41 patients with CML entered onto a single Cancer and Leukemia Group B (CALGB) treatment study. QRT-PCR analysis of PB and BM samples was performed prior to initiation of, and during, treatment with homoharringtonine and cytarabine on a CALGB study for previously untreated CML. Statistical analyses demonstrated good agreement of PB and BM pre-treatment samples. However, using the Bland-Altman statistical method that measures true agreement between PB and BM values, we found that there was only modest agreement of BCR-ABL measurements in PB and BM for samples obtained during treatment. PB values obtained during treatment tended to be lower than the corresponding BM values [average difference = -0.37 (p<0.001) in 36 paired samples] and the 95% limits of agreement ranged from -1.23 to 0.48. Nevertheless, our study demonstrates that BM and PB QRT-PCR values followed a similar trend during treatment (Spearman correlation coefficient, 0.83; 95% CI, 0.70, 0.96). Our data suggest that, quantitatively, PB and BM measurements of BCR-ABL are frequently disparate. Since BM values tended to be higher than PB values, BM sampling provides the most accurate assessment of minimal residual disease (MRD). Based on these results, we caution against interchanging BM with PB sampling for MRD monitoring during treatment of CML since this may lead to misinterpretation of treatment results.

Topics: Antineoplastic Combined Chemotherapy Protocols; Base Sequence; Bone Marrow; Cytarabine; DNA Primers; Fusion Proteins, bcr-abl; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Monitoring, Physiologic; Reverse Transcriptase Polymerase Chain Reaction; Transcription, Genetic

The aims of this study were to evaluate the feasibility of using the non-clonogenic fluorometric microculture cytotoxicity assay in drug sensitivity testing of tumor cells from patients with chronic myeloid leukemia. In nine samples (six chronic phase, three blast crisis), the drug sensitivities in tumor cells from blood versus from bone marrow and fresh tumor cells versus cryopreserved were compared. In 26 samples obtained in chronic phase (pretreatment), in six samples from patients in blast crisis and in the K 562 cell line, the activity of imatinib alone and in combination with cytarabine, vincristine, daunorubicin, interferon, arsenic trioxide and homoharringtonine was evaluated. All chronic myeloid leukemia chronic phase samples were sensitive to imatinib, with a mean IC50 at 10.3 mumol/l. The chronic myeloid leukemia samples from blast crisis (n=6) were significantly more sensitive to imatinib than the samples from chronic phase (n=26) (P<0.05), with an IC50 mean at 0.4 mumol/l. In blast crisis samples, significant positive interaction effects were observed between imatinib and all other tested drugs except for interferon. In chronic phase samples, interferon, daunorubicin and arsenic trioxide were the drugs with the highest frequency of positive interactions with imatinib (P<0.05). We conclude that the fluorometric microculture cytotoxicity assay may be a useful method for drug sensitivity testing in chronic myeloid leukemia patient samples from both chronic phase and blast crisis, and that testing primary tumor cells may have advantages over cell line studies. Imatinib shows a higher in vitro activity and more positive drug interactions in cells from blast crisis than chronic phase chronic myeloid leukemia patients. Combinations between imatinib and interferon, daunorubicin and arsenic trioxide may be interesting for future clinical trials in patients with chronic myeloid leukemia chronic phase.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Benzamides; Blast Crisis; Cytarabine; Daunorubicin; Feasibility Studies; Harringtonines; Homoharringtonine; Humans; Imatinib Mesylate; In Vitro Techniques; Interferons; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Oxides; Piperazines; Pyrimidines; Vincristine

