Homoharringtonine

Kantarjian, Hagop M.; Talpaz, Moshe; Santini, Valeria; Murgo, Anthony J.; Cheson, Bruce D.; O’Brien, Susan

doi:10.1002/1097-0142(20010915)92:6<1591::aid-cncr1485>3.0.co;2-u

Cited by 168 publications

(56 citation statements)

References 42 publications

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“…Anticancer activity was originally observed in association with Chinese herbal medicine practices using extracts from the bark of species of the Chinese plum yew, Cephalotaxus (4). It was brought to the western world by the Earl of Harrington and the species name was designated Cephalotaxus harringtonii , from which the names of the pharmacologically active forms were derived.…”

Section: What Is Omacetaxine?mentioning

confidence: 99%

Omacetaxine: A Protein Translation Inhibitor for Treatment of Chronic Myelogenous Leukemia

Gandhi

Plunkett

Cortés

2014

Clinical Cancer Research

105

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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, TKIs) have revolutionized how CML is treated. While the majority of patients respond to these kinase inhibitors, a subset become resistant to these therapeutics. Synribo (omacetaxine mepesuccinate) was recently FDA approved for Philadelphia-positive CML either in chronic or accelerated phase whose disease failed two prior TKIs. With omacetaxine 1.25 mg/m2 twice daily for 14 days during induction and for 7 days during maintenance, a major cytogenetic response occurred in 20% of patients in chronic phase and major hematologic response in 27% of patients in 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 which 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.

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Section: What Is Omacetaxine?mentioning

confidence: 99%

Omacetaxine: A Protein Translation Inhibitor for Treatment of Chronic Myelogenous Leukemia

Gandhi

Plunkett

Cortés

2014

Clinical Cancer Research

105

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“…HHT and congeners cause the breakdown of polyribosomes to monosomes, the release of completed globin chains, and delayed inhibition of the initiation of protein synthesis without affecting chain elongation. HHT has been tested clinically in advanced breast cancer, acute myelogenous leukemia, myelodysplastic syndrome (MDS), and MDS evolving to acute myeloid leukemia [7][8][9][10][11]. Although the chemical synthesis of cephalotaxine and its esters has been reported, extraction from plants is still the major source of HHT [12,13].…”

Section: Introductionmentioning

confidence: 99%

Characterization of solvent induced crystalline and amorphous homoharringtonine

Kim

2009

Korean J. Chem. Eng.

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The morphologies of homoharringtonine were conveniently controlled by solvent treatment and the morphologies of homoharringtonine were characterized by XRD and SEM. Crystalline homoharringtonine was simply made by dissolving homoharringtonine in a special polar solvent containing a small amount of water (methanol/water= 98/2, v/v). On the other hand, amorphous homoharringtonine was made by dissolving homoharringtonine in relatively non-polar solvent (methylene chloride/methanol=98/2, v/v). Amorphous homoharringtonine, with a fine particle size, was obtained by dissolving in methylene chloride/methanol (98/2, v/v), following by spray drying. Also, residual solvents, methanol and methylene chloride, were easily removed to less than concentration limit in ICH (International Conference on Harmonisation) guidance by spray drying and successive drying in a vacuum oven. Amorphous homoharringtonine was more soluble in water than crystalline homoharringtonine, and the water content of amorphous homoharringtonine was less changeable than crystalline homoharringtonine at given humidity (95 RH%) during storage. This information is very useful for production and quality control of pharmaceuticals in the commercialization step.

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“…[98] For many years and in most cases using a racemic mixture, Chinese scientists identified harringtonine as active antineoplastic agent for the treatment of acute myelogenous leukemia (AML), myelodysplastic syndrome, acute promyelocytic leukemia, and intrathecal therapy for central nervous system leukemia. [99100101] The treatment therapy developed by Chinese produced increased survival of patients at reduced expenses. [102] The racemic mixture of harringtonine and homoharringtonine is regarded favorable agents to treat aged cancer patients due to their relative mild cytotoxicity with efficacy against leukemia of different kinds.…”

Section: Introductionmentioning

confidence: 99%

“…[103] Studies on the alkaloid in the 1980s and 1990s were mostly as a single agent, in combined with interferon-alpha, low-dose cytarabine, and with both in late and early chronic-phase chronic myelogenous leukemia (CML). [100101104105106] Similar to many anticancer alkaloids, development into a useful anticancer drug was hindered by difficult production of the alkaloid due to unreliable source supply, toxicity profile of original treatment schedules, large quantity of Cephalotaxus trees required, success of tyrosine kinase inhibitors (TKIs) in CML, and uncertainty in role of homoharringtonine to TKIs. [23107] Purified homoharringtonine showed efficacy against leukemias of various kinds including resistant ones to standard treatment and produced complete hematological remission in patients with late chronic-phase CML.…”

Section: Introductionmentioning

confidence: 99%

Anticancer alkaloids from trees: Development into drugs

Isah¹

2016

Phcog Rev

113

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Trees have made an enormous phytochemical contribution in anticancer drugs' development more than any other life form. The contributions include alkaloids that are biosynthesized in various ways and yield. Lead alkaloids isolated from the trees are taxol and camptothecins that currently have annual sales in billion dollars. Other important alkaloids isolated from these life forms include rohitukine, harringtonine, acronycine, thalicarpine, usambarensine, ellipticine, and matrines. Studies on their mechanism of action and target on the DNA and protein of cancerous cells aided the development of potent hemisynthesized congeners. The molecules and their congeners passed/are passing a long period of historical development before approved as antineoplastic drugs for cancer chemotherapy. Some of them did not find the application as anticancer drugs due to ineffectiveness in clinical trials; others are generating research interest in the antineoplastic activity at the present and have reached clinical trial stages. Potentials in antineoplastic molecules from trees are high and are hoped to be commensurate with cancer types afflicting human society in the future.

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Homoharringtonine

Cited by 168 publications

References 42 publications

Omacetaxine: A Protein Translation Inhibitor for Treatment of Chronic Myelogenous Leukemia

Omacetaxine: A Protein Translation Inhibitor for Treatment of Chronic Myelogenous Leukemia

Characterization of solvent induced crystalline and amorphous homoharringtonine

Anticancer alkaloids from trees: Development into drugs

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