Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Homoharringtonine (HHT) is a cephalotaxine alkaloid with reported efficacy in acute myelogenous leukemia (AML). In a phase II trial, we evaluated HHT 5 mg/m2 by continuous infusion daily for 9 days in patients with relapsed or refractory acute leukemia and blastic phase of chronic myelogenous leukemia (BLCML). Sixty-six patients were entered. There were 40 males and 26 females with a median age of 41 years (range 15-81). Of 43 patients with relapsed AML, seven achieved a complete remission (16%, 95% confidence interval 5%-27%). Although 11 patients with AML primarily resistant to an anthracycline/cytarabine combination did not respond, two of three patients primarily resistant to low-dose cytarabine achieved complete remission. No patients with acute lymphoblastic leukemia, biphenotypic leukemia, or BLCML responded. Hypotension during the administration of HHT was the most difficult toxicity encountered, requiring multiple interruptions of therapy in several patients and the administration of intravenous saline. Fluid retention and weight gain occurred in 29% of patients. Transient asymptomatic hyperglycemia was observed in 63% of patients. Other toxicity was mild and included nausea and vomiting, diarrhea, mucositis, hepatic dysfunction, and cardiac arrhythmias. As expected, severe myelosuppression occurred in all patients. HHT is well tolerated, but with unique problems associated with administration. It has demonstrable efficacy in pre-treated patients with AML, but its role in the treatment of this disease remains to be defined.
 ...
PMID:Homoharringtonine is safe and effective for patients with acute myelogenous leukemia. 143 2

Homoharringtonine (HHT) is one of several cephalotaxine alkaloids that has shown clinical efficacy in patients with acute myelogenous leukemia (AML). In a phase I trial we evaluated cytarabine 100 mg/m2 by continuous infusion daily for 7 days in combination with four dose levels of HHT ranging from 1.5-5 mg/m2 by continuous infusion daily for 7 days to see if an effective regimen could be developed. Twenty-two patients with relapsed and/or primary refractory AML were treated. Seventeen males and five females were treated, with a median age of 40 years (range 19-63). There were five remissions in 14 patients with relapsed AML and none of eight responders in patients with primary refractory AML. None of the three patients treated at 1.5 mg/m2 dose level of HHT responded. Of three patients treated at the 3 mg/m2 dose level, there was one complete remission. At both 4 mg/m2 and 5 mg/m2, two of eight patients achieved complete remission. Four of the five remissions occurred in patients with acute promyelocytic leukemia. Drug induced pancytopenia was universal, and hypotension and fluid retention were more common at the higher dose levels. Other toxicity was mild and included nausea, vomiting, diarrhea, and mucositis. No significant hepatic, renal, or cardiac toxicity was seen. We conclude that the dose of HHT 4 mg/m2 for 7 days by continuous infusion in combination with cytarabine is safe for patients with AML; and this combination is appropriate for a phase II evaluation.
 ...
PMID:Homoharringtonine in combination with cytarabine for patients with acute myelogenous leukemia. 143 3

Four new and clinically relevant antineoplastic natural products are reviewed. Taxol is derived from the bark of the western yew. It promotes the formation of microtubule bundles which deform the cytoskeleton and interfere with mitosis. Although phase II efficacy testing is incomplete, taxol is effective in the treatment of patients with ovarian carcinoma and has some activity in patients with non-small cell lung cancer and melanoma. It remains untested against several other neoplasms. The chief toxicities of taxol are myelosuppression, mucositis, anaphylactoid reactions, and peripheral neuropathy. Homoharringtonine is the most active and abundant of the cephalotaxine esters derived from the genus Cephalotaxus. This agent appears to act at the ribosome to inhibit protein synthesis and has clinical activity in patients with acute myelogenous leukemia. The dose limiting toxicities of homoharringtonine are hypotension and myelosuppression. SKF 104864 and CPT-11 are derivatives of camptothecin which are still in early clinical trials. They are cytotoxic in vitro, acting through an interaction with topoisomerase I to induce DNA fragmentation. The spectra of activity and toxicity of SKF 104864 and CPT-11 are still undefined. All four of these new natural products offer possibilities for clinical activity for patients with a variety of malignancies.
 ...
PMID:New natural products in cancer chemotherapy. 198 Apr 98

