Curative effect of harringtonine semisynthetic harringtonine and HOAP on nonlymphocytic leukemias. Analysis of 304 cases.
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Adult↗
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[Studies on mechanism of inhibition of harringtonine on DNA synthesis. III. Relationship between inhibition of harringtonine on DNA and protein synthesis].
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Alkaloids↗
Combinatorial treatment of ovarian cancer cells with harringtonine and cisplatin results in increased cisplatin-DNA adducts.
The current studies represent the first step in assessing the utility of harringtonine in combination with cisplatin as an improved approach for treating ovarian cancer. Three ovarian cancer cell lines, platinum-sensitive A2780, and platinum-resistant A2780/CP70 and OvCar-3, were exposed to their respective IC(50) dose of cisplatin for 1 h with or without a 24-h pretreatment with harringtonine. The level of platinum-DNA adducts was determined by atomic absorption spectrometry (AAS). These studies show for the first time that harringtonine pretreatment significantly increased the amount of platinum-DNA adducts in all ovarian cancer cell lines by 2-4 fold, immediately following 1-h exposure to cisplatin. Moreover, the level of cisplatin-DNA adducts in harringtonine-pretreated cells remained elevated by 3-4.7-fold for at least 6 h after cisplatin was removed, relative to cells only exposed to cisplatin. In all three cell lines the removal (repair) of platinum-DNA adducts was not significantly altered by harringtonine. In addition, the extent to which harringtonine altered the expression of select DNA damage response genes (p53, P16, ERCC1 and XPB) was determined using RT-PCR and Southern hybridization in A2780 and A2780/CP70 cells. The expression of ERCC1 and XPB RNAs were only modestly altered by harringtonine, consistent with a lack of effect of harringtonine on repair of cisplatin-DNA damage. However, harringtonine altered expression of p53 and P16 RNAs in both cell lines, although the down-regulation of p53 and P16 RNAs by harringtonine were more pronounced in A2780 cells. The novel observation that harringtonine augments platinum-DNA adducts in both platinum-sensitive and -resistant ovarian cancer cells indicates this combination of drugs may have utility in treating ovarian cancer and may be especially useful in managing platinum-resistant cancers. Additional studies are required to determine which sequence of these drugs is most beneficial, as well as the mechanism by which harringtonine increases cisplatin-DNA damage in ovarian cancer cells.
Actins↗
Induction of chromosomal aberrations, cytotoxicity, and morphological transformation in mammalian cells by the antiparasitic drug flubendazole and the antineoplastic drug harringtonine.
The antiparasitic drug flubendazole and the antineoplastic compound harringtonine were studied for ability to induce chromosomal damage in Chinese hamster lung (CHL) cells and cytotoxicity and morphological transformation in C3H/10T1/2 Cl 8 (10T1/2) mouse embryo fibroblasts. Flubendazole caused a dose- and time-dependent induction of polyploidy in CHL cells. In cells treated with 0.78 micrograms/ml flubendazole, the yield of polyploid cells was 95%. Harringtonine caused a dose- and time-dependent induction of chromosome breaks, and 0.195 micrograms/ml harringtonine induced chromosome breaks in 47% of CHL cells. Both flubendazole and harringtonine caused dose-dependent cytotoxicity to 10T1/2 cells at concentration ranges of 0.04-1.60 and 0.05-0.8 micrograms/ml, respectively. Flubendazole and harringtonine at concentrations of 0.08-0.4 and 0.4-0.8 micrograms/ml, respectively, induced morphological transformation (predominantly type II foci) in 10T1/2 cells. Three of four harringtonine-transformed cell lines and two of four flubendazole-transformed cell lines formed foci in reconstruction experiments with non-transformed 10T1/2 cells. All four harringtonine-transformed and all four flubendazole-transformed cell lines formed colonies in soft agar. Similar concentrations of flubendazole and harringtonine induced chromosome damage in CHL cells and cytotoxicity and morphological transformation in 10T1/2 cells. The ability of flubendazole to induce polyploidy may be part of the mechanism by which this compound induces morphological transformation. Similarly, the ability of harringtonine to induce chromosomal aberrations may be part of the mechanism by which this compound induces morphological transformation. Therefore, flubendazole and harringtonine induce cytotoxicity and morphological and anchorage-independent transformation, harringtonine induces chromosome aberrations (breakage, translocation, and rings), and flubendazole induces polyploidy in cultured mammalian cells. The clastogenic and cell transformation-inducing properties of these compounds suggest that these drugs may have carcinogenic potential. This should be investigated rigorously in animal carcinogenesis bioassays. The genotoxicity of these drugs should be considered during their development as antiparasitic and antineoplastic agents.
