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PubMed1981

Antitubulin activity of vinblastine and vincristine. Clinical implications of the radial segmentation test.

The antitubulin activity of vinblastine and vincristine was compared by means of the radial segmentation test. Vinblastine was found to have antitubulin activity at least 6 times higher than that of vincristine. It is concluded that, if the differential indications for vinblastine or vincristine are balanced, it may be decisive for clinical treatment that more antitubulin activity can be administered as vinblastine than as vincristine.

Cell Nucleus↗
PubMed1993

Differential effects of cytoskeletal agents on hemispheric functional expression of cell membrane receptors in Xenopus oocytes.

1. We studied the effects of three cytoskeleton-disrupting agents, colchicine (COL), vinblastine (VIN), cytochalasins, on the functional hemispheric expression of native muscarinic and acquired thyrotropin-releasing hormone receptors TRH-Rs). Responses in oocytes of common donors, which express M3-like receptors (M3Rs), were not affected by either COL or VIN on the animal hemisphere. The functional expression of M3Rs on the vegetal hemisphere was inhibited by 50%. Cytochalasin B caused a uniform inhibition (by 31-33%) of receptor functional expression on either hemisphere. 2. Oocytes of variant donors express predominantly M1-like receptors (M1Rs) on the animal and M3Rs on the vegetal hemisphere. In these oocytes, both COL and VIN caused approximately 50% inhibition of functional expression on either hemisphere. Cytochalasin B caused more extensive, though variable inhibition on both hemispheres. Both antitubulin agents had no effect on the functional expression of the TRH-Rs on either hemisphere. Cytochalasin B, however, caused an extensive inhibition of the functional expression of this receptor (by 70-75%). 3. Induction of maturation of oocytes (7-hr incubation with progesterone) resulted in a 66% decrease in the response to TRH, reflecting mainly a decrease on the animal hemisphere. Maturation in the presence of colchicine had no further effect on the activity measured on the animal hemisphere but caused a major increase in the activity on the vegetal hemisphere. This resulted in a dramatic change in animal/vegetal activity ratio (4.8 +/- 1.5 to 0.8 +/- 0.2). 4. It appears that while antitubulin drugs affect the functional expression of the three receptors at the two hemispheres differently, disruption of the microfilaments interferes uniformly with receptor functional expression. We suggest that microfilaments may be involved in a common component of the signal transduction pathway in oocytes or in the anchoring of receptors coupled to the guaninine nucleotide-binding regulatory proteins. Moreover, progesterone-induced changes in the functional organization of the signal transduction pathway appear to be controlled to a large extent by the tubulin component of the cytoskeleton.

Amino Acids↗
PubMed1990

Microtubule inhibitors block the morphological changes induced in Drosophila blood cells by a parasitoid wasp factor.

The shape change of Drosophila melanogaster blood cells (lamellocytes) from discoidal to bipolar that is caused by a factor from the female parasitoid Leptopilina heterotoma is blocked by the tubulin inhibitors vinblastine and vincristine in vitro. The actin inhibitor, cytochalasin B, causes arborization of Drosophila lamellocytes and acts synergistically with the wasp factor to alter lamellocyte morphology. Lamellocyte aborization induced by cytochalasin B is blocked by simultaneous treatment with vinblastine. These observations indicate that the changes in lamellocyte shape induced by both the wasp factor and cytochalasin B require microtubule assembly.

Animals↗
PubMed1989

Isolation and structure of the strong cell growth and tubulin inhibitor combretastatin A-4.

The African tree Combretum caffrum (Combretacae) has been found to contain a powerful inhibitor of tubulin polymerization (IC50 2-3 microM), the growth of murine lymphocytic leukemia (L 1210 and P 388 with ED50 approximately 0.003 microM and human colon cancer cell lines [(e.g. LoVo (ED50 = 0.005 microgram/ml), HT 29 (ED50 0.02 microgram/ml, Colo 205 (ED50 = 0.07 microgram/ml), DLD-1 (ED50 = 0.005 microgram/ml) and HCT-15 (ED50 = 0.0009 microgram/ml] designated combretastatin A-4 (1c). The structure assigned by spectral techniques was confirmed by synthesis.

Animals↗
PubMed1977

Smooth muscle sensitization induced by colchicine: is it an in vitro property of antitubulin agents?

