homoharringtonine and Acute-Disease

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

To determine the maximum-tolerated dose (MTD), dose-limiting toxicities and pharmacokinetic of semisynthetic homoharringtonine (ssHHT), given as a twice daily subcutaneous (s.c.) injections for 9 days, in patients with advanced acute leukaemia, 18 patients with advanced acute myeloid leukaemia were included in this sequential Bayesian phase I dose-finding trial. A starting dose of 0.5 mg m(-2) day(-1) was explored with subsequent dose escalations of 1, 3, 5 and 6 mg m(-2) day(-1). Myelosuppression was constant. The MTD was estimated as the dose level of 5 mg m(-2) day(-1) for 9 consecutive days by s.c. route. Dose-limiting toxicities were hyperglycaemia with hyperosmolar coma at 3 mg m(-2), and (i) one anasarque and haematemesis, (ii) one life-threatening pulmonary aspergillosis, (iii) one skin rash and (iv) one scalp pain at dose level of 5 mg m(-2) day(-1). The mean half-life of ssHHT was 11.01+/-3.4 h, the volume of distribution at steady state was 2+/-1.4 l kg(-1) and the plasma clearance was 11.6+/-10.4 l h(-1). Eleven of the 12 patients with circulating leukaemic cells had blood blast clearance, two achieved complete remission and one with blast crisis of CMML returned in chronic phase. The recommended daily dose of ssHHT on the 9-day schedule is 5 mg m(-2) day(-1).

Topics: Acute Disease; Adult; Aged; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Harringtonines; Homoharringtonine; Humans; Injections, Subcutaneous; Leukemia, Myeloid; Male; Maximum Tolerated Dose; Middle Aged; Remission Induction; Survival Rate; Treatment Outcome

As phospho-eIF4E (p-eIF4E), unlike total eIF4E (t-eIF4E) essential for normal cells, is specifically required by cancer cells, it is an attractive, yet unrealized, target for anti-tumor intervention. Here we identify a small molecule, homoharringtonine (HHT), that antagonizes p-eIF4E function and eradicates acute myeloid leukemia (AML) expressing high level of p-eIF4E in vitro and in vivo. HHT selectively reduces p-eIF4E levels of leukemia cells without affecting t-eIF4E. HHT targets the phosphorylated serine 209 residue of p-eIF4E and induces p-eIF4E oligomerization, which enhances its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9, resulting in proteasome-dependent degradation of p-eIF4E via SUMO2/3-mediated SUMOylation. These results suggest that the phosphorylated serine 209 residue of p-eIF4E might be a potential target for developing small molecule-based new therapies for leukemia.

Topics: Acute Disease; Animals; Antineoplastic Agents, Phytogenic; Blotting, Western; Cell Line, Tumor; Dose-Response Relationship, Drug; Eukaryotic Initiation Factor-4E; Harringtonines; Homoharringtonine; Humans; Interleukin Receptor Common gamma Subunit; Leukemia, Myeloid; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Molecular Structure; Phosphorylation; Proteasome Endopeptidase Complex; Protein Multimerization; Proteolysis; Serine; Small Ubiquitin-Related Modifier Proteins; Sumoylation; Tumor Cells, Cultured; Ubiquitins; Xenograft Model Antitumor Assays

Glivec was approved by Food & Drug Administration (FDA) in May 2001 as a gene target drug for treatment of chronic myeloid leukemia (CML) and showed a good curative effect for patients with chronic myeloid leukemia in chronic phase. But its effectiveness was poor in patients with CML blast phase treated with Glivec alone. Glivec was reported having synergetic effect with other chemical agents in vitro, but there is few report in clinical combined application. In this paper, we analyzed effectiveness of Glivec in combination with homoharringtonine (HHT) and cytarabine (Ara-C) for patients with Ph chromosome positive acute leukemia (Ph(+)-AL), and investigated patients' tolerance to side effects of this trial.. A total of 20 patients (16 males and 4 females, median age was 43 years) were eligible. Blasts in peripheral blood (PB) or bone marrow (BM) were both more than 30%, bcr/abl fusion genes were detected positive in 90% cells by analysis of karyotype or fluorescence in situ hybridization (FISH). Five patients showed t(9;22) and other 15 patients showed more complicated chromosome abnormality. Of these 20 patients, 17 patients developed Ph(+)-ANLL from CML, 1 case developed Ph(+)-ALL, and other 2 cases were primary Ph(+)-ALL. The median interval from diagnosis to Glivec treatment was 4 months. Eighteen of 20 patients received different chemotherapy regimens for 2-4 treatment cycles, but no one reached hematological complete remission (HCR). All patients were given oral Glivec daily at the doses of 0.3-0.6 g in a median treatment time of 2.5 months (range, 1-6.5 months). Ph(+)-ANLL patients were infused with HHT over 6-24 hours daily at the doses of 1-2 mg intravenously and Ara-C 30-50 mg daily subcutaneously for 10-14 days; 3 patients with Ph(+)-ALL received HOAP or DOP combination treatment regimens (One cycle consists of HA with the same dosage described above for Ph(+)-ANLL patients for 7 days, daunorubicin at the dose of 40 mg/d intravenously for 3 days, vincristine at the dose of 2 mg/wk for two weeks, and prednisone at the doses of 60-80 mg/d for 14 days). Median treatment cycle was 2 (range, 1-3). The dosage of Glivec could be reduced or treatment was suspended when bone marrow inhibition happened. G-CSF was used when necessary. The curative effect was evaluated by international hematology and cytogenetics standards, in which bone marrow was examined every chemotherapy cycle and chromosome was analyzed 3 months later.. Among the 20 patients receiving Glivec, 40% achieved HCR, and 25% achieved hematological partial remission (HPR), but only 15% patients approached a partial cytogenetic remission and no cytogenetic responses were found in other 85% patients. White blood cells (WBC) in peripheral blood reduced from 41+/-31 x 10(9)/L to normal level within 1 week. The blasts decreased from (50+/-30)% to(1.9+/-2.9)% (P< 0.001) in median time of 21.0+/-16.8 days. Three patients with high fever recovered normal temperature after 3 days treatment. When follow-up median time at 8 months, the total survival rate reduced to 40%, the rate of death and lost follow-up number of patients added to 60%.. Regimen of Glivec in combination with HA could increase chemotherapy effect for the patients with Ph(+)-AL, prolong their life time and the side-effects were tolerable.