Animals↗
Uptake, initial effects, and chemotherapeutic efficacy of harringtonine in murine leukemic cells sensitive and resistant to vincristine and other chemotherapeutic agents.
[3H]Harringtonine was shown to be taken up rapidly by L1210/0 cells using a fast-mixing, fast-separating technique and was retained with a slow rate of limited release to the medium. Cells resistant to vincristine (L1210/VCR) showed impaired capability to take up the drug at 20 degrees. Its initial uptake in L1210 sublines in vitro was: L1210/0 greater than L1210/cyclophosphamide, L1210/1-beta-D-arabinofuranosylcytosine, L1210/6-mercaptopurine greater than L1210/5-fluorouracil, L1210/Adriamycin greater than L1210/VCR. In [3H]harringtonine-preloaded cells, L1210/0 retained significantly more radioactivity than did L1210/VCR cells after repeated washing with fresh medium at 37 degrees. The radioactivity appeared to be predominantly bound to the microsomal fractions. [3H]Leucine incorporation into protein in L1210/0 cells was inhibited 90% within 15 min by harringtonine (0.5 micrograms/ml); incorporation of [3H]thymidine into DNA and [3H]cytidine into RNA was much less inhibited and showed an apparent lag of onset for 5 and 10 min, respectively. The relative potency of harringtonine to inhibit [3H]leucine incorporation in the above sublines in vitro follows an order similar to their rates of uptake of harringtonine by these sublines of cells. The efficacy of harringtonine, 2.4 or 3.6 mg/kg i.p., in increasing the life span of C57BL/6 X DBA/2 F1 mice bearing the sublines of leukemic cells, on the average, was: L1210/0 greater than L1210/cyclophosphamide, L1210/6-mercaptopurine greater than L1210/1-beta-D-arabinofuranosylcytosine, L1210/5-fluorouracil greater than L1210/Adriamycin, L1210/VCR. These results suggest that: (a) protein synthesis is the major initial target for the effect of harringtonine; (b) harringtonine bound more tightly to the cellular components of VCR-sensitive leukemic cells than to VCR-resistant cells; and (c) cellular uptake of harringtonine and the relative potency of inhibiting protein synthesis in sublines have a rank order similar to the chemotherapeutic efficacy of harringtonine in these cells.
Alkaloids↗
[Growth inhibition of human myeloid leukemia cells in vitro by harringtonine].
Harringtonine was discovered as an anticancer agent in China. It has been shown to be effective against myeloid leukemia. In this report, we have demonstrated that harringtonine inhibited the growth of human myeloid leukemia cells in vitro at low concentrations. Together with the clinical data in which 28% of the patients could be induced into complete remission only by harringtonine, this agent may be used as a first choice of antileukemia agents in the treatment of myeloid leukemia. The mechanism of the antitumor action of harringtonine is considered to be an effect on protein synthesis and is characterized by breakdown of polysomes to monosomes. The mechanism of action appears to be different from those of the other antileukemia agents, such as cyclophosphamide, daunorubicin, vincristine, or cytosine arabinoside. Harringtonine could be added to the other anti-leukemia agents used routinely in treatment of leukemia, and the combination of harringtonine with the other agents is expected to improve the therapy of myeloid leukemia.
Alkaloids↗
Potentiation of harringtonine cytotoxicity by calcium antagonist diltiazem and biscoclaurine alkaloid cepharanthine in adriamycin-resistant P388 murine leukemia and K562 human leukemia cells.
Harringtonine showed cross resistance in adriamycin-resistant murine leukemia P388 (P388/ADM) and human leukemia K562 (K562/ADM) cells. The relative resistance of the P388/ADM and K562/ADM cells to harringtonine was about 7 and 40, respectively. Calcium influx blockers, diltiazem and the biscoclaurine alkaloid cepharanthine enhanced the cytotoxicity of harringtonine in P388/ADM and K562/ADM cells. The extent of enhancement was different for the two drugs, and up to a 9- to 10-fold increase in harringtonine cytotoxicity occurred in P388/ADM cells, and 14- to 22-fold enhancement in K562/ADM cells with diltiazem or cepharanthine. Harringtonine resistance of P388/ADM was circumvented completely, and the resistance of K562/ADM was circumvented partially, by diltiazem or cepharanthine. The mechanism of enhanced cytotoxicity by diltiazem and cepharanthine is probably inhibition of active efflux of harringtonine in P388/ADM and K562/ADM cells.