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.
 ...
PMID:Heterogenous response of primary cultured bone marrow cells of patients with different varieties of leukemia to differentiation inducers. 250 3

Thirty-one patients with a diagnosis of refractory acute myelogenous leukemia received homoharringtonine as their first (15 patients) or second (16 patients) salvage therapy. Homoharringtonine was given as a continuous infusion of 2.5 mg/m2 daily for 15 to 21 days to 13 patients (schedule 1), and of 3.0 mg/m2 daily for 15 days in 18 patients (schedule 2). Overall, one patient achieved complete remission (3%), and three (10%) had a hematologic improvement with normalization of the marrow and peripheral blood picture except for persistent thrombocytopenia. Six patients (19%) demonstrated prolonged myelosuppression, three (23%) on schedule 1 and three (17%) on schedule 2. Cardiovascular complications were minimal consisting of hypotension in one patient (3%) and supraventricular arrhythmias in two patients (6%). Hyperglycemia was observed in 42% of patients and was significant in 10%. The authors conclude that homoharringtonine, at the dose schedule investigated, has definite but low antileukemic efficacy. The low-dose continuous infusion schedule was associated with prolonged myelosuppression but no serious cardiovascular complications. The role of such therapy in myeloproliferative disorders, especially chronic myelogenous leukemia, deserves consideration.
 ...
PMID:Phase II study of low-dose continuous infusion homoharringtonine in refractory acute myelogenous leukemia. 291 87

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). Seventy-one patients with Philadelphia chromosome-positive (Ph+) CML in late chronic phase (time from diagnosis to therapy longer than 12 months) were treated with a continuous infusion of HHT at a daily dose of 2.5 mg/m2 for 14 days for remission induction and for 7 days every month for maintenance. The median number of courses given was 6 (range, 1 to 35) and 21 patients (30%) continue on treatment. Forty-two of 58 patients (72%) evaluable for hematologic response achieved a complete hematologic remission, and 9 (16%) had a partial hematologic remission. Twenty-two of 71 patients (31%) developed a cytogenetic response; it was major (Ph+ cells less than 35%) in 11 (15%) and complete (Ph+ cells 0%) in 5 (7%). Significant myelosuppression occurred in 39% of induction courses and 9% of maintenance courses. Fever or documented infection was present in 26% of induction courses and in only 8% of maintenance courses. Nonmyelosuppressive toxicity was minimal. 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. Future studies investigating homoharringtonine in combination with other active agents in CML, such as interferon, are warranted.
 ...
PMID:Homoharringtonine therapy induces responses in patients with chronic myelogenous leukemia in late chronic phase. 757 34

Current anti-leukemic chemotherapy in patients with myelodysplastic syndromes (MDS) and MDS evolving to acute myeloid leukemia (AML) is associated with low response rates and high treatment-related toxicity. Homoharringtonine (HHT) is a novel cephalotaxime alkaloid with reported efficacy in relapsed and de novo AML and more recently, chronic myeloid leukemia. Although its mechanism(s) of action is not completely understood, in vitro studies have demonstrated both cytotoxic and differentiating activity in leukemic cells, as well as intra-cellular changes suggestive of apoptotic cell death. In a phase II trial, HHT was administered at a dose od 5 mg/m2 by 24-h continuous infusion daily for 9 days to patients with MDS and MDS evolving to AML (MDS/AML). Twenty-eight patients (MDS 16, MDS/AML 12) with a median age of 67 years (range 23-83) were entered. A complete remission was achieved in seven patients, a partial remission was achieved in one patient for an overall response rate of 28% (8/28). There were four of 13 responders in MDS/AML patients and four of 15 in patients with MDS. The median duration of complete response was 7 months (range 2-10). Significant myelosuppression was universal and resulted in a high incidence of induction deaths (13/28) due to neutropenic-related infections. Extramedullary toxicity was mild and consisted of hypo-tension, fluid retention, hypoglycemia, diarrhea, nausea and vomiting. HHT given in this dose and schedule demonstrated limited activity in MDS and MDS/AML and was associated with prolonged pancytopenia and marrow hypoplasia in many patients. Administration of HHT at a lower dose or in combination with hematopoietic growth factors may lead to better results, but treatment with HHT as single agent at this dose and schedule is not currently recommended for these patients.
 ...
PMID:Homoharringtonine in patients with myelodysplastic syndrome (MDS) and MDS evolving to acute myeloid leukemia. 855 35