Topics: Acute Disease; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Female; Follow-Up Studies; Harringtonines; Homoharringtonine; Humans; Imatinib Mesylate; Leukemia; Male; Middle Aged; Philadelphia Chromosome; Piperazines; Pyrimidines

Homoharringtonine (HHT) has been reported to induce hyperglycemia. This report describes a study conducted to characterize the effect of HHT on insulin production and action. Our data indicate that HHT-induced hyperglycemia results from the development of insulin resistance. A review of the literature suggests that patients receiving HHT continuous infusions of 5 mg/m2/d or greater and patients greater than 10 years of age may be at increased risk for the development of HHT-induced hyperglycemia. We recommend that patients with these risk factors, as well as diabetic patients and patients concurrently receiving asparaginase and/or prednisone, have their blood glucoses routinely monitored for hyperglycemia.

Topics: Acute Disease; Alkaloids; Antineoplastic Agents, Phytogenic; Blood Glucose; C-Peptide; Drug Evaluation; Harringtonines; Homoharringtonine; Humans; Hyperglycemia; Infusions, Intravenous; Insulin; Insulin Resistance; Leukemia; Risk Factors; Time Factors

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cells, Cultured; Female; Harringtonines; Homoharringtonine; Humans; Leukemia; Male; Middle Aged; Retrospective Studies; Tumor Stem Cell Assay

Homoharringtonine (HHT) is a new plant alkaloid originally isolated in the People's Republic of China. Preliminary studies have suggested antitumor activity in several neoplastic diseases. We treated 49 patients with relapsed or resistant acute leukemia with escalating doses of homoharringtonine administered by continuous infusion. Three dose levels were examined: 5 mg/m2 for seven days, 7 mg/m2 for seven days, and 5 mg/m2 for nine days. Of 28 patients with acute nonlymphoblastic leukemia who received cumulative doses of 45 to 49 mg/m2, seven patients (25%) achieved complete remission. Four of these remissions occurred in a subset of ten patients previously resistant to two or more induction attempts with conventional chemotherapy. There were no remissions in three patients with secondary leukemia or in seven patients with acute lymphoblastic leukemia. Reversible hypotension, fluid retention, diarrhea, and tumor lysis syndrome were the major toxic effects of this treatment. Our results indicate that homoharringtonine is an effective new drug for the treatment of acute nonlymphoblastic leukemia and that this drug does not share cross-resistance with conventional antileukemic agents. The recommended dose is 5 mg/m2/d administered by continuous infusion for nine days.

Topics: Acute Disease; Adolescent; Adult; Aged; Alkaloids; Antineoplastic Agents; Bone Marrow; Bone Marrow Transplantation; Drug Evaluation; Harringtonines; Homoharringtonine; Humans; Hyperglycemia; Hypotension; Infusions, Parenteral; Leukemia; Leukocyte Count; Middle Aged; Platelet Count

Topics: Acute Disease; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Female; Harringtonines; Homoharringtonine; Humans; Leukemia; Lymphocytes; Male; Middle Aged; Sister Chromatid Exchange

Topics: Acute Disease; Adolescent; Alkaloids; Antineoplastic Agents; Child; Child, Preschool; Drug Therapy, Combination; Female; Harringtonines; Homoharringtonine; Humans; Leukemia; Male; Prednisone; Vincristine

Topics: Acute Disease; Adolescent; Adult; Antineoplastic Agents; Child; Cytarabine; Drug Therapy, Combination; Female; Harringtonines; Homoharringtonine; Humans; Leukemia; Male; Medicine, Chinese Traditional; Middle Aged; Prednisone; Vincristine