Alkaloids↗
[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↗
Leukemic cell differentiation in vivo and in vitro: arrest of proliferation parallels the differentiation induced by the antileukemic drug Harringtonine.
A variety of chemical agents have been shown to induce differentiation in in vitro cultured neoplastic cell lines. We noted that blast cells in the peripheral blood of acute nonlymphoid leukemia patients treated with the drug Harringtonine appeared to undergo morphological changes that suggested differentiation. In view of the relatively minimal myelotoxicity of Harringtonine, we hypothesized that harringtonine was acting by differentiation-induction, which concomitantly arrested cell division. We tested this hypothesis using two different experimental approaches. First, the promyelocytic leukemic cell line, HL-60, was cultured with Harringtonine and shown to differentiate into a cell, which, by functional cell surface marker and morphological criteria, closely resembled normal monocytes. Furthermore, these changes were accompanied, and indeed slightly preceded by, loss of proliferative capacity. Second, to prove that the leukemic blasts were the cells undergoing the changes observed in vivo, freshly isolated leukemia cell populations were cultured with Harringtonine, and morphological changes paralleling those seen in the patients were observed. Thus, the antileukemic effect of Harringtonine appeared to be due to diversion of the proliferating blast cells into a differentiation pathway, which, as in normal myeloid cells, resulted in the arrest of proliferation.
Acute Disease↗
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↗
[Study of the efficiency and stability of harringtonine encapsulation in whole phospholipid vesicle from human erythrocyte membrane].
The whole phospholipid of human erythrocyte membrane was used to prepare small unilamellar vesicles (SUV) of harringtonine by reversed phase evaporation combined with sonication scattering method. The percentage of harringtonine encapsulation and its stability were also studied. The results showed that the concentration of phospholipid and its degree of oxidation were the main influencing factors. The percentage of harringtonine encapsulation under our experimental conditions reached 21.5%. Stability test showed that the rate of leakage of harringtonine from liposome was 7.3% when stored at 4 degrees C for two months.
Alkaloids↗
Quantification of homoharringtonine and harringtonine in serum by chemical ionization mass spectrometry.
Homoharringtonine and harringtonine are esters of cephalotaxine and are naturally occurring alkaloids in certain coniferous trees in China. These compounds have been shown to have activity against certain types of leukemia in cell cultures, experimental animals, and initial clinical trials in China, and will undergo Phase I trials in several institutions. A gas chromatographic mass spectrometric technique was developed for the quantification of both drugs in serum. One drug serves as internal standard for the other. The drugs are extracted from serum with dichloromethane and are quantified by monitoring the protonated molecular ions of the trimethylsilyl derivatives obtained by chemical ionization (methane). Masses monitored are: m/z = 690 for homoharringtonine and m/z = 676 for harringtonine. Detection limit: 10 ng ml-1 (20 nmol); reproducibility: 1.6-15.0% in the 0-200 ng ml-1 range. Serum levels of harringtonine reached 145 ng mg-1 upon intraperitoneal injection of 3 mg kg-1 in BDF-3 mice.
Alkaloids↗
Activity of camptothecin, harringtonin, cantharidin and curcumae in the human tumor stem cell assay.
The antitumor activity of four investigational natural products (camptothecin, harringtonin, cantharidin and curcumae) obtained from China were tested on human tumor biopsies in an in vitro soft agar clonogenic assay system. Significant antitumor activity was seen with camptothecin against human ovarian cancer and some other adenocarcinomas. Antitumor activity was also observed for harringtonin against adenocarcinoma and sarcoma. Both drugs also appeared to show activity in melanoma and mesothelioma. However, cantharidin and curcumae were relatively ineffective on the human tumors tested. For purposes of comparing the intensity of antitumor effects with standard cytotoxic drugs to those of the four new agents, the ID50 values were calculated. The ratio of ID50S of new drugs to the standard agents doxorubicin, cis-platinum and vinblastine (ID50 of the standard drug/ID50 of tested drug) were 10.2, 64.1 and 1.9 for camptothecin and 1.5, 10.3 and 0.9 for harrington respectively. A relationship was observed between the duration of drug exposure (1 hr prior to plating vs continuous contact in the agar) and inhibition of clonogenic tumor cells for camptothecin, harringtonin and doxorubicin.
Alkaloids↗
Treatment of acute leukemia with rifampin and low dose harringtonine. Analysis of 14 cases.
