Omacetaxine mepesuccinate--a semisynthetic formulation of the natural antitumoral alkaloid homoharringtonine, for chronic myelocytic leukemia and other myeloid malignancies.
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.
Quintás-Cardama
Alfonso
A
Alfonso Quintás-Cardama, MD Anderson Cancer Center, Department of Leukemia, Unit 428, 1515 Holcombe Boulevard, Houston, TX 77030, USA. aquintas@mdanderson.org
Cortes
Jorge
J
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D006248:Harringtonines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077863:Homoharringtonine; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000473:pathology; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000473:pathology; D010330:Patents as Topic; D013329:Structure-Activity Relationship; D016896:Treatment Outcome
D000972:Antineoplastic Agents, Phytogenic; D006248:Harringtonines; D000077863:Homoharringtonine