homoharringtonine and Neoplasms

Cephalotoxine esters, including homoharringtonine (HHT), have shown encouraging activity in leukemia in initial studies in China and in later studies in the U.S.. The authors conducted a review of the literature to examine the studies pertinent to HHT in relation to preclinical studies and Phase I-II trials in patients with hematologic malignancies and solid tumors.. HHT and analogues appear to induce differentiation and apoptosis. Studies from China reported high response rates in patients with leukemia. Trials in the U.S. using short HHT infusions (3-4 mg/m(2) daily for 5 days) resulted in a high incidence of cardiovascular complications that were reduced using continuous infusion schedules of 3-7 mg/m(2) daily for 5-7 days initially, and later lower dose schedules of 2.5 mg/m(2) daily for 7-14 days. Results in solid tumors were negative. However encouraging results were reported in patients with acute myeloid leukemia, myelodysplastic syndrome, acute promyelocytic leukemia, and, most important, chronic myeloid leukemia (CML). In CML patients, HHT has been investigated alone and in combination with interferon-alpha and low-dose cytarabine in late and early chronic phases, with positive results. Additional areas of interest include the potential use of HHT for the treatment of central nervous system leukemia, polycythemia vera, and other nonmalignant conditions such as malaria. New semisynthetic preparations and HHT derivatives that bypass multidrug resistance may improve the efficacy and toxicity profiles, and broaden the range of antitumor efficacy.. HHT and its derivatives appear to have promising activity in hematologic malignancies, a finding that needs to be pursued.

Topics: Antineoplastic Agents, Phytogenic; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Forecasting; Harringtonines; Homoharringtonine; Humans; Leukemia; Neoplasms; Research

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.

Topics: Animals; Antineoplastic Agents, Phytogenic; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Synergism; Harringtonines; Homoharringtonine; Humans; In Vitro Techniques; Interphase; Mice; Neoplasms; Neoplasms, Experimental; Ribosomes; Tumor Cells, Cultured

Background Omacetaxine mepesuccinate is indicated in adults with chronic myeloid leukemia resistant and/or intolerant to ≥ 2 tyrosine kinase inhibitor treatments. This phase I study assessed the disposition, elimination, and safety of (14)C-omacetaxine in patients with solid tumors. Methods The study comprised a 7-days pharmacokinetic assessment followed by a treatment period of ≤ six 28-days cycles. A single subcutaneous dose of 1.25 mg/m(2) (14)C-omacetaxine was administered to six patients. Blood, urine, and feces were collected through 168 h or until radioactivity excreted within 24 h was <1 % of the dose. Total radioactivity (TRA) was measured in all matrices and concentrations of omacetaxine, 4'-desmethylhomoharringtonine (4'-DMHHT), and cephalotaxine were measured in plasma and urine. For each treatment cycle, patients received 1.25 mg/m(2) omacetaxine twice daily for 7 days. Results Mean TRA recovered was approximately 81 % of the dose, with approximately half of the radioactivity recovered in feces and half in urine. Approximately 20 % of the dose was excreted unchanged in urine; cephalotaxine (0.4 % of dose) and 4' DMHHT (9 %) were also present. Plasma concentrations of TRA were higher than the sum of omacetaxine and known metabolites, suggesting the presence of other (14)C-omacetaxine-derived compounds. Fatigue and anemia were common, consistent with the known toxicity profile of omacetaxine. Conclusion Renal and hepatic processes contribute to the elimination of (14)C-omacetaxine-derived radioactivity in cancer patients. In addition to omacetaxine and its known metabolites, other (14)C-omacetaxine-derived materials appear to be present in plasma and urine. Omacetaxine was adequately tolerated, with no new safety signals.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Carbon Radioisotopes; Feces; Female; Harringtonines; Homoharringtonine; Humans; Male; Middle Aged; Neoplasms