Colchicine 0.1 microgram/ml induces a reversible increase of guinea-pig isolated ileum contractions (50 to 60% of maximal contractions) to acetylcholine, nicotine and PGE2. At 1 microgram/ml, it induces an irreversible increase of similar contractions to acetylcholine and 5-hydroxytryptamine. Low concentrations of indomethacin are able to reduce or even to abolish this increase. This smooth muscle sensitization could be related to the ability of colchicine to stimulate prostaglandin biosynthesis. Vinblastine has been described to induce a similar in vitro sensitization of guinea-pig isolated ileum. This effect might be also a non-specific property of antitubulin agents. The relationships between such an in vitro sensitization and the clinical effects of colchicine, including diarrhea, remain unclear.

Animals↗
PubMed1985

Enhanced expression of Epstein-Barr virus early antigens by antitubulin agents in a latently infected human lymphoblastoid cell line.

28 anticancer agents have been surveyed for Epstein-Barr virus (EBV) activating potency. Two vinca alkaloids with antitubulin activity, vinblastine (VLB) and vincristine (VCR), enhanced the expression of EBV early antigens (EA) in a latently infected human lymphoblastoid cell line (Raji), when used in combination with n-butyrate. Other antitubulin agents, colchicine, colcemid, and podophyllotoxin, had the same effect, although their effects were less than that of the potent tumor promoter, 12-O-tetradecanoyl phorbol-13-acetate (TPA).

Antigens, Viral↗
PubMedDate not supplied

Anticancer drug design based on plant-derived natural products.

This review article focuses on recent research in my laboratory on various classes of compounds that possess potent antitumor activity. These compounds were obtained by bioactivity- and mechanism of action-directed isolation and characterization coupled with rational drug design-based modification and analog synthesis. Structural modification, structure-activity relationship, and mechanism of action studies will be discussed.

Animals↗
PubMed1998

Role of the cytoskeleton in stimulation of Na+ channels in A6 cells by changes in osmolality.

Permeable supports with A6 cell monolayers were mounted in an Ussing chamber and bilaterally bathed with Ringer solution at room temperature. Short-circuit current (Isc) was recorded continuously, and noise analysis revealed microscopic channel current characteristics. Our investigation focuses on the stimulation of apical Na+ entry caused by exposing the serosal surface of the A6 cell monolayers to hyposmotic Ringer solution. To evaluate the possible role of the cytoskeleton in the regulation of Na+ channels in response to a change in osmolality we used four different experimental approaches. In the control group, which were not exposed to any cytoskeleton-influencing drugs, there was a 1.5-fold increase in Isc and in the number of open Na+ channels after osmotic stimulation. For the second group cytochalasin D (0.1 microg/ml) was present on the serosal side during the experiments. Neither Isc nor the number of open Na+ channels increased after osmotic stimulation. In the third group colchicine (0.2 mM) or nocodazole (20 microM) was present on the serosal side, which resulted in 1.8-fold and 1.5-fold increases in Isc as well as 3-fold and 2-fold increases in the number of Na+ channels, respectively. In the fourth experimental group erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride (EHNA, 0.5 mM), a dynein inhibitor, was present on the serosal side. In this group Isc decreased to about 0.4 microA/cm2, and subsequent application of amiloride abolished Isc completely. Under hyposmolar conditions EHNA abolished entirely the sensitivity of Isc to the osmotic challenge. Because of the EHNA-induced down-regulation of Isc, the density of apical Na+ channels in this experimental group could not be determined. These results show that the cytoskeleton is dominantly involved in osmotic channel regulation at the apical membrane, and that actin filaments, microtubules and molecular motors are involved in the recruitment of additional Na+ channels.

Actins↗
PubMed2000

Resistance to arsenite modulates levels of alpha-tubulin and sensitivity to paclitaxel in Leishmania donovani.

Tubulin expression is known to alter due to drug resistance. Differentiation of Leishmania promastigotes into infectious amastigotes has been reported to be accompanied by differential tubulin gene expression. In this study, alpha-tubulin expression under various stages of differentiation was measured in an in vitro generated arsenite-resistant L. donovani strain. While levels of expression of alpha-tubulin were similar in wild type and resistant promastigotes, during conversion into axenic amastigotes the changes in the expression levels of alpha-tubulin varied widely between the two strains. Sensitivity of the two strains to paclitaxel (known to promote tubulin assembly) differed, with the resistant strain being two-fold more sensitive than the wild type strain. Paclitaxel was also seen to cause differential effects on alpha-tubulin levels in the two strains.