Some tumors are dependent on the continued activity of a single oncogene for maintenance of their malignant phenotype. The best-studied example is the Bcr-Abl fusion protein in chronic myelogenous leukemia (CML). Although the clinical success of the Abl kinase inhibitor imatinib against chronic-phase CML emphasizes the importance of developing therapeutic strategies aimed at this target, resistance to imatinib poses a major problem for the ultimate success of CML therapy by this agent. We hypothesized a sequential blockade strategy that is designed to decrease the expression of the Bcr-Abl protein, with the goal of complementing the action of imatinib on kinase activity. In this study, flavopiridol, an inhibitor of transcription, homoharringtonine (HHT), a protein synthesis inhibitor, and imatinib were used singly and in combination against the Bcr-Abl-positive human CML cell line K562. Flavopiridol alone inhibited phosphorylation of the RNA polymerase II COOH-terminal domain, specifically reduced RNA polymerase II-directed mRNA synthesis, and decreased the Bcr-Abl transcript levels. HHT inhibited protein synthesis and reduced the Bcr-Abl protein level. Imatinib directly inhibited the kinase activity of Bcr-Abl. The combinations of flavopiridol and HHT and flavopiridol and imatinib synergistically decreased clonogenicity as evaluated by the median-effect method. Greater synergy was observed when HHT and imatinib were given sequentially compared with simultaneous administration. Imatinib-resistant Ba/F3 cells that were transfected to express the E255K and T315I mutations of Bcr-Abl were not cross-resistant to flavopiridol and HHT. These results provided a rationale for the combination of inhibitors of transcription and/or translation with specific kinase inhibitors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzamides; Drug Synergism; Flavonoids; Fusion Proteins, bcr-abl; Harringtonines; Homoharringtonine; Humans; Imatinib Mesylate; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Piperazines; Piperidines; Pyrimidines; RNA, Neoplasm

Homoharringtonine (HHT) is a cephalotaxine ester derived from an evergreen tree found wildely throughout southern China, which has antileukemic activities against a variety of acute myeloid leukemic cells. For the sake of illustrating the mechanisms of HHT in the treatment of leukemia, we assessed the effect of HHT on the apoptosis of human chronic myeloid leukemic cell line K562.. The apoptosis of K562 cells induced by HHT was analyzed by transmission electron microscopy, agarose gel electrophoresis of DNA, flow cytometry and terminal deoxyribonucleotidyl transferase-mediated dUTP-biotin nick labeling.. Characteristic apoptosis-related features emerged in K562 cells after exposed to HHT at a concentration 0.05-100 microg/ml. Transmission electron microscopy of HHT treated K562 cells displayed chromatin condensation and aggregation under the nuclear membrane, nuclear fragmentation and apoptosis body formation. Typical DNA ladder in agarose gel electrophoresis was observed in the cells exposed to HHT. The cell cycle analysis measured by flow cytometry showed G1 phase cells decreased with the increase of S phase cells while apoptosis was induced by HHT in K562 cells. The percentage of apoptotic cells in K562 cells treated with 50 microg/ml of HHT decreased significantly when pretreated with 1 microg/ml of cycloheximide, 0.05 microg/ml of Actinomycin D respectively.. HHT has apoptotic effects on K562 cells. The HHT induced apoptosis mainly of the cells in G1 phase and this process required RNA transcription and protein synthesis.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cycloheximide; Dactinomycin; G1 Phase; Harringtonines; Homoharringtonine; Humans; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Chronic myelogenous leukemia (CML) is characterized by a molecular aberration, a fusion BCR-ABL gene encoding for aberrant tyrosine kinase activity, which is crucial in the pathogenesis of CML. In vitro, inhibition of BCR-ABL protein tyrosine kinase activity by a tyrosine kinase inhibitor, Imatinib mesylate (STI571; formerly CGP57148B), successfully suppressed proliferation/survival of the BCR-ABL positive clones. In clinical studies, hematologic and cytogenetic remissions have been achieved in most patients with chronic phase CML; in accelerated and blastic phases of CML, STI571 appeared less effective. In the current study, the authors tested combinations of STI571 and cytarabine and homoharringtonine (HHT), drugs with documented activity in CML.. The single agents and their combinations were studied for in vitro effect on proliferation of BCR-ABL positive cell lines KBM5 and KBM7 by 3(4,5-dimethylthiazol-2yl)-2,5 diphenyl-tetrazolium bromide assay and on primary patient-derived BCR-ABL cells by clonogenic assays. The in vitro additive, synergistic, or antagonistic effects of cytarabine and HHT with STI571 were then investigated by computer-assisted analysis using the CalcuSyn software.. STI571 consistently suppressed BCR-ABL positive cell proliferation with a dose-effect correlation. In the model system used, STI571/cytarabine and STI571/HHT combinations were more effective in inhibiting KBM5 and KBM7 cell growth than each drug as single agent. These results were also verified in primary CML-derived clonogenic cells in semisolid cultures.. In this experimental system, our studies documented additive or synergistic effects with STI571 plus cytarabine or HHT, supporting the future use of STI571 combinations in clinical trials in patients with Philadelphia chromosome-positive leukemias.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Cytarabine; Dose-Response Relationship, Drug; Drug Synergism; Harringtonines; Homoharringtonine; Imatinib Mesylate; In Vitro Techniques; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome; Piperazines; Protein-Tyrosine Kinases; Pyrimidines; Tumor Cells, Cultured; Tumor Stem Cell Assay

