Harringtonine and Leukemia--Myeloid--Acute

Harringtonine (HT) is a naturally occurring alkaloid isolated from the plant genus Cephalotaxus. It possesses antileukemic activity and has been clinically utilized for the treatment of acute leukemia and lymphoma. Sodium periodate (NaIO

Topics: Alkaloids; Antibodies, Monoclonal; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cephalotaxus; Harringtonines; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Lymphoma; Periodic Acid

In this study, we investigated the effect of pre-treatment with demethylating agent decitabine on susceptibility to chemotherapeutic drugs in HL60/ADR, Kasumi-1 and primary AML cells. Cytotoxic effect was increased by decitabine through activation of p53 and inhibition of c-Myc, Survivin and Bcl-2. We demonstrated in clinic that combination of decitabine and HAA consisting of harringtonine, aclarubicin and cytarabine was effective and safe to treat patients with refractory, relapsed or high-risk AML. Decitabine prior to HAA regimen improved the first induction complete response rate, and significantly prolonged overall survival and disease-free survival in these patients compared with HAA alone. These findings support clinic protocols based on decitabine prior to chemotherapy to overcome resistance and improve therapeutic efficacy in AML patients.

Topics: Aclarubicin; Adolescent; Adult; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Cell Line, Tumor; Cytarabine; Decitabine; Disease-Free Survival; Female; Harringtonines; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Neoplasm Recurrence, Local; Treatment Outcome; Young Adult

To analyze the prognosis and risk factors of acute nonlymphocytic leukemia (ANLL), 94 patients with acute nonlymphocytic leukemia were enrolled in this study, while survival rate and risk factors of prognosis were analyzed. The results indicated that the complete remission (CR) ratio was 51.1%. Overall survival and event-free survival rates of month 6, 12, 18, 24 were 68.6%, 55.8%, 53.8%, 46.4%, 21.3% and 57.9%, 38.6%, 33.3%, 31.6%, 0% respectively. The factors such as age<40 years, WBC<10.0x10(9)/L before chemotherapy, WBC in the period of bone marrow suppression<1.0x10(9)/L, chemotherapy within 1 month after occurrence of leukemia, blood transfusion before chemotherapy of APL had favourable influence on remission and survival rates of ANLL patients. CR1, the time to get CR, length of CR and relapse significantly correlated with prognosis (p<0.05). It is concluded that the individualized therapy concerning the risk factors should be applied to ANLL patients for improving the remission, survival rate and prognosis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Female; Harringtonines; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Prognosis; Tretinoin; Young Adult

The mechanism of refractory leukemia is very complex. Recent studies have shown that overexpression of vascular endothelial growth factor (VEGF) was detected in bone marrow from acute myeloid leukemia (AML) patients, suggesting it may play an important role in AML. However,the effect of VEGF in the development of refractory leukemia is not clear. The current study was designed to explore the effect of overexpression of VEGF on the abnormal proliferation and harringtonine-induced apoptosis of HL-60 cells and to observe VEGF expression in the progression of refractory AML.. HL-60 cells were transfected with the VEGF(165)cDNA sense vector (HL-60/VEGF(165)) and with the pcDNA3.1-vector (HL-60/neo) as the control using lipofectamine. Reverse transcription-polymerase chain reaction (RT-PCR) was used to determine VEGF mRNA. VEGF concentrations in the cell cultural supernatant were determined by enzyme linked immunosorbent assay (ELISA). Cell proliferation was determined by MTT and colony forming assay in vitro.Flow cytometric Annexin-V-FITC/PI dual labeling technique was performed to observe the effect of VEGF(165) cDNA transfection on harringtonine-induced apoptosis of HL-60 cells. ELISA was used to detect VEGF concentrations in the plasma from refractory and non-refractory AML patient.. The mean VEGF concentration in the cell cultural supernatant of HL-60/VEGF(165) cells (399.07+/-12.45 ng/L) was 2-folds higher than that in HL-60/neo cells (184.45+/-10.53 ng/L)(P< 0.01). The VEGF(165)cDNA sense vector transfected HL-60 exhibited a 2-fold increase in VEGF secretion. The growth rate of HL-60/VEGF(165) cells was significantly higher than those of the controls, and colony formation capacity of HL-60/VEGF(165) increased significantly(P< 0.05);the colony numbers were (157.00+/-17.00)/500 cells and (110+/-12.90)/500 cells for HL-60/VEGF(165) and HL-60/neo, respectively. HL-60/VEGF(165) had less apoptotic cells than HL-60/neo in the same culture condition. High expression of VEGF could reduce the harringtonine-induced apoptosis of HL-60 cells. Refractory AML patients had higher mean plasma VEGF levels (558.90+/-271.25 ng/L) than non-refractory patients(392.54+/-217.82 ng/L), and significant difference was observed between them (P< 0.05).. VEGF expression in refractory AML patients is higher than that in non-refractory AML patients. VEGF plays an important role in the abnormal proliferation and apoptosis of AML cells. High expression of VEGF could reduce the harringtonine- induced apoptosis of HL-60 cells.