We evaluate the efficacy of rifampin combined with low dose harringtonine in acute leukemia (Group A, acute lymphocytic leukemia (ALL) 6 cases and acute non-lymphocytic leukemia (ANLL) 8 cases) in comparison with the patients treated with low dose harringtonine only (Group B, 8 ALL, and 5 ANLL). The complete remission (CR) rate in Groups A and B was 64.3% and 23.1%, while the median CR duration, 17 months and 8 months respectively, Group A was more effective than Group B. We also consider that rifampin and low dose harringtonine are more applicable for treatment of ANLL patients without peripheral leukocytosis and those complicated with infection.
Adolescent↗
Small-dose Harringtonine induces complete remission in patients with acute promyelocytic leukemia.
Small-dose Harringtonine (1-3 mg infused during 4-5 hr) was used as a single agent to treat 10 patients with acute promyelocytic leukemia. Every patient received one to three courses, each lasting 13-81 days (mean 33 days). The interval between courses (i.e., interruptions) was 5-11 days. During treatment, marrow aplasia occurred in one patient and hypoplasia in three. Pancytopenia occurred in all 10 patients. Complete remission was achieved in seven patients (70%) and cytoreduction in two. In vitro studies showed that, although Harringtonine produced a decrease in leukemic cells in all five series of marrow cultures from five patients, there was only one wherein the decrease was accompanied by a simultaneous absolute increase in differentiated myeloid cells. Considerable discrepancy existed between the culture results and clinical responses. These results seem to suggest that the therapeutic effect of Harringtonine on acute promyelocytic leukemia originates chiefly from cytotoxicity.
Adolescent↗
Inhibition of translation in eukaryotic systems by harringtonine.
The Cephalotaxus alkaloids harringtonine, homoharringtonine and isoharringtonine inhibit protein synthesis in eukaryotic cells. The alkaloids do not inhibit, in model systems, any of the steps of the initiation process but block poly(U)-directed polyphenylalanine synthesis as well as peptide bond formation in the fragment reaction assay, the sparsomycin-induced binding of (C)U-A-C-C-A-[3H]Leu-Ac, and the enzymic and the non-enzymic binding of Phe-tRNA to ribosomes. These results suggest that the Cephalotaxus alkaloids inhibit the elongation phase of translation by preventing substrate binding to the acceptor site on the 60-S ribosome subunit and therefore block aminoacyl-tRNA binding and peptide bond formation. However, the Cephalotaxus alkaloids do not inhibit polypeptide synthesis and peptidyl[3H]puromycin formation in polysomes. Furthermore, these alkaloids strongly inhibit [14C]trichlodermin binding to free ribosomes but hardly affect the interaction of the antibiotic with yeast polysomot interact with polysomes and therefore only inhibit cycles of elongation. This explains the polysome run off that has been observed by some workers in the presence of harringtonine.
Alkaloids↗
Influence of harringtonine on human leukemia cell differentiation.
The influence of low doses of harringtonine (Ht) on differentiation of blood cells from acute myeloblastic (AML) and lymphoblastic leukemia (ALL) patients diagnosed according to FAB classification was tested. Out of five cases of ALL only in one case differentiation into mature lymphocytes appeared. In two cases out of four of AML differentiation was seen in one case into more mature granulocytic series and in another one into monocytes. Two out of 3 acute myelomonocytic leukemias (AMMOL) differentiated, one into more mature granulocyte cells and one into monocytes. One of our patients with AML (M2) in relapse was treated with ht using HOAP (harringtonine, oncovin, adriblastine, prednisone) schedule with good but transient effect. Prior to therapy in vitro tests performed with ht showed differentiation of leukemic cells into more mature granulocyte cells.
Alkaloids↗
Partial synthesis of harringtonine.
The partial synthesis of harringtonine from cephaltotaxine has been described. A key intermediate, 5, 5-dimethyl-2-hydroxytetrahydrofuran-2-carboxylic acid (V), prepared from 4-methyl-1, 4-valerolactone, was dehydrated smoothly to give 5, 5-dihydrofuran-2-carboxylic acid (VI), Through its sodium salt, VI was converted into the corresponding acyl chloride VIII, which reacted with cephalotaxine in the presence of pyridine to give ester IX. After being treated with hydrichloric-acetic acid, ester IX unerwent Reformatsky reaction to give a mixture (XIV) of harringtonine and its diastereoisomer (epiharringtonine) as the final product which was purified either by countercurrent distribution or column chromatography on neutral alumina. The amounts of the two epimers in the mixture shown by TLC were roughly equal.
Alkaloids↗