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Results for “Homoharringtonine”

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At least 19 recordsLinked to original sources

PubMed1998

[Effects of homoharringtonine liposomes and homoharringtonine solution on glaucoma filtration surgery in rabbits].

OBJECTIVE: Homoharringtonine (HHT), a Chinese herbal drug, was used in the form of liposome or solution as an adjunct to glaucoma filtration surgery in rabbits to determine its effect in preventing closure of sclerostomy. METHODS: Forty rabbits that underwent a standard posterior-lip sclerectomy in both eyes were divided into 5 post-operative groups. Group 1 received subconjunctival HHT liposomes (0.025%). Group 2 received subconjunctival blank liposomes and served as control. Group 3 and 5 received subconjunctival HHT solution at low (0.025%) and high (0.1%) doses respectively. Group 4 received subconjunctival normal saline and served as control. Intraocular pressure, interval between operation and bleb failure, rate of scleral fistula occlusion and ocular toxicity were determined in each group. RESULTS: Subconjunctival treatment with HHT solution at a high dose transiently prolongs the survival of filtration surgery, but the subconjunctival use with HHT liposomes or HHT solution at a low dose does not significantly prolong the survival of filtration surgery in rabbits. Significant corneal haze and corneal neovascularization resulted from using HHT at a high dose. CONCLUSIONS: The success rate of rabbit filtration surgery can not be markedly increased by the postoperative use of HHT liposomes or its low dose solution. When the high dosage of HHT solution is used, transient elevation of the success rate can be obtained, however the side-effect is also significantly increased.

Animals↗

PubMed2003

[Inhibition of activation of nuclear factor-kappaB enhanced apoptosis of leukemic cells induced by homoharringtonine].

OBJECTIVE: To explore the effects of dexamethasone (DXM) and vincristine (VCR) on apoptosis of K562-n cells and activation of nuclear factor-kappaB-gene binding (NF-kappaB) in K562-n cells induced by homoharringtonine. METHODS: K562-n cells were cultured in RPMI-1640 medium. Homoharringtonine of various concentrations was added into the cultures. Twelve hours later, the apoptosis induced by homoharringtonine in K562-n cells was analysed by TdT-mediated X-dUTP nick and end labeling (TUNEL) and DNA electrophoresis. Another sample of K562-n cells was culture together with DXM (1 micro mol/L) or VCR (0.1 micro mol/L) for 2 hours, then homoharringtonine was added into the cultures. Twelve hours later, the apoptosis in K562-n cells was analysed by TUNEL and DNA electrophoresis. Still another sample of K562-n cells was cultured for 3 hours with homoharringtonine, then electrophoretic mobility shift assay (EMSA) was conducted to determine the DNA-binding activation of NF-kappaB. A fourth sample of K562-n cells was cultured together with DXM (1 micro mol/L) or VCR (0.1 micro mol/L) for 2 hours, then homoharringtonine was added into the cultures. Three hours later, EMSA was conducted. RESULTS: The apoptosis rates of K562-n cells induced by homoharringtonine of various concentrations were (30.00 +/- 3.34)%, (47.13 +/- 3.18)% and (68.63 +/- 8.14)%, respectively. The apoptosis rates of K562-n cells induced by homoharringtonine being pre-processed with DXM or VCR were (55.75 +/- 3.88)% and (64.38 +/- 4.60)%, respectively, being 85.8% and 114.6% higher than that induced by homoharringtonine alone (30.00 +/- 3.34)% (all P < 0.05). Activation of NF-kappaB in K562-n cells was induced significantly by homoharringtonine. Activation of NF-kappaB in K562-n cells induced by homoharringtonine could be suppressed by being pre-processed with 1.0 micro mol/L DXM or 0.1 micro mol/L VCR. The rate of suppression was 32.0% and 39.4% respectively. CONCLUSION: Homoharringtonine induces apoptosis of K562-n cells and induces NF-kappaB activation in K562-n cells. The mechanism of increased apoptosis of K562-n cells with DXM or VCR may be related to suppression of activation of NF-kappaB of K562-n cells.

Antineoplastic Agents↗

PubMed1983

Comparative in vitro antitumor activity of homoharringtonine and harringtonine against clonogenic human tumor cells.