Omacetaxine mepesuccinate is a first-in-class cephalotaxine demonstrating clinical activity in chronic myeloid leukemia. A subcutaneous (SC) formulation demonstrated efficacy and safety in phase 1/2 trials in patients previously treated with ≥1 tyrosine kinase inhibitor. This study assessed pharmacokinetics and safety of SC omacetaxine in patients with advanced cancers.. Omacetaxine 1.25 mg/m(2) SC was administered BID, days 1-14 every 28 days for 2 cycles, until disease progression or unacceptable toxicity. Blood and urine were collected to measure omacetaxine concentrations and inactive metabolites. Adverse events, including QT interval prolongation, were recorded. Tumor response was assessed at cycle 2 completion.. Pharmacokinetic parameters were estimated from cycle 1, day 1 data in 21 patients with solid tumors or hematologic malignancies and cycle 1, day 11 data in 10 patients. Omacetaxine was rapidly absorbed, with mean peak plasma concentrations observed within 1 h, and widely distributed, as evidenced by an apparent volume of distribution of 126.8 L/m(2). Plasma concentration versus time data demonstrated biexponential decay; mean steady-state terminal half-life was 7 h. Concentrations of inactive metabolites 4'-DMHHT and cephalotaxine were approximately 10 % of omacetaxine and undetectable in most patients, respectively. Urinary excretion of unchanged omacetaxine accounted for <15 % of the dose. Grade 3/4 drug-related adverse events included thrombocytopenia (48 %) and neutropenia (33 %). Two grade 2 increases in QTc interval (>470 ms) were observed and were not correlated with omacetaxine plasma concentration. No objective responses were observed.. Omacetaxine is well absorbed after SC administration. Therapeutic plasma concentrations were achieved with 1.25 mg/m(2) BID, supporting clinical development of this dose and schedule.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Female; Half-Life; Harringtonines; Hematologic Neoplasms; Homoharringtonine; Humans; Injections, Subcutaneous; Long QT Syndrome; Male; Middle Aged; Neoplasms; Neutropenia; Thrombocytopenia; Tissue Distribution

Although progress has been made in developing tumor microenvironment-responsive delivery systems, the list of cargo-releasing stimuli remains limited. In this study, we report DNA nanothread-cloaked nanoparticles for reactive oxygen species (ROS)-rich tumor microenvironment-responsive delivery systems. ROS is well known to strongly induce DNA fragmentation via oxidative stress. As a model anticancer drug, hydrophobic omacetaxine was entrapped in branched cyclam ligand-modified nanoparticles (BNP). DNA nanothreads were prepared by rolling-circle amplification and complexed to BNP, yielding DNA nanothread-cloaked BNP (DBNP). DBNP was unmasked by DNA nanothread-degrading ROS and culture supernatants of LNCaP cells. The size and zeta potential of DBNP were changed by ROS. In ROS

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; DNA; Homoharringtonine; Ligands; Mice; Nanoparticles; Neoplasms; Reactive Oxygen Species; Tumor Microenvironment

Topics: Antineoplastic Agents, Phytogenic; Harringtonines; Homoharringtonine; Metabolome; Neoplasms

One hallmark of cancer cells is their ability to evade physiologic signals causing regulated cell death (RCD). Correspondingly, TRAIL-based therapies to eliminate human cancer cells via enforced induction of apoptosis have been established and represent a promising approach in anti-cancer research. However, due to frequently appearing intrinsic or acquired resistances of tumor cells against apoptosis, TRAIL-based apoptotic strategies for the treatment of cancer patients have shown limited efficacy. As a potential alternative, regulated necrosis (and necroptosis triggered e.g. by TRAIL receptors 1/2) has recently gained considerable attention. Regulated necrosis represents a mode of RCD molecularly distinct from apoptosis whose potential in anti-cancer therapy is almost uncharacterized. Since in most cancer cells survival pathways counteract the effects of TRAIL-induced RCD, sensitizers such as cycloheximide (CHX) are frequently added in cell culture to overcome this problem. Unfortunately, those sensitizers are cytotoxic and therefore not suitable for the treatment of cancer patients. Here, we have alternatively employed homoharringtonine (HHT), a plant alkaloid which was recently approved by the U. S. Food and Drug Administration to treat patients with chronic myeloid lymphoma.. We show that HHT is an efficient sensitizer for TRAIL-induced necroptosis in multiple human cancer cell lines. In addition, HHT-enhanced TRAIL-mediated necroptosis occurs via the same signaling pathways (involving RIPK1/RIPK3/MLKL) as CHX-enhanced necroptosis. Importantly, consecutive treatment schedules of necroptosis and apoptosis in either combination revealed remarkable additive effects not reached by repetitive apoptotic treatments alone.. Taken together, our data demonstrate that HHT can replace harmful substances such as CHX to sensitize human cancer cells to TRAIL-induced necroptosis. Thus, HHT represents a promising enhancer in TRAIL-based necroptotic anti-cancer therapies also in patients.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cycloheximide; Harringtonines; Homoharringtonine; Humans; Necrosis; Neoplasms; Protein Synthesis Inhibitors; Receptors, TNF-Related Apoptosis-Inducing Ligand; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand

