homoharringtonine and Leukemia--Promyelocytic--Acute

Since the introduction of all-trans-retinoic acid, the use of this molecularly targeted treatment in combination with anthracycline-based chemotherapy has completely changed the prognosis of acute promyelocytic leukemia (APL) turning it into the most curable acute myeloid leukemia. Also, the use of risk-adapted protocols has optimized the drug combination and the most appropriate dose intensity for each subset of patients classified according to both risk of relapse and vulnerability to drug toxicity. Recent developments have included the investigation of the role of arsenic trioxide (ATO) as front-line treatment after its success in relapsed APL, both to minimize or even omit the use of cytotoxic agents and to reinforce the conventional chemotherapy-based approach. In the present chapter we will address the achievements of conventional treatment with ATRA and chemotherapy, as well as the opportunity to cure more patients with modifications of this therapeutic backbone with the addition of ATO in any phase of treatment.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Clinical Trials as Topic; Consolidation Chemotherapy; Daunorubicin; Harringtonines; Homoharringtonine; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Maintenance Chemotherapy; Mercaptopurine; Methotrexate; Mitoxantrone; Multicenter Studies as Topic; Oxides; Remission Induction; Tretinoin

Homoharringtonine (HHT) is commonly used for the treatment of Chinese adult AML, and all-trans retinoic acid (ATRA) has been verified in acute promyelocytic leukemia (APL). However, the efficacy and safety of HHT-based induction therapy have not been confirmed for childhood AML, and ATRA-based treatment has not been evaluated among patients with non-APL AML.. This open-label, multicenter, randomized Chinese Children's Leukemia Group-AML 2015 study was performed across 35 centers in China. Patients with newly diagnosed childhood AML were first randomly assigned to receive an HHT-based (H arm) or etoposide-based (E arm) induction regimen and then randomly allocated to receive cytarabine-based (AC arm) or ATRA-based (AT arm) maintenance therapy. The primary end points were the complete remission (CR) rate after induction therapy, and the secondary end points were the overall survival (OS) and event-free survival (EFS) at 3 years.. We enrolled 1,258 patients, of whom 1,253 were included in the intent-to-treat analysis. The overall CR rate was significantly higher in the H arm than in the E arm (79.9%. HHT is an alternative combination regimen for childhood AML. The effects of ATRA-based maintenance are comparable with those of cytarabine-based maintenance therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Cytarabine; East Asian People; Homoharringtonine; Humans; Leukemia, Promyelocytic, Acute; Multicenter Studies as Topic; Remission Induction; Survival Rate; Treatment Outcome; Tretinoin

To compare the efficacy and toxicities of combining homoharringtonine (HHT)±daunorubicin (DNR) with all-trans-retinoic acid (ATRA) based therapy and DNR plus ATRA based therapy in newly diagnosed low/intermediate risk acute promyelocytic leukemia (APL).. A total of 96 newly diagnosed patients with APL were randomized to HHT group, DNR group and HHT+ DNR group prospectively. The complete remission (CR) rate, the overall survival (OS) and event-free survival (EFS) of three groups were analyzed.. There were 31 patients in HHT group, 33 patients in DNR group and 32 patients in HHT+ DNR group. The baseline characteristics of three groups were similar. No patient died during induction therapy. The morphologic CR rate was 100.0%. The median time to peak WBC counts in HHT+DNR group (4 days, range: 1-23 days) was significantly shorter than that in HHT group (9 days, range: 1-27 days) (P=0.008) and DNR group (7 days, range: 1-27 days) (P=0.240). There was no difference among three groups about the incidence of differentiation syndrome, the median interval to achieve CR, peak WBC counts and transfusions (P >0.05). All patients achieved complete molecular remission (CMR) during consolidation therapy. The interval to achieve CMR was no significantly difference among three groups (P >0.05). The 3-year OS rates for HHT group, DNR group and HHT+DNR group were 95.0%, 100.0% and 91.0%, respectively (P=0.595). The 3-year EFS rates for three groups were 93.0%, 90.0% and 85.0% (P=0.382). No difference was found in the incidence of adverse events among three groups (P >0.05).. Similar to DNR plus ATRA based therapy, HHT plus ATRA based induction and consolidation therapy should be one of highly-efficient treatment options for newly diagnosed APL. Clinical trial registration Chinese Clinical Trial Registry, ChiCTR-TRC-12002628.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Daunorubicin; Disease-Free Survival; Harringtonines; Homoharringtonine; Humans; Incidence; Leukemia, Promyelocytic, Acute; Leukocyte Count; Neoadjuvant Therapy; Platelet Transfusion; Prospective Studies; Remission Induction; Survival Rate; Treatment Outcome; Tretinoin