Harringtonine and its derivative homoharringtonine are ester-containing anti-leukemic alkaloids isolated from the tree Cephalotaxus harringtonia. In order to compare their antitumor activity against solid tumors, in vitro culture of fresh tumor cells from 23 patients was carried out with a soft agar assay system. Tumor cells were exposed to 0.001-1.0 micrograms/ml of each agent for either 1 h prior to plating or by continuous exposure. Significant antitumor activity was noted for harringtonine in ovarian and endometrial carcinoma at the 0.01 micrograms/ml concentration. In the continuous exposure studies, homoharringtonine proved to be more potent than harringtonine. Significant antitumor activity of homoharringtonine was noted in sarcoma and breast cancer as well as in ovarian and endometrial carcinoma. In the continuous exposure studies the mean area under the survival-concentration curve was significantly less for homoharringtonine than for harringtonine (5.04 +/- 3.87 and 6.15 +/- 3.46, respectively (p less than 0.005). The ratio of mean ID50 (harringtonine/homoharringtonine) was 5.2. However, there was no significant difference between those two agents with a 1 h exposure. Our results suggest that homoharringtonine and harringtonine may be of use in selected solid tumors, and that homoharringtonine has a greater degree of colony inhibition with continuous exposure.

Alkaloids↗

PubMed1999

[Apoptosis inductive effect of homoharringtonine and isoharringtonine on human acute promyelocytic leukemia HL-60 cells].

OBJECTIVE: To study the effects of homoharringtonine and isoharringtonine on the induction of apoptosis on human promyelocytic leukemia HL-60 cells. METHODS: By using flow cytometry, DNA gel electrophoresis, microscopy and electron microscopy. RESULTS: It was demonstrated that homoharringtonine and isoharringtonine can induce apoptosis of HL-60 cells significantly and rapidly. The activity of homoharringtonine was higher than that of isoharringtonine, and it was time and concentration dependent. CONCLUSIONS: Both homoharringtonine and isoharringtonine could induce apoptosis of HL-60 cells in terms of morphology, and DNA ladder assay. The activity of homoharringtonine was much higher than that of isoharringtonine.

Apoptosis↗

PubMed1984

[Antitumor activities and mechanisms of action of harringtonine and homoharringtonine].

The antitumor activities and the mechanisms of action of harringtonine and homoharringtonine, alkaloids isolated from cephalotaxus hainanensis Li, were compared to those of vincristine. The results obtained were as follows: Harringtonine and homoharringtonine Significantly inhibited the growth of L1210 cells in culture. The IC50 values were similar to that of vincristine. Harringtonine and homoharringtonine had little effects on changes in the DNA histograms of FL cells at any concentrations, which suggesting that these drugs prolong the duration of each phase of the cell cycle evenly. Harringtonine and homoharringtonine had only a minor effect in arresting P388 cells in mitosis. Harringtonine significantly inhibited the DNA synthesis of P388 leukemia cells in culture, while vincristine weakly inhibited RNA and DNA synthesis. The successive treatment with harringtonine and homoharringtonine were as effective as the successive treatment with vincristine against P388 and L1210 leukemia, while both drugs were ineffective against Lewis lung carcinoma.

Alkaloids↗

PubMed2005

[Vascular endothelial growth factor antisense oligodeoxynucleotide enhance drug-sensitivity of myeloid leukemia cells to homoharringtonine].

OBJECTIVE: To explore the effects of antisense phosphorothioate oligodeoxynucleotides (AS PS-ODN) of vascular endothelial growth factor (VEGF) on drug-sensitivity of AML and CML cells to homoharringtonine and its possible mechanism. METHODS: A7, which was the most effective AS PS-ODN selected by computer aid-designing and experimental assay, contains 20-mer modified with phosphorothioate. It was transferred into cells by lipofectin while cultured in 2% serum medium for 8 h and then in 10% serum medium. Twenty four hours later, homoharringtonine was added into the culture and cultured for another 48 h. Cell viability was detected by trypan blue exclusion every 24 hours, cell apoptosis by flow cytometry, and level of VEGF protein by a VEGF ELISA kit. RESULTS: The combination of A7 and homoharringtonine was able to inhibit cell survival (AML cell survival reduced 38%, CML cell survival reduced 25%), down-regulate VEGF protein expression (VEGF protein expression of AML cell and CML cell declined 25.44% and 30.81%, respectively) and increase homoharringtonine induced apoptosis in both AML and CML cells (apoptotic rates of AML and CML cells increased 48.29% and 52.76%, respectively). CONCLUSION: The VEGF AS PS-ODN is able to enhance the drug-sensitivity to homoharringtonine, suggesting that inner VEGF proteins in myeloid leukemia cells had a drug-resistant effect.

