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HOMOHARRINGTONINE (HHT)


RESEARCH

Homoharringtonine and leukemia

Homoharringtonine (HHT), first isolated from the Chinese evergreen Cephalotaxus harringtonia, has been demonstrated to have a broad antitumor activity in rodents and antileukemic effects in humans. It was found that HHT was metabolized to an acid product [HHTacid; 2'hydroxy2'(acetic acid)6'hydroxy6'methylheptanoyl cephalotaxine] when incubated with either human plasma or mouse plasma in vitro. Highpressure liquid chromatography and mass spectrometry were used to confirm the identity and quantify HHT and its metabolite, HHTacid. The HHT concentration inhibiting 50% of the growth of human leukemic HL60 cells was 20 ng/ml, while for HHTacid it was 14,500 ng/ml, indicating that the acid form was more than 700 times less cytotoxic than HHT. The lethal dose of HHT affecting 50%(LD50) of mice was 6.7 mg/kg, but HHTacid produced no apparent toxic effects at doses up to 280 mg/kg.
Ni D, Ho DH, Vijjeswarapu M, Felix E, Rhea PR & Newman RA. Metabolism of homoharringtonine, a cytotoxic component of the evergreen plant Cephalotaxus harringtonia. Journal of Experimental Therapeutics and Oncology Volume 3 Issue 1 Page 47 - January 2003

The response to remission induction in elderly patients with acute myeloid leukemia (AML) remains poor. patients were treated with the HA regimen consisting of homoharringtonine (2 mg/m2/day for 7 days) and cytarabine (Ara-C, 100 mg/m2/day for 7 days). The overall response rate was 56.5% with complete remission (CR) rate of 39.1% and partial remission of 17.4%. There was no early death in this cohort of patients. The estimated median overall survival (OS) time of all patients was (12.0 ± 3.0) months. The estimated OS time of the CR patients was 15 months. The estimated one-year OS rate of all patients treated with HA protocol was (49.3 ± 13.5) %. The estimated one-year OS rate of the CR patients was (62.5 ± 17.1) %.
Wang J, Lü S, Yang J, Song X, Chen L, Huang C, Hou J & Zhang W. A homoharringtonine-based induction regimen for the treatment of elderly patients with acute myeloid leukemia: a single center experience from China. Journal of Hematology & Oncology 2009, 2:32 doi:10.1186/1756-8722-2-32

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). 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.
O'Brien S, Kantarjian H, Keating M, Beran M, Koller C, Robertson LE, Hester J, Rios MB, Andreeff M & Talpaz M. Homoharringtonine therapy induces responses in patients with chronic myelogenous leukemia in late chronic phase. Blood. Volume 86, Issue 9, Pp.3322-6, 11/01/1995

The effect of HHT on the telomerase activity and apoptosis of human leukemia HL-60 cells. Telomerase activity of HL-60 cells was examined by the telomeric repeat amplification protocol (TRAP)--an enzyme-linked immunosorbent assay (ELISA). Apoptosis was analyzed by morphological observation, DNA agarose gel electrophoresis, flow cytometry (FCM), and TdT-mediated dUTP-biotin nick end labeling (TUNEL). After treatment with HHT at 5-500 microg/l for 48 hours, the level of telomerase activity in HL-60 cells decreased in a dose-and time-dependent manner. Simultaneously, HL-60 cells underwent apoptosis. In conclusion, our data suggest that HHT can inhibit the telomerase content of HL-60 cells effectively and induce apoptosis.
Xie WZ, Lin MF, Huang H, Cai Z. Homoharringtonine-induced apoptosis of human leukemia HL-60 cells is associated with down-regulation of telomerase. Am J Chin Med. 2006;34(2):233-44.

HHT 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.
Luo CY, Tang JY, Wang YP. Homoharringtonine: a new treatment option for myeloid leukemia. Hematology. 2004 Aug;9(4):259-70.

 
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