A comprehensive herbal medicine information system for cancer (CHMIS-C) has been developed. The current version of the database integrates information on more than 200 anticancer herbal recipes that have been used for the treatment of different types of cancer in clinic, 900 individual ingredients, and 8500 small organic molecules isolated from herbal medicines. Furthermore, subsidiary databases of literature references and molecular targets have been constructed. A number of web-based searching tools have been developed and integrated into the information system for efficient data mining. The compounds in the database have been linked to the corresponding entries in the National Cancer Institute's database, and to a database of drugs approved by the U.S. Food and Drug Administration. This paper provides a description of the individual subsidiary databases, integration of the entire database, and data mining tools. We demonstrate that this comprehensive information system may be used as an effective informatics tool for anticancer drug discovery.

Topics: Antineoplastic Agents, Phytogenic; Databases, Factual; Internet; National Institutes of Health (U.S.); Neoplasms; Phytotherapy; Plant Preparations; United States; United States Food and Drug Administration

The BCR/ABL tyrosine kinase has been implicated in the pathogenesis of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL). STI571 is a novel anticancer agent that selectively inhibits the BCR/ABL tyrosine kinase. The cytotoxic effects of STI571 were studied in combination with antileukemic agents against Ph(+) leukemia cell lines, KU812, K-562, TCC-S, and TCC-Y. The cells were exposed to STI571 and to other agents simultaneously for 5 or 7 days. Cell growth inhibition was determined by MTT assay. The cytotoxic effects in combinations at the inhibitory concentration of 80% level were evaluated by the isobologram. STI571 produced synergistic effects with recombinant and natural alpha-interferons in 2 of 3 and 3 of 3 cell lines, respectively. STI571 produced additive effects with hydroxyurea, cytarabine, homoharringtonine, doxorubicin, and etoposide in all 4 cell lines. STI571 with 4-hydroperoxy-cyclophosphamide, methotrexate, or vincristine produced additive, antagonistic, and synergistic effects in 3 of 4 cell lines, respectively. These findings suggest that the simultaneous administration of STI571 with other agents except methotrexate would be advantageous for cytotoxic effects against Ph(+) leukemias. Among them, the simultaneous administration of STI571 and alpha-interferons or vincristine would be highly effective against Ph(+) leukemias and these combinations would be worthy of clinical trials. In contrast, the simultaneous administration of STI571 with methotrexate would have little therapeutic efficacy. Although there are gaps between in vitro studies and clinical trials, the present findings provide useful information for the establishment of clinical protocols involving STI571. (Blood. 2001;97:1999-2007)

Topics: Antineoplastic Agents; Apoptosis; Benzamides; Cytarabine; Dose-Response Relationship, Drug; Drug Interactions; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Enzyme Inhibitors; Fusion Proteins, bcr-abl; Harringtonines; Homoharringtonine; Humans; Hydroxyurea; Imatinib Mesylate; Interferon-alpha; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Methotrexate; Microbial Sensitivity Tests; Neoplasm Proteins; Neoplasms; Piperazines; Pyrimidines; Tumor Cells, Cultured; Vincristine