Acute Disease↗

PubMed1989

Quantitation of homoharringtonine in plasma by high-performance liquid chromatography with amperometric detection.

A high-performance liquid chromatographic procedure was developed for the quantitation of homoharringtonine in plasma. Harringtonine was used as an internal standard, and 1 ml of sample was required. The single-step extraction with dichloromethane resulted in almost 100% recovery for homoharringtonine and harringtonine. Analysis was performed on a reversed-phase CN column with amperometric detection. Chromatography was completed in 12 min. At an oxidation potential of +1.0 V, the detection limit was 1 ng/ml at a signal-to-noise ratio of 2. The mean analytical recovery for homoharringtonine was 99.5%. The within-run precision and between-run precision were both less than 11%. The method is equally applicable for plasma or serum, and it has been demonstrated to be applicable for study of the pharmacokinetics of homoharringtonine in patients suffering from acute non-lymphocytic leukaemia.

Alkaloids↗

PubMed1990

Treatment of chloroquine-resistant malaria with esters of cephalotaxine: homoharringtonine.

The esters of cephalotaxine-harringtonine, homoharringtonine and deoxyharringtonine--have been reported by both Chinese and American oncologists as useful in the treatment of human nonlymphoblastic leukaemias and selected solid tumours of the head and neck. We report our results with homoharringtonine, currently a Phase II clinical trial drug with the National Cancer Institute, in the treatment of malaria. Homoharringtonine, 2.7-3.4 nM, was effective in causing 50% growth inhibition of two strains of chloroquine-resistant Plasmodium falciparum malaria in vitro. In vivo tests in mice infected with P. yoelii showed that this drug was effective in inhibiting parasite growth in this system as well. Histologically, the drug was associated with karyorrhexis. Drug-exposed cells showed decreased levels of putrescine and spermidine and increased spermine levels. Our findings not only demonstrate the potential usefulness of homoharringtonine in the treatment of chloroquine-resistant malaria, but also demonstrate the advantage of applying comparative biochemistry and an understanding of biological mechanisms in a rational approach to the development and treatment of diseases including malaria.

Animals↗

PubMed2000

[Effects of homoharringtonine on proliferation of human retro-ocular fibroblasts].

This is a study amied at the effects of homoharringtonine on the proliferation of human retro-ocular fibroblasts. The human retroocular fibroblasts (HROFb) were cultured and MTT colorimetry assay was used to determine the proliferation of HROFb. The influence of homoharringtonine on the proliferation of HROFb was observed in vitro. The results showed that MTT colorimetry assay could precisely reflect the proliferation of HROFb. The absorbance was directly proportional to the number of the cells (r = 0.996, P < 0.001). The proliferation of HROFb was inhibited by the homoharringtonine and the cell proliferation percentage was correlated positively to the homoharringtonine level (r = 0.6932, P < 0.001).

Cell Division↗

PubMed1986

Phase II studies of homoharringtonine in patients with advanced malignant melanoma; sarcoma; and head and neck, breast, and colorectal carcinomas.

Five phase II trials of the antitumor agent homoharringtonine were conducted in 80 patients who had advanced solid tumors. The five categories of solid tumors included malignant melanoma; sarcoma; and head and neck, breast, and colorectal carcinomas. The starting dose of homoharringtonine was 3.0-4.0 mg/m2 by short iv infusion daily X 5 days every 21 days. Seventy-eight of 80 patients had had prior chemotherapy and 49 had had prior radiation therapy. Among the 74 evaluable patients in the five tumor categories, there were no complete or partial remissions. Homoharringtonine was generally well-tolerated. Nausea and vomiting, diarrhea, and fever and chills were the most common side effects. Serious reversible cardiovascular toxicity, which occurred in three patients, included symptomatic hypotension in two and short runs of ventricular tachycardia in one. The investigations thus conclude that homoharringtonine given by intermittent schedule is an inactive drug against these solid tumors previously exposed to chemotherapy.