Animals↗
PubMed2004

A quantitative evaluation of the effects of inhibitors of tubulin assembly on polymerization induced by discodermolide, epothilone B, and paclitaxel.

PURPOSE: To determine whether inhibitors of microtubule assembly inhibit polymerization induced by discodermolide and epothilone B, as well as paclitaxel, and to quantitatively measure such effects. METHODS: Inhibition was quantitated by measuring polymer formation either by turbidimetry or by centrifugation, and the amount of inhibitor required to inhibit 50% relative to an appropriate control reaction was determined. RESULTS: The inhibitory drugs evaluated were four colchicine site agents (combretastatin A-4, podophyllotoxin, nocodazole, and N-acetylcolchinol- O-methyl ether), maytansine, which competitively inhibits the binding of Catharanthus alkaloids to tubulin, halichondrin B and phomopsin A, which noncompetitively inhibit the binding of Catharanthus alkaloids to tubulin, and the depsipeptide dolastatin 15. While relative inhibitory effects were highly variable, a few broad generalizations can be made. First, assembly reactions that were either enhanced or dependent upon all three stimulatory drugs were subject to inhibition by all inhibitors. Second, the more readily the tubulin assembled, the greater the concentration of inhibitor required to inhibit polymerization. Drug IC50 values were generally lowest with no stimulatory drug and highest when discodermolide was present; IC50 values were higher as reaction temperature increased; and IC50 values were higher as the tubulin concentration increased. Third, inhibition of assembly by inhibitors of Catharanthus alkaloid binding to tubulin changed much less as a function of changes in reaction conditions than inhibition by inhibitors of colchicine binding. CONCLUSIONS: Since there was no apparent quantitative predictability of combined drug interactions with tubulin, any combination of interest must be studied in detail.

Alkanes↗
PubMed2005

Differential sensitivity of paclitaxel-induced apoptosis in human esophageal squamous cell carcinoma cell lines.

PURPOSE: Paclitaxel is a highly effective chemotherapy agent against adenocarcinomas and squamous cell carcinomas of the esophagus. However, its precise effects in human esophageal cancer cells are not well understood. This study was designed to examine the relationship between cell-cycle phases of paclitaxel-activated checkpoints and to elucidate the molecular pathway of the effect of paclitaxel in human esophageal squamous cell carcinoma (ESCC) cell lines. METHODS: The three human ESCC cell lines--TE-2, TE-13 and TE-14--were examined for their response to paclitaxel. ESCC cells were treated with various concentrations of paclitaxel for 1-3 days using MTT assay. The cell-cycle progression and apoptosis were examined by flow cytometry. DNA fragmentation assay was carried out to confirm the fragmented cells as hallmark for apoptotic cells. In additional, the expression of apoptosis-related proteins in ESCC-treated cells was then examined by Western blot analysis. RESULTS: TE-14 cells demonstrated the highest sensitivity among all cells. G2/M cell-cycle arrest occurs prior to paclitaxel-induced apoptosis in ESCC cells. The fragmentation of chromatin was observed in drug treated TE-13 and TE-14 cells by flow cytometry and DNA ladder formation. In contrast, the measurement for TE-2 cells was more suggestive of phenotype a resistant in response to paclitaxel treatment. Western blot analysis results showed that the mitochondrial pathway might be involved in paclitaxel-induced apoptosis in ESCC cell lines. CONCLUSION: Differential sensitivity was observed in human ESCC cell lines in response to paclitaxel treatment. G2/M arrest occurs with a prior to paclitaxel-induced apoptosis and might be mediated by the mitochondrial (intrinsic) apoptosis pathway in human ESCC cells.

Antineoplastic Agents, Phytogenic↗
PubMed2006

Retention of paclitaxel in cancer cells for 1 week in vivo and in vitro.