To study the clinical outcome, adverse effect and treatment cost of homoharringtonine (HHT) in combination with all-trans retinoic acid (ATRA) and arsenic trioxide (AS2O3) for newly diagnosed with patients acute promyelocytic leukemia (APL).. Clinical data of treatment of newly diagnosed patients with APL in experimental group (HHT + ATRA + AS2O3, n = 14) and control group \\[Idarubicin (IDA) + ATRA + AS2O3, n = 21\\] were analyzed retrospectively. The therapeutic effects, side effects and costs during induction therapy were compared between the two groups.. (1) The complete remission (CR) rate were 92.9% (13/14) and 95.2% (20/21) in experimental group and control group, respectively. The time to achieve CR were (28.1 ± 3.8) and (31.7 ± 4.2) days, respectively (P > 0.05). The negative rate of PML-RARα fusion gene at the time of CR were 76.9% (10/13) and 75.0% (15/20), respectively, and that in CR patient at the end of the first cycle treatment were 100.0% (13/13) and 95.0% (19/20), respectively (P > 0.05). (2) 5-year overall survival (OS) rate were (92.6 ± 0.6)% and (89.9 ± 0.5)%, respectively (P > 0.05), 5-year disease free survival (DFS) rate were 100.0% and (86.8 ± 0.6)%, respectively (P > 0.05). (3) During induction therapy, the incidence of infection in experimental and control group were 23.1% (3/13), 60.0% (12/20), respectively (P < 0.05). The amount of platelet transfusion were (54.7 ± 29.6) and (76.5 ± 25.6) units, respectively (P > 0.05), and that of fresh frozen plasma were (1157.1 ± 238.4) and (1423.5 ± 324.6) ml, respectively (P > 0.05). The total medical costs (excluding HHT and IDA) in experimental and control group were (36074.9 ± 1245.6) and (50564.5 ± 3658.4)CNY, respectively (P < 0.05).. HHT in combination with ATRA and AS2O3 regimen for newly diagnosed APL has a better efficacy, a higher long-term survival rate, and a lower costs, which is one of the reasonable choice.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Female; Harringtonines; Homoharringtonine; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oxides; Retrospective Studies; Treatment Outcome; Tretinoin

Topics: Homoharringtonine; Humans; Leukemia, Promyelocytic, Acute; Ligands; Oncogene Proteins, Fusion; Protein Domains; Retinoic Acid Receptor alpha; Tretinoin

Harringtonine (HT), produced from

Topics: Esters; Harringtonines; HeLa Cells; HL-60 Cells; Humans; Leukemia, Promyelocytic, 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

Homoharringtonine (HHT), a natural plant alkaloid derived from Cephalotaxus, has demonstrated to have a broad antitumor activity and efficacy in treating human chronic myeloid leukemia. An alternative source is required to substitute for the slow-growing and scarce Cephalotaxus to meet the increasing demand of the drug market. The objective of this study was to screen HHT-producing endophytic fungi from Cephalotaxus hainanensis Li. By screening 213 fungal isolates obtained from the bark parts of Cephalotaxus hainanensis Li, one isolate was found to be capable of biosynthesizing HHT. The fungus was identified as Alternaria tenuissima by morphological characteristics and internal transcribed spacer (ITS) sequence analysis and was named as CH1307. HHT obtained from CH1307 was analyzed through the HPLC and LC-MS/MS and NMR spectroscopy. The extract of the fermentation broth of CH1307 showed antiproliferative activities against K562 (chronic myelocytic leukemia), NB4 (acute promyelocytic leukemia), and HL-60 (promyelocytic leukemia) human cancer cell lines with IC50 values of 67.25 ± 4.26, 65.02 ± 4.75, and 99.23 ± 4.26 μg/mL, respectively. The findings suggest that HHT-producing endophytic fungus, Alternaria tenuissima CH1307 might provide a promising source for the research and application of HHT.