Homoharringtonine (HHT) has antileukemic activity in patients with Philadelphia chromosome (Ph) positive chronic myelogenous leukemia (CML). Combinations of HHT, interferon-alpha (IFN-alpha), and cytarabine (ara-C) have been studied in various CML phases. The objectives of this study were to evaluate the efficacy and toxicity profiles of a combination regimen of simultaneous HHT and IFN-alpha therapy in patients with chronic-phase CML who were not exposed previously to either agent.. Forty-seven patients were treated: 37 patients with early chronic-phase CML (2 patients with clonal evolution) and 10 patients with late chronic-phase CML. Their median age was 62 years (range, 23-73 years). HHT was given at a dose of 2.5 mg/m(2) by continuous intravenous infusion over 24 hours daily for 5 days every month, and IFN-alpha was given daily at a target dose of 5 x 10(6) units/m(2) subcutaneously. Response, survival, and treatment toxicity were analyzed.. Overall, the complete hematologic response (CHR) rate was 85%; the cytogenetic response rate was 66%, with major cytogenetic responses (Ph positive in < 35% of metaphases) in 49% of patients and complete cytogenetic responses in 21% of patients. The CHR rate, cytogenetic response rate, and major cytogenetic response rate were 84%, 69%, and 52%, respectively, in patients with early chronic-phase CML. Among the 10 patients with late chronic-phase CML, the CHR rate, cytogenetic response rate, and major cytogenetic response rate were 80%, 50%, and 40%, respectively. Response rates in patients age > 60 years were 84%, 62%, and 49% for CHR, cytogenetic response, and major cytogenetic response. Myelosuppression was frequent but manageable: Anemia with hemoglobin < 8.0 g/dL occurred in 36% of patients, requiring dose adjustments and erythropoietin therapy. Nonhematologic toxicities were mainly fatigue, aches, and gastrointestinal disturbances. Dose reductions with multiple courses were significant and were due to myelosuppression: After 6-24 courses, the median daily IFN-alpha dose was 1 MU/m(2), and the median number of days on HHT per month was 2 days. With a median follow-up of 26 months, the estimated 2-year survival rate was 90% (95% confidence interval, 79-100%).. The simultaneous combination of HHT and IFN-alpha is safe and effective, but the dose schedules that actually were delivered were significantly lower than the planned dose schedules. With the availability of signal-transduction inhibitor 571 (imatinib mesylate), studies of combination of HHT and IFN-alpha chemotherapy in patients with CML who have disease that fails to respond to imatinib mesylate and of combinations with imatinib mesylate need to be explored.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Harringtonines; Homoharringtonine; Humans; Interferon-alpha; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Male; Middle Aged; Prognosis; Risk Factors; Survival Rate

Topics: Antineoplastic Combined Chemotherapy Protocols; Harringtonines; Homoharringtonine; Humans; Interferon-alpha; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Prognosis; Risk Factors; Survival Rate