PURPOSE: Clinically, the administration of paclitaxel for ovarian cancer on a dose-dense weekly schedule, rather than the conventional every-3-week schedule, might demonstrate greater tumor-cell death. Here, we investigate the pharmacokinetics and the pharmacodynamics of weekly paclitaxel in cancer cells in vivo and in vitro. EXPERIMENTAL DESIGN: Paclitaxel concentrations were measured by HPLC, and apoptotic cells were detected by TUNEL assay in paclitaxel-pretreated cervical cancer cells treated with paclitaxel (10 ng/ml) and in the tissues of cervical cancer patients treated with weekly paclitaxel (60 mg/m2/week). Polymerized tubulin was detected with a tubulin polymerization assay, and the BrdU cell proliferation assay was used to assess the effect of paclitaxel. RESULTS: Paclitaxel remained in the cancer tissues of six patients for 6 days after the last medication. In vitro, paclitaxel was retained in all cell lines for 24 h after its removal from the medium, and paclitaxel was still detectable in CaSki cells on day 7. Simultaneous treatment with depolymerizing drugs inhibited the retention of paclitaxel in cells and paclitaxel-induced polymerization of tubulin. After paclitaxel treatment, apoptotic cells were detected in cancer tissues and CaSki cells for 1 week. Under high magnification, apoptotic cells on day 7 after paclitaxel treatment showed multinucleation. CONCLUSIONS: Paclitaxel is unusual in that it accumulates especially in cancer cells and induces apoptosis for 1 week in vivo and in vitro. On the other hand, paclitaxel could not be detected in cancer tissues after 2 weeks. The administration of paclitaxel on a weekly schedule, rather than the standard every-3-week schedule, might produce greater tumor-cell death.

Antineoplastic Agents, Phytogenic↗
PubMed2006

Phase I study of TZT-1027, a novel synthetic dolastatin 10 derivative and inhibitor of tubulin polymerization, which was administered to patients with advanced solid tumors on days 1 and 8 in 3-week courses.

PURPOSE: To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of TZT-1027 (soblidotin), a dolastatin 10 analogue, in Japanese patients with advanced solid tumors when administered on days 1 and 8 in 3-week courses. METHODS: Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was available, and also met the following criteria: prior chemotherapy < or = 2 regimens, Eastern Cooperative Oncology Group (ECOG) performance status < or = 1, and acceptable organ function. The MTD was defined as the highest dose at which no more than one of six patients experienced a DLT during course 1. Pharmacokinetic samples were collected in courses 1 and 2. RESULTS: Eighteen patients were enrolled in the present study. Three doses (1.5, 1.65, and 1.8 mg/m(2)) were evaluated. Neutropenia was the principal DLT at doses of 1.65 and 1.8 mg/m(2). In addition, one patient also experienced grade 3 pneumonia with neutropenia, and another patient experienced grade 3 constipation, neuropathy, grade 4 neutropenia, and hyponatremia as DLTs at 1.65 mg/m(2). Phlebitis, the most frequent nonhematological toxicity, was improved by administration of additional saline after TZT-1027 administration. The MTD was 1.5 mg/m(2), at which DLT was not observed in a total of nine patients. The pharmacokinetic profile did not differ from that for the European population. One patient with metastatic esophageal cancer achieved partial response, and each of two patients with non-small cell lung cancer had a minor response. CONCLUSIONS: When TZT-1027 was administered on days 1 and 8 in 3-week courses to Japanese patients, the MTD was 1.5 mg/m(2) and was lower than the value of 2.4 mg/m(2) in European patients. However, antitumor activity was observed at low doses. TZT-1027 was tolerated well at the MTD, without grade 3 nonhematological toxicities or neutropenia up to grade 2. TZT-1027 is a promising new tubulin polymerization inhibitor that requires further investigation in phase II studies.

Aged↗
PubMed2006

Comparison of the slow-release polymer-based paclitaxel-eluting Taxus-Express stent with the bare-metal Express stent for saphenous vein graft interventions.

BACKGROUND: The paclitaxel-eluting Taxus-Express stent is superior regarding angiographic and clinical outcome compared with its bare-metal platform for lesions in native coronary arteries. We studied the potential impact of the Taxus-Express stent in comparison with its bare-metal counterpart for treatment of lesions in saphenous vein grafts (SVGs). Furthermore, a meta-analysis was performed regarding use of drug-eluting (DES) vs bare-metal stents (BMS) in SVG lesions. METHODS: We analyzed 13 consecutive patients who underwent percutaneous revascularization in SVG lesions using the slow-release, paclitaxel-eluting Taxus-Express stent. These lesions