Topics: Alkaloids; Alternaria; Antineoplastic Agents; Cell Line, Tumor; Cephalotaxus; Drug Screening Assays, Antitumor; Endophytes; Fermentation; Harringtonines; HL-60 Cells; Homoharringtonine; Humans; K562 Cells; Leukemia, Promyelocytic, Acute

We conducted a retrospective study to evaluate the efficacy of combining homoharringtonine (HHT) with all-trans-retinoic acid (ATRA)-based induction therapy, followed by three courses of consolidation chemotherapy and 2-year sequential maintenance therapy in acute promyelocytic leukemia (APL). Fifty-three patients were enrolled in the study. The complete remission (CR) rate was 100 %. No patient died during induction therapy. The 9-year event-free survival (EFS) and 9-year overall survival (OS) for all patients were 79.0 and 83.0 %, respectively. Outcome estimates according to the body mass index (BMI) were carried out. Twenty-three (43.4 %) were underweight/normal (BMI < 23.0 kg/m(2)), whereas 30 patients (56.6 %) were overweight/obese (BMI ≥ 23.0 kg/m(2)). Underweight/normal-weight patients had a 9-year OS of 100 %, compared with 73.0 % for overweight/obese patients (P = 0.044). These results indicate that HHT plus ATRA-based induction and consolidation therapy may be a highly efficacious treatment option for newly diagnosed APL. Increased BMI had an adverse prognostic impact in APL.

Topics: Adolescent; Adult; Antineoplastic Agents; Body Mass Index; Consolidation Chemotherapy; Disease-Free Survival; Female; Follow-Up Studies; Harringtonines; Homoharringtonine; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Retrospective Studies; Tretinoin; Young Adult

We evaluated the efficacy of low-dose all-trans retinoic acid (ATRA) plus minimal chemotherapy for induction in newly diagnosed acute promyelocytic leukaemia (APL). Furthermore, we compared its long-term outcome with or without the addition of intravenous arsenic trioxide (ATO) in post-remission therapy. From January 2004 to September 2011, a total of 109 patients with a median age of 41 years (range 14-73) were enrolled in the study. Two arms were assigned according to post-remission protocols: ATO group cases were subsequently treated with intravenous ATO, standard chemotherapy, and ATRA. No-ATO group cases were subsequently treated with chemotherapy and ATRA only. Patients were monitored of minimal residual disease (MRD) by reverse-transcriptase polymerase chain reaction. The haematologic complete remission (CR) rate was 96.3%. The early death rate was 0.9%. At a median follow-up of 49 months (range 8-102 months), the Kaplan-Meier estimates of 5-year relapse-free survival were significantly better for patients in the ATO group than in the no-ATO group, 94.4% vs 54.8% (p = 0.0001), and the 5-year overall survival rate was 95.7% vs 64.1%, in the two groups (p = 0.003). Our data show that low-dose ATRA plus minimal chemotherapy exhibits efficacy in induction therapy for untreated APL and suggest that the addition of ATO to post-remission therapy significantly improves the long-term outcome.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; China; Consolidation Chemotherapy; Cytarabine; Daunorubicin; Dexamethasone; Drug Evaluation; Female; Harringtonines; Homoharringtonine; Humans; Idarubicin; Infusions, Intravenous; Kaplan-Meier Estimate; Leukemia, Promyelocytic, Acute; Male; Methotrexate; Middle Aged; Neoplasm, Residual; Oncogene Proteins, Fusion; Oxides; Recurrence; Remission Induction; Retrospective Studies; Salvage Therapy; Treatment Outcome; Tretinoin; Young Adult