The BCR/ABL tyrosine kinase has been implicated in the pathogenesis of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL). STI571 is a novel anticancer agent that selectively inhibits the BCR/ABL tyrosine kinase. The cytotoxic effects of STI571 were studied in combination with antileukemic agents against Ph(+) leukemia cell lines, KU812, K-562, TCC-S, and TCC-Y. The cells were exposed to STI571 and to other agents simultaneously for 5 or 7 days. Cell growth inhibition was determined by MTT assay. The cytotoxic effects in combinations at the inhibitory concentration of 80% level were evaluated by the isobologram. STI571 produced synergistic effects with recombinant and natural alpha-interferons in 2 of 3 and 3 of 3 cell lines, respectively. STI571 produced additive effects with hydroxyurea, cytarabine, homoharringtonine, doxorubicin, and etoposide in all 4 cell lines. STI571 with 4-hydroperoxy-cyclophosphamide, methotrexate, or vincristine produced additive, antagonistic, and synergistic effects in 3 of 4 cell lines, respectively. These findings suggest that the simultaneous administration of STI571 with other agents except methotrexate would be advantageous for cytotoxic effects against Ph(+) leukemias. Among them, the simultaneous administration of STI571 and alpha-interferons or vincristine would be highly effective against Ph(+) leukemias and these combinations would be worthy of clinical trials. In contrast, the simultaneous administration of STI571 with methotrexate would have little therapeutic efficacy. Although there are gaps between in vitro studies and clinical trials, the present findings provide useful information for the establishment of clinical protocols involving STI571. (Blood. 2001;97:1999-2007)

Topics: Antineoplastic Agents; Apoptosis; Benzamides; Cytarabine; Dose-Response Relationship, Drug; Drug Interactions; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Enzyme Inhibitors; Fusion Proteins, bcr-abl; Harringtonines; Homoharringtonine; Humans; Hydroxyurea; Imatinib Mesylate; Interferon-alpha; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Methotrexate; Microbial Sensitivity Tests; Neoplasm Proteins; Neoplasms; Piperazines; Pyrimidines; Tumor Cells, Cultured; Vincristine

Homoharringtonine (HHT) is a novel plant alkaloid that produced a complete hematologic remission (CHR) in 72% of patients with late chronic phase chronic myelogenous leukemia (CML). Cytogenetic (CG) remissions were noted in 31%. In this study, six courses of HHT were administered to 90 patients with early chronic phase CML (< 1 year from diagnosis). Patients then received interferon-alpha (IFN-alpha) with a target dose of 5 MU/m2 daily. Results were compared with those in a prior group of patients treated with IFN-alpha-based therapy between 1982 and 1990. Ninety-two percent of patients achieved CHR with HHT; CG responses were observed in 60% and were major in 27%. Both CHR and CG response rates were significantly higher than those seen in historical control patients after 6 months of IFN-alpha therapy. After receiving HHT, patients required lower doses of IFN-alpha to maintain a CHR. The median dose delivered was 2.4 MU/m2. This reduction in IFN-alpha dose was associated with a lower incidence of myalgia and gastrointestinal (GI) disturbances than that seen in patients treated at the 5 MU/m2 dose. Overall, CG responses were seen in 66% of the patients who received HHT and IFN-alpha compared with 61% of the historical control patients. HHT is a very effective treatment of early chronic phase CML, and ongoing trials are investigating the simultaneous administration of HHT and IFN-alpha, as well as that of HHT and low-dose cytosine arabinoside in patients failing IFN-alpha therapy.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Granulocytes; Harringtonines; Hematopoietic Stem Cell Transplantation; Homoharringtonine; Humans; Interferon-alpha; Karyotyping; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukocyte Count; Middle Aged; Platelet Count; Remission Induction; Thrombocytopenia

Homoharringtonine (HHT) is a cephalotaxine alkaloid that showed clinical efficacy in the chronic phase of chronic myeloid leukemia (Ph1+CML). As a single agent, it resulted in effectively controlling leukocytosis and in producing sporadic karyotypic conversions; its clinical use in combination with interferon (IFN-alpha) for the treatment of CML could thus be considered. In this study we evaluated the growth inhibition and the induction of apoptosis determined by HHT alone and in combination with IFN-alpha and cytosine arabinoside (Ara-C) on normal and CML (both in chronic, CML-CP and in blastic phase; CML-BP) hematopoietic progenitors. HHT is able to determine a dose-dependent cell growth inhibition; evaluation of cytotoxic activity on semisolid cultures showed an activity significantly higher on CML-CP than on normal cells (P = 0.02 for HHT 50 ng/ml and P = 0.01 for HHT 200 ng/ml). HHT exerted a synergistic effect with IFN-alpha, Ara-C and IFN-alpha + Ara-C in inhibiting CML-CP colony growth; the same activity was demonstrated by the combination of HHT with Ara-C and by the triple combination, but not by HHT + IFN-alpha, on normal myeloid progenitors. The triple combination only was able to exert a synergistic effect in CML-BP. The induction of apoptosis resulted HHT dose-dependent in CML-CP and normals; at higher drug concentrations (100-200-1000 ng/ml), HHT induced a significant increase of apoptotic cells (for normals: P = 0.04, P = 0.02 and P = 0.04; for CML-CP: P = 0.01, P = 0.01 and P = 0.04, respectively); no significant changes were observed in CML-BP. In conclusion, the differences in cytotoxic effect and apoptosis induction observed, depending on the various phases of CML, add experimental evidence to the different clinical results between the chronic phase, where the clone is responsive to HHT, and the acute phase, where the drug is ineffective. The in vitro synergism of HHT with Ara-C and IFN-alpha in CML-CP suggests further evaluation in the clinical setting.