Topics: Adult; Apoptosis; Disease Progression; Female; Harringtonines; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Transfection; Vascular Endothelial Growth Factor A

To study sensitivity of drug resistance indexes and resistance manner in acute myeloid leukemia (AML), MTT drug sensitivity, growth types of CFU-L in vitro, Bcl-2 antigen and Bcl-2/Bax ratio and intracellular fluorescence intensity of daunorubicin (DNR) were determined. In 62 cases of AML, the positive coincidence rate was 73% with MTT test and the negative coincidence rate was 70%. In 3 commonly used drugs, if one drug showed sensitivity, the coincidence remission rate reached 71%. In 51 cases of AML, there were 31 patients in the group of complete remission (CR), in which CFU-L of 29 patients showed independent growth. CFU-L of 2 patients showed no growth. However, there were 20 patients in the group of non-remission (NR), in which CFU-L of 14 patients showed independent growth. CFU-L of 6 patients showed non-growth pattern. Statistical analysis showed significant difference (P < 0.05). In 32 cases of AML, the expression rate of Bcl-2 was 59.55% +/- 19.56% in drug-sensitive group, and one was 77.36% +/- 11.91% in drug-resistant group, respectively (P < 0.05). At the same time, the ratio of Bcl-2/Bax was 7.50 +/- 5.04 in drug-sensitive group and one was 14.32 +/- 8.99 in drug-resistant group, respectively (P < 0.05). In 15 case of clinically drug-resistant AML, the fluorescence histogram of DNR showed left-shift of main peak (LSMP) in 12 patients. They were diagnosed as classical drug resistance. Meanwhile, 1 patient showed right-shift of main peak (RSMP) in 3 patients. They were diagnosed as re-growth drug resistance. It is concluded that MTT and CFU-L might be used for prediction of drug sensitivity or resistance when patients were on treatment. Bcl-2 and ratio of Bcl-2/Bax might be associated with the prognosis. DNR histogram could be employed for identify the pattern drug resistance. The strength and weakness of these techniques were discussed.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; bcl-2-Associated X Protein; Cell Division; Cytarabine; Daunorubicin; Drug Resistance, Neoplasm; Harringtonines; Humans; Leukemia, Myeloid, Acute; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Tumor Stem Cell Assay

Harringtonine was discovered as an anticancer agent in China. It has been shown to be effective against myeloid leukemia. In this report, we have demonstrated that harringtonine inhibited the growth of human myeloid leukemia cells in vitro at low concentrations. Together with the clinical data in which 28% of the patients could be induced into complete remission only by harringtonine, this agent may be used as a first choice of antileukemia agents in the treatment of myeloid leukemia. The mechanism of the antitumor action of harringtonine is considered to be an effect on protein synthesis and is characterized by breakdown of polysomes to monosomes. The mechanism of action appears to be different from those of the other antileukemia agents, such as cyclophosphamide, daunorubicin, vincristine, or cytosine arabinoside. Harringtonine could be added to the other anti-leukemia agents used routinely in treatment of leukemia, and the combination of harringtonine with the other agents is expected to improve the therapy of myeloid leukemia.

Topics: Alkaloids; Antineoplastic Agents; Cell Division; Harringtonines; Humans; Leukemia, Myeloid, Acute; Neoplastic Stem Cells; Tumor Cells, Cultured

We evaluate the efficacy of rifampin combined with low dose harringtonine in acute leukemia (Group A, acute lymphocytic leukemia (ALL) 6 cases and acute non-lymphocytic leukemia (ANLL) 8 cases) in comparison with the patients treated with low dose harringtonine only (Group B, 8 ALL, and 5 ANLL). The complete remission (CR) rate in Groups A and B was 64.3% and 23.1%, while the median CR duration, 17 months and 8 months respectively, Group A was more effective than Group B. We also consider that rifampin and low dose harringtonine are more applicable for treatment of ANLL patients without peripheral leukocytosis and those complicated with infection.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Female; Harringtonines; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Rifampin