To assess complete remission (CR), the overall survival (OS), event-free survival (EFS) and adverse events of newly diagnosed acute promyelocytic leukemia (APL) with homoharringtonine (HHT) plus ATRA, to evaluate the therapeutic effect by comparing HHT plus ATRA with daunorubicin plus ATRA as induction regimen (HA with DA as post-remission regimen).. 115 APL patients (54 in HHT group, 61 in DNR group) after long-term follow-up were enrolled in the analyses of clinical feature, chromosome karyotype, molecular biology, OS and EFS.. The overall CR of 115 patients was 100%, the median interval to achieve hematological CR was 32 (22 - 43) days, the overall median OS was within 0.23 - 77.34 months, median EFS was within 0.23 - 77.34 months. 3-year OS rate was 93%, 5-year OS rate 93%, 3-year EFS rate 85% and 5-year RFS rate 75% respectively. Converting to PML-RARα PCR-negative after the induction therapy in the HHT and DNR group was 31.3% and 15.5% respectively, at the end of 1 consolidation course was 68.6% and 77.6% respectively, while the remaining 4 patients tested PML-RARα PCR-negative at the end of 2 consolidation courses in the DNR group. While both groups obtained the identical molecular biology relapse rate (9.8% and 8.6%, respectively). Survival analysis indicated that no significant difference was found on OS and EFS between the HHT group and the DNR group (P = 0.206 and 0.506). 5-year OS rate was 87% for the HHT group while 98% for the DNR group, 5-years EFS rate was 80% for the HHT group while 71% for the DNR group. And the risk group was not the factor affecting OS and EFS (P = 0.615 and 0.416). Grade 2 fever in the HHT group was less than in the DNR group during induction therapy. And no difference was found in terms of liver dysfunction, renal dysfunction, cardiac dysfunction, and hematologic toxicity between two groups.. Our study demonstrated comparable therapeutic effect of HHT or DNR on APL. HHT was also well tolerated and didn't cause serious adverse events.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Harringtonines; Homoharringtonine; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Prognosis; Treatment Outcome; Tretinoin; Young Adult

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.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Clinical Trials as Topic; Drug Evaluation, Preclinical; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Myelodysplastic Syndromes; Patents as Topic; Structure-Activity Relationship; Treatment Outcome

Semisynthetic homoharringtonine (ssHHT) is now being evaluated in phase II clinical trials for the treatment of chronic myelogenous leukemia and acute myelogenous leukemia patients. Here, we examined the mechanism of the apoptosis induced by ssHHT in myeloid leukemia cells. First, we have shown that ssHHT induces apoptosis in HL60 and HL60/MRP cell lines in a time- and dose-dependent manner, and independently of the expression of Bax. The decrease of mitochondrial membrane potential and the release of cytochrome c were observed in the apoptotic cells induced by ssHHT. To unveil the relationship between ssHHT and the mitochondrial disruption, we have shown that ssHHT decreased myeloid cell leukemia-1 (Mcl-1) expression and induced Bcl-2 cleavage in HL60 and HL60/MRP cell lines. The Bcl-2 cleavage could be inhibited by the Z-VAD.fmk caspase inhibitor. However, Mcl-1 turnover was very rapid and occurred before caspase activation. The Mcl-1 turnover was only induced by ssHHT and cycloheximide, but not by daunorubicin and cytosine arabinoside, and could be restored by proteasome inhibitors. Second, we confirmed that ssHHT rapidly induced massive apoptosis in acute myelogenous leukemia patient cells. We have also confirmed the release of cytochrome c and a rapid turnover of Mcl-1 in these patient cells, taking place only in apoptotic cells induced by ssHHT but not in cells undergoing spontaneous apoptosis. Finally, we have shown that ssHHT inhibits protein synthesis in both cell line and patient cells. We suggest that the inhibition of protein synthesis and resulting Mcl-1 turnover play a key role in the apoptosis induced by ssHHT. Our results encourage further clinical trials for the use of ssHHT in acute myelogenous leukemia.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; Caspase Inhibitors; Caspases; Cytarabine; Cytochromes a; Cytochromes c; Daunorubicin; Down-Regulation; Harringtonines; HL-60 Cells; Homoharringtonine; Humans; Leukemia, Promyelocytic, Acute; Membrane Potentials; Mitochondria; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins; Proteasome Inhibitors; Protein Biosynthesis; Protein Synthesis Inhibitors; Proto-Oncogene Proteins c-bcl-2