Topics: Adult; Antineoplastic Agents, Phytogenic; Apoptosis; Blast Crisis; Bone Marrow; Bone Marrow Cells; Cell Division; Cell Survival; Cells, Cultured; Colony-Forming Units Assay; Cytarabine; Female; Harringtonines; Hematopoietic Stem Cells; Homoharringtonine; Humans; Interferon-alpha; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male

Homoharringtonine (HHT) is a plant alkaloid with potent myelosuppressive activity and little toxicity when used in a continuous infusion schedule. The antileukemic efficacy of HHT has been shown in acute myeloid leukemia, but has not been investigated in chronic myelogenous leukemia (CML). Seventy-one patients with Philadelphia chromosome-positive (Ph+) CML in late chronic phase (time from diagnosis to therapy longer than 12 months) were treated with a continuous infusion of HHT at a daily dose of 2.5 mg/m2 for 14 days for remission induction and for 7 days every month for maintenance. The median number of courses given was 6 (range, 1 to 35) and 21 patients (30%) continue on treatment. Forty-two of 58 patients (72%) evaluable for hematologic response achieved a complete hematologic remission, and 9 (16%) had a partial hematologic remission. Twenty-two of 71 patients (31%) developed a cytogenetic response; it was major (Ph+ cells less than 35%) in 11 (15%) and complete (Ph+ cells 0%) in 5 (7%). Significant myelosuppression occurred in 39% of induction courses and 9% of maintenance courses. Fever or documented infection was present in 26% of induction courses and in only 8% of maintenance courses. Nonmyelosuppressive toxicity was minimal. Homoharringtonine produced hematologic remissions in the majority of patients with advanced chronic-phase CML. Cytogenetic response occurred in some patients without an association with myelosuppression, and these responses may be prolonged. Future studies investigating homoharringtonine in combination with other active agents in CML, such as interferon, are warranted.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Combined Modality Therapy; Diarrhea; Female; Harringtonines; Homoharringtonine; Humans; Immunologic Factors; Infections; Interferon-alpha; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Leukopenia; Male; Middle Aged; Remission Induction; Survival Rate; Thrombocytopenia; Treatment Outcome

The in vitro induced differentiation of a number of human leukemia cell lines by chemical inducers not only provides a valuable model system for the study on the mechanism of hematopoietic cell proliferation and differentiation at both cellular and molecular levels, but also reveals a new prospect in the treatment of leukemia. In order to find out the possibility of applying inducing agents to the patients with various types of leukemia, the bone marrow cells in primary culture from 50 patients with leukemia were tested for their inducibility in response to the inducers. Only M3 leukemia bone marrow cells can be markedly induced by retinoic acid to the myeloid terminal cells with positive NBT reduction while the cells of other types respond with uncertainty. TPA is able to cause a macrophage-like differentiation in bone marrow cells of all types of leukemia except M1. However, the leukemic cells of chronic myelogenous leukemia in lymphocytic blast crisis will lose response to TPA. The cultured bone marrow cells of acute lymphocytic leukemia respond neither to retinoic acid nor to TPA. Homoharringtonine, a chemotherapeutic drug used in the so-called HOAP regimen for acute nonlymphocytic leukemia, seems to possess the capability of inducing HL-60, the promyelocytic leukemia cell line, to NBT positive myeloid terminal cells, although the inducing effect is weaker than retinoic acid.

Topics: Adolescent; Adult; Aged; Bone Marrow; Child; Female; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tetradecanoylphorbol Acetate; Tretinoin; Tumor Cells, Cultured