Adolescent↗

PubMed1984

Phase I clinical investigation of homoharringtonine.

Homoharringtonine is a cephalotaxine ester derived from Cephalotaxus harringtonia, which is a Chinese evergreen tree. A limited clinical evaluation of this drug in China revealed antileukemic activity, which prompted clinical trials in the United States. We have treated 43 patients with a variety of refractory malignancies using a daily iv treatment for 5 days at 3-4-week intervals. The starting dose of homoharringtonine was 0.2 mg/m2/day and it was escalated to a maximum of 8 mg/m2/day. The dose-limiting toxic effect was hypotension, which was generally mild with daily dose levels of 3-4.5 mg/m2/day and required no specific treatment besides iv fluid supplements in some patients. Hypotension became increasingly severe at the higher dose levels and resulted in cardiovascular collapse in four of 16 patients treated with dose levels of 5-6 mg/m2/day. A moderately severe degree of myelosuppression was observed with homoharringtonine doses of greater than or equal to 3 mg/m2. Myelosuppression was clearly related to the extent of prior treatment and was minimal in patients who had not received extensive prior treatment. Gastrointestinal toxic effects of nausea, vomiting, and diarrhea were observed in approximately two-thirds of the patients but these side effects were generally mild and self-limited. Drug-related fever and alopecia were also observed in some patients. No major responses were observed, although three patients with solid tumors evidenced minor responses and three of five patients with acute leukemia showed some degree of antileukemic activity. For phase II studies of homoharringtonine in solid tumors, a daily dose of 3 mg/m2 for 5 days in patients with extensive prior treatment and 4 mg/m2/day for 5 days in patients with good bone marrow reserve will be utilized. The daily dose must not exceed 4 mg/m2 to avoid serious hypotension; further dose escalations should be accomplished by extending the number of days of treatment beyond 5 days.

Adult↗

PubMed1989

Phase II study of low-dose continuous infusion homoharringtonine in refractory acute myelogenous leukemia.

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.

Adult↗

PubMed1985

Homoharringtonine: a phase I evaluation.

Homoharringtonine is one of several Cephalotaxine esters which have shown experimental antineoplastic activity as well as anti-leukemia effects in patients in China. In a Phase I trial of homoharringtonine administered daily X 5 by bolus intravenous injection, the dose limiting toxicity was hypotension and the maximum tolerated dose was 3.5 mg/m2/d X 5. Evidence of drug induced cardiac irritability with resulting ventricular and atrial dysrhythmias was seen. Minimal myelosuppression was seen at this dose. Treatment of patients by 5 day continuous intravenous (rather than bolus) infusion resulted in more pronounced myelosuppression and clinically significant but tolerable hypotension. Significant reduction of white blood cell and platelet counts occurred at a dose of 3.5 mg/m2/day. Further investigations of the hypotensive and cardiac effects of homoharringtonine and Phase II trials using continuous infusion are indicated.

Aged↗

PubMed1996

A phase II trial of amonafide, caracemide, and homoharringtonine in the treatment of patients with advanced renal cell cancer.

Forty-eight previously untreated, ambulatory patients with advanced or unresectable renal carcinoma were treated with either amonafide (17 patients), caracemide (17 patients), or homoharringtonine (14 patients). No objective responses were observed in any of the treatment cohorts. Amonafide and caracemide were well tolerated with no unexpected toxicities. One patient each died of pulmonary thromboembolism and sepsis with severe metabolic acidosis on the homoharringtonine arm. An additional 4 patients experienced grade 4 complications including myelosuppression, neurologic dysfunction, and respiratory failure. These severe and unexpected complications caused early termination of accrual to the homoharringtonine arm of the study. These agents have no activity in the treatment of advanced renal cell carcinoma.

Adenine↗

PubMed1993

Etoposide-resistant human colon and lung adenocarcinoma cell lines exhibit sensitivity to homoharringtonine.