To explore the myelo-protection effect of mdr1 transfected cord blood cells (CBMNCs) graft against high-dose homoharringtonine leukemia-bearing severe combined immunodeficient (SCID) mice model.. Multidrug resistant (mdr1)gene was transferred into CBMNCs by a retrovirus vector, containing full-length cDNA of human mdr1 gene. CBMNCs and high-titer retrovirus supernatant were cocultured with cytokine combinations for 5 - 6 days. The SCID mouse models bearing human HL-60 cell leukemia were divided into three groups. Group A received tail vein injection of 2 x 10(6) mdr1 gene transduced CBMNCs at day 1 and 3, groups B and C 2 x 10(6) un-transduced CBMNCs and same volume of normal saline, respectively. The 3 groups of the mouse model were treated with weekly escalated doses of homoharringtonine. The peripheral white blood cell (WBC) counts, the human leukemia cells percentage in peripheral blood, the histological findings of main organs were assayed. The CD33 positive HL-60 cells in bone marrow were determined by flow cytometry. The function and expression of mdr1 gene were examined by PCR, immunochemistry (IC) and DNR extrusion test in vivo.. (1) mdr1 gene was transferred into CBMNCs successfully and the transfection frequency was 30%. (2) Leukemia SCID mice were xenotransplanted with mdr1-transfected BMMNCs by a programmed procedure and could be used as a valuable model for in vivo evaluating myelo-protection effects. (3) The transfected mice could tolerate homoharringtonine 5 approximately 6 folds higher than conventional dose and kept peripheral WBC count at a mean of 3 x 10(9)/L, with the peripheral human myeloid leukemia cells percentage decreasing to less than 5%. Histological examination showed that there was no leukemia infiltration in the main organs, the CD33 positive HL-60 cells in bone marrow were less than 5%. (4) The repopulation frequency of the transfected CBMNs in marrow were 9.13%. DNR extrusion test confirmed that the P-gp product maintained its biological function in the marrow.. mdr1 transferred-human CBMNC can xenotransplanted and repopulated in leukemia-bearing SCID mouse and are protected from chemotherapy-induced myelosuppression.

Topics: Animals; Antineoplastic Agents, Phytogenic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cord Blood Stem Cell Transplantation; Female; Fetal Blood; Genetic Vectors; Harringtonines; HL-60 Cells; Homoharringtonine; Humans; Leukemia, Promyelocytic, Acute; Leukocytes, Mononuclear; Male; Mice; Mice, SCID; Random Allocation; Retroviridae; Transfection; Treatment Outcome; Xenograft Model Antitumor Assays

Sixty-three cases with acute promyelocytic leukemia (APL) were treated with all-trans retinoic acid (ATRA). The rates of hyperleukocytosis, intracranial hypertension, retinoic acid syndrome were 57.1%, 9.5%, and 3.2% respectively. Mortality of the treatment was 11.1%. Under ATRA treatment, hyperleukocytosis leading to leukostasis was the cause of death in patients with APL. We therefore suggest that the patients with such leukocyte levels (that is, 5.0 x 10(9).L-1 on the 6th day, 10.0 x 10(9).L-1 on the 10th day, 15.0 x 10(9).L-1 on the 15th day) can be used as guidelines for starting chemotherapy(homoharringtonine); before ATRA treatment, while leukocyte counts are > 10 x 10(9).L-1, the patients only receive homoharringtonine; when leukocyte counts are < or = 5.0 x 10(9).L-1, the patients receive a combination of homoharringtonine and ATRA. Retinoic acid syndrome is a distinctive complication of ATRA therapy in the patients with APL. While the syndrome occurs, the treatment of ATRA must be stopped and corticosteroids must be used.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Harringtonines; Homoharringtonine; Humans; Intracranial Hypertension; Leukemia, Promyelocytic, Acute; Leukemoid Reaction; Male; Middle Aged; Tretinoin