Clinical pharmacokinetics of homoharringtonine (HHT) were studied in eight patients who received uniformly labeled HHT at 3-4 mg/m2 (150 mu Ci) by continuous 6-hour infusion. The drug and metabolites were quantified by radiochemical and high-performance liquid chromatographic techniques. Computerized nonlinear least-square regression and curve stripping were used to characterize HHT and total [3H]HHT equivalent pharmacokinetics. Unchanged HHT in the plasma declined biphasically, with an alpha-half-life of 0.5 +/- 0.1 hours and a beta-half-life of 9.3 +/- 1.4 hours. The total clearance of HHT was 177.4 +/- 27.7 ml X hour-1 X kg-1, and the apparent volume of distribution, estimated from the area under the drug concentration versus time curve, was 2.4 +/- 0.4 L X kg-1. Correspondingly, the total [3H]HHT equivalent disappeared from the plasma in a triphasic manner. Compared with the pharmacokinetic parameters of unchanged HHT, the terminal half-life of total 3H was 67.5 +/- 7.5 hours, 7.4 times longer; the total clearance was 30.9 +/- 3.1 ml X hour-1 X kg-1, 5.5 times slower; but the volume of distribution by area was 2.7 +/- 0.1 L X kg-1, nearly the same. The 72-hour cumulative urinary excretion of total tritium was 28.2% of the administered dose and only 38.3% of this resided in unchanged HHT. Thus, urinary excretion was not a major route of elimination of HHT. Moreover, HHT underwent extensive metabolism; one major and two minor unidentified products were detected in both plasma and urine.

Topics: Adolescent; Alkaloids; Chromatography, High Pressure Liquid; Drug Evaluation; Half-Life; Harringtonines; Homoharringtonine; Humans; Kinetics; Neoplasms; Scintillation Counting

Cephalotaxine alkaloids have been extensively used in the Peoples Republic of China for treatment of acute leukemias and solid tumors (Yu-hua, L., Shu-fen, G., Fu-ying, Z., Shu-zhi, X., and Hui-lin, Z. Chin. Med. J., 96: 303-305, 1983). Several Phase I trials of homoharringtonine have been completed in the United States using either bolus administration or continuous infusion over a 5-day period. The major toxicities have been hypotension following rapid administration and myelosuppression when lower doses are infused over 5 to 7 days. None of these studies, however, reproduce the schedule used in China which is i.v. infusion of approximately 1 mg/day over 4-8 h for a period of 14-28 days or more, followed by a rest period of approximately 7-14 days. This study more closely reproduces that schedule as a Phase I trial by decreasing the daily dose of homoharringtonine and using a continuous infusion schedule to allow escalation of total days of treatment. Forty-eight patients entered the study. The final recommended dose of homoharringtonine is 1 mg/m2/day for 30 days followed by a 2-week rest period. The dose limiting toxicity of myelosuppression was severe and prolonged in some patients. Nonhematological toxicities were minimal and generally well tolerated. Patients should be followed with at least weekly blood counts and treatment interrupted pending full marrow recovery if the granulocyte count falls below 1,000/mm3 or the platelet count falls below 100,000/mm3.

Topics: Adult; Aged; Alkaloids; Drug Evaluation; Female; Harringtonines; Hematopoiesis; Homoharringtonine; Humans; Infusions, Parenteral; Male; Middle Aged; Neoplasms

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.

Topics: Aged; Alkaloids; Antineoplastic Agents; Drug Evaluation; Female; Harringtonines; Heart; Homoharringtonine; Humans; Infusions, Parenteral; Leukocyte Count; Male; Middle Aged; Neoplasms; Platelet Count; Time Factors

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.

Topics: Adult; Aged; Alkaloids; Bone Marrow Diseases; Dose-Response Relationship, Drug; Drug Evaluation; Female; Harringtonines; Homoharringtonine; Humans; Hypotension; Leukemia; Male; Middle Aged; Neoplasms

Topics: Acenaphthenes; Alkaloids; Animals; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Evaluation Studies as Topic; Harringtonines; Homoharringtonine; Humans; Kidney; Mice; Neoplasm Transplantation; Neoplasms; Ribonucleotides

Homoharringtonine is one of a group of cephalotaxine esters reported by the Chinese to have significant antitumor efficacy, with particularly good activity in human leukemias. Preclinical antitumor activity against P388 leukemia, colon 38 carcinoma, and mammary carcinoma led to phase I trials which are currently nearing completion in this country. The phase I study reported here used a single infusion of homoharringtonine over 90 minutes given every 21 days. Dose-related and life-threatening hypotension, without significant myelosuppression, was the dose-limiting toxic effect. The mechanism of hypotension is not understood but it is not related to cardiac arrhythmias. Myelosuppression was not seen regularly. We do not recommend this schedule for phase II trials.

Topics: Adult; Aged; Alkaloids; Blood Cell Count; Blood Pressure; Dose-Response Relationship, Drug; Drug Evaluation; Female; Harringtonines; Homoharringtonine; Humans; Male; Middle Aged; Neoplasms