Only two classes of chemotherapeutic agents have shown activity in acute myeloid leukemia (AML): ara-C and topoisomerase II reactive agents. Frontline combinations of these agents produce complete response (CR) rates of 70% and long-term event free survival rates of 25%. New agents with different mechanisms of action are being explored. Nucleoside analogs such as chlorodeoxyadenosine (2-CdA) or fludarabine have shown single-agent efficacy and may be synergistic with ara-C. Combination therapy with ara-C and nucleoside analogs have shown promising results both as salvage therapy and in newly diagnosed patients. Combinations of topotecan with ara-C, VP16, and anthracyclines are being pursued, as is testing of other Topo-I inhibitors. Hypomethylating agents (5-azacytidine, decitabine) are showing activity in AML, producing CR rates of 5% to 30% as AML salvage therapy as a single agent, and 40%-60% in combinations. Decitabine may be synergistic with topo I inhibitors, biologic agents, and differentiating agents. Homoharringtonine has modest anti-AML activity, with CR rates of 10% to 30% as salvage therapy. Other classes of agents worthy of continuing investigation are platinum analogs and agents with novel mechanisms of action such as tallimustine.
 ...
PMID:New chemotherapeutic agents in acute myeloid leukemia. 861 70

Homoharringtonine (HHT) is a cytotoxic alkaloid isolated from the evergreen tree cephalotaxus harringtonia native to the southern provinces of China. The principal mechanism of action of HHT is the inhibition of protein synthesis in a dose- and time-dependent manner by acting on the ribosomes of cancer cells. It blocks the progression of cells from G1 phase into S phase and from G2 phase into M phase. It is synergestic or additive in vitro with AraC, amsacrine, actinomycin D and dexamethasone. Clinical studies have indicated that HHT is effective in treating acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and myelodysplastic syndrome (MDS), but not acute lymphoblastic leukemia (ALL) and solid tumors. The dose limiting toxicities are hypotention and myelosuppression. Homoharringtonine has relatively mild extramedullary toxicities and no anthracycline-like cardiac toxicity, which make it a suitable candidate for the treatment of aged patients. Pharmacological studies indicate that HHT belongs to the category of multidrug resistance (MDR)-related drugs. The cells resistant to HHT are cross-resistant to anthracycline, vinca alkaloids, mitoxantrone, but not cis-platine and AraC. Multiple mechanisms, including the sequential emergence of overexpression of multidrug resistance-associated protein (MRP) and MDR1 genes, are involved in the cross-resistance of tumor cells to HHT.
 ...
PMID:Homoharringtonine: an effective new natural product in cancer chemotherapy. 874 64

Homoharringtonine (HHT) is a plant alkaloid with antileukemia activity that is currently being used for treatment of acute, chronic leukemias and MDS. In this study, we show that HHT can induce apoptosis in a variety of human myeloid leukemia cell lines (U937, HL-60, HEL, THP, and K562). U937 and HL60 cells undergo rapid apoptosis on treatment with HHT, as indicated by increased annexin V binding capacity, caspase-3 activation, and cleavage of poly(ADP-ribose) polymerase (PARP). In addition, the expression of bax is upregulated during HHT-induced cell death, whereas the expression of bcl-2 is only slightly decreased. Importantly, treatment of primary leukemic cells, obtained from acute myeloid leukemia patients, resulted in rapid apoptosis. Thus, our data provide the mechanism of HHT and justify the use of HHT in the treatment of human myeloid leukemia.
 ...
PMID:Homoharringtonine mediates myeloid cell apoptosis via upregulation of pro-apoptotic bax and inducing caspase-3-mediated cleavage of poly(ADP-ribose) polymerase (PARP). 1522 52


1 2 3 Next >>