To study the mechanism of drug resistance of APL to ATRA and the methods of reversion.. ATRA-resistant HL60 cell line and bone marrow (BM) leukemia cells from recurrent APL patients who did not respond to ATRA treatment were used in this study. Multiple drug resistance gene (mdr1) expression was determined by RT-PCR and flow cytometry. Cell proliferation and differentiation were assessed by MTT uptake and NBT reduction respectively.. The response of ATRA-resistant HL60 and APL cells from recurrent patients to the differentiation inducing activity of ATRA was significantly reduced, and ATRA had little effect on cell proliferation. Expression of mdr-1 was nagative in ATRA-resistant HL60 cells. It was negative in resistant APL cells even after ATRA treatment. Arsenic trioxide and homoharringtonine (HHT) could inhibit proliferation of HL60 and ATRA-resistant HL60 cells, indicating no cross-resistance with ATRA. Interferon alpha (IFN-alpha) and PGE1 could significantly inhibit proliferation of ATRA-resistant HL60 cells and restore cell differentiation induced by ATRA.. Drug resistance of APL to ATRA is not related to mdr-1. It can be reversed by IFN-alpha. There is no cross-resistance between HHT or arsenic trioxide and ATRA.

Topics: Alprostadil; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Arsenic Trioxide; Arsenicals; Cell Survival; Drug Interactions; Drug Resistance; Harringtonines; HL-60 Cells; Homoharringtonine; Humans; Interferon alpha-2; Interferon-alpha; Leukemia, Promyelocytic, Acute; Oxides; Recombinant Proteins; Tretinoin

To investigate the potentiated effects of total saponins of Panax Ginseng (TSPG) on inhibition of leukemic progenitor cells by cytotoxic drugs in acute myelocytic leukemia.. Using bone marrow culture of colony forming unite-acute myeloid leukemia (CFU-AML) method, the sensitivity of leukemic cells obtained from 18 patients to homoharringtonin (HHr), cytarabine (Ara), adriamycin (Adr) and etoposide (VP-16) were detected separately.. TSPG alone (20 micrograms/ml) could stimulate proliferation of CFU-AML obviously, and increase the colony numbers by 37.98% over the non-TSPG control (P < 0.01). In the presence of TSPG, the inhibition rates of CFU-AML of HHr, Ara, Adr and VP-16 were 51.2%-62.0% respectively, which were significantly higher than 30.4%-47.4% of non-TSPG control (all P < 0.01). In the combination of TSPG with cytotoxic drugs, the leukemic progenitor cells became more sensitive to cytotoxic drugs, CFU-AML colony numbers at 1.84-2.23 fold as more as those of non-TSPG control were inhibited by HHr, Ara, Adr and VP-16. Sensitivity test of 17 among 72 drugs reversed from resistant (suppression rate less than 30%) to sensitive (suppression rate more than 30%) by TSPG.. TSPG could drive non-cycling leukemic progenitors to enter cell cycle, and thereby enhance their susceptibility to cytotoxic drugs.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Drug Resistance, Neoplasm; Drug Synergism; Female; Ginsenosides; Harringtonines; Homoharringtonine; Humans; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Panax; Saponins; Tumor Cells, Cultured; Tumor Stem Cell Assay