Human colon (HCT116/VP48) and lung (A549B/VP29) adenocarcinoma cell lines selected for resistance to etoposide exhibited modified patterns of multi-drug resistance (MDR) that included a differential sensitivity to other DNA topoisomerase II inhibitors and to the plant alkaloids homoharringtonine, vinblastine, and vincristine. The resistance and cross-resistance drug phenotype of the A549B/VP29 cell line was different from that of the HCT116/VP48 cell line. The HCT116/VP48 cell line was 50-fold resistant to etoposide and 30-fold resistant to teniposide. The degree of resistance to other DNA topoisomerase II inhibitors was of a lower magnitude: Adriamycin, 9-fold; daunomycin, 3-fold; 4'-[(9-acridinyl)-amino]-methanesulfone-m-anisidide (m-AMSA), 3-fold; and actinomycin D, 6-fold. The HCT 116/VP48 cell line exhibited a 7-fold resistance to vincristine and a 2-fold resistance to vinblastine but was sensitive to homo-harringtonine. The A549B/VP29 cell line was 5-fold resistant to etoposide and 2-fold resistant to teniposide. The A549B/VP29 cell line exhibited a 2-fold resistance to Adriamycin but was sensitive to daunomycin and showed a 3-fold resistance to m-AMSA. This cell line was sensitive to actinomycin D. The A549B/VP29 cell line was 2-fold resistant to vinblastine and sensitive to homoharringtonine. Both cell lines (HCT116/VP48 and A549/VP29) exhibited no amplification of the human mdr1 DNA sequence, the 4.3-kb P-glycoprotein transcript, or the membrane P-glycoprotein. The sensitivity of cells exhibiting an MDR phenotype not mediated by P-glycoprotein suggests a potential use for homoharringtonine in treating tumors with this type of drug resistance.

Adenocarcinoma↗

PubMed1988

Inhibition of intraocular proliferation by homoharringtonine. An experimental study.

Homoharringtonine, an alkaloid indigenous to China, was studied for its effect on fibroblast growth in cell culture and on intraocular proliferation produced in rabbits by injecting homologous fibroblasts into the vitreous. The results demonstrate that homoharringtonine reduced the cell growth by 50% at a concentration of 0.005 mg/l in vitro, significantly inhibited vitreous proliferation, and prevented the occurrence of retinal detachment in vivo. Light and electron microscopy revealed no ocular toxicity in drug-treated eyes. Homoharringtonine may be of considerable value in the prevention and treatment of intraocular proliferation in patients.

Alkaloids↗

PubMed1989

Alkaloid homoharringtonine inhibits polypeptide chain elongation on human ribosomes on the step of peptide bond formation.

The aim of the present study was to investigate homoharringtonine alkaloid effect on: (i) the nonenzymatic and eEF-1-dependent Phe-tRNAPhe binding to poly(U)-programmed human placenta 80 S ribosomes; (ii) diphenylalanine synthesis accompanying nonenzymatic Phe-tRNAPhe binding; and (iii) acetylphenylalanyl-puromycin formation. Neither nonenzymatic nor eEF-1-dependent Phe-tRNAPhe binding were noticeably affected by the alkaloid, whereas diphenylalanine synthesis and puromycin reaction were strongly inhibited by homoharringtonine. It has been proposed that the site of homoharringtonine binding on 80 S ribosomes should overlap or coincide with the acceptor site of the ribosome.

Alkaloids↗

PubMed1999

A phase II trial of homoharringtonine and caracemide in the treatment of patients with advanced large bowel cancer.

Twenty-four previously untreated, ambulatory patients with advanced colorectal carcinoma were treated with either caracemide (11 patients) or homoharringtonine (13 patients). No objective responses were observed in any of the treatment cohorts. Caracemide was well tolerated with the exception of one death due to sepsis. On the homoharringtonine arm one patient died of pulmonary sepsis, one patient experienced grade 4 leukopenia requiring more than 4 weeks of recovery, and an additional patient developed grade 4 renal failure. These severe and unexpected complications caused early termination of accrual to the homoharringtonine arm of the study. These agents have no activity in the treatment of advanced colorectal carcinoma.

Adult↗