Harringtonine (HT) and homoharringtonine (HHT) are two alkaloids isolated from the bark of the evergreen tree Cephalotaxus hainanensis Li in the 1970s. They were found to have activity against murine leukemia, Lewis lung carcinoma and B16 melanoma, and used as anti-leukemia drugs clinically. Apoptosis is an active process of programmed cell suicide and now is believed to be an important target for tumor chemotherapy. In this report, the apoptosis inducing effect of HT and HHT in HL-60 cells were observed. The experiments demonstrated that 2 x 10(-7) mol.L-1 of HT and 10(-7) mol.L-1 of HHT could induce apoptosis in HL-60 cells when the cells were exposed to HT and HHT for 4 h. In agarose gel electrophoresis, DNA extracted from HL-60 cells treated with HT and HHT showed a typical internucleosomal DNA degradation, i.e., DNA ladder and parallel morphological changes as nuclear chromosome segmentation and condensation as well as cytoplasma vacuolation. This effect of HT and HHT was shown to appear in a concentration- and time-dependent manner. The efficacy of HT and HHT in inducing apoptosis of HL-60 cells was found to parallel with their cytotoxic activity in HL-60 cells. These results suggest that the mechanism of antitumor action of HT and HHT is related to their apoptosis inducing activity.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; DNA, Neoplasm; Harringtonines; Homoharringtonine; Humans; Leukemia, Promyelocytic, Acute; Tumor Cells, Cultured

Ten esters of cephalotaxine with amino acids possessing widely different structural features have been synthesized and tested for antitumor activity. Preliminary data showed that compound 6 is the most active one. However, it is still less potent than harringtonine. Other synthetic esters possess varying activities at 10 micrograms/ml. Preliminary structure activity relationship of these esters was discussed.

Topics: Antineoplastic Agents, Phytogenic; Harringtonines; Homoharringtonine; Humans; Leukemia, Promyelocytic, Acute; Structure-Activity Relationship; Tumor Cells, Cultured

Four analogs of cephalotaxine esters (C1Z, C2E, C3E, C4E) were synthesized. The ratio of the Z, E isomers of the side chain alpha, beta-unsaturated ester carboxylic acids is reported. The Z isomer was easy to transform to the E isomer. Compound C1Z showed significant activity of inducing cancer cell HL-60 differentiation. It also showed inhibitory activity on Leukemia L1210.

Topics: Animals; Antineoplastic Agents, Phytogenic; Harringtonines; Homoharringtonine; Humans; Leukemia L1210; Leukemia, Promyelocytic, Acute; Tumor Cells, Cultured

The in vitro induced differentiation of a number of human leukemia cell lines by chemical inducers not only provides a valuable model system for the study on the mechanism of hematopoietic cell proliferation and differentiation at both cellular and molecular levels, but also reveals a new prospect in the treatment of leukemia. In order to find out the possibility of applying inducing agents to the patients with various types of leukemia, the bone marrow cells in primary culture from 50 patients with leukemia were tested for their inducibility in response to the inducers. Only M3 leukemia bone marrow cells can be markedly induced by retinoic acid to the myeloid terminal cells with positive NBT reduction while the cells of other types respond with uncertainty. TPA is able to cause a macrophage-like differentiation in bone marrow cells of all types of leukemia except M1. However, the leukemic cells of chronic myelogenous leukemia in lymphocytic blast crisis will lose response to TPA. The cultured bone marrow cells of acute lymphocytic leukemia respond neither to retinoic acid nor to TPA. Homoharringtonine, a chemotherapeutic drug used in the so-called HOAP regimen for acute nonlymphocytic leukemia, seems to possess the capability of inducing HL-60, the promyelocytic leukemia cell line, to NBT positive myeloid terminal cells, although the inducing effect is weaker than retinoic acid.

Topics: Adolescent; Adult; Aged; Bone Marrow; Child; Female; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tetradecanoylphorbol Acetate; Tretinoin; Tumor Cells, Cultured

Topics: Alkaloids; Cell Nucleolus; Cytoplasm; Harringtonines; Homoharringtonine; Leukemia, Promyelocytic, Acute; Oncogenes; RNA, Messenger; RNA, Neoplasm; Tumor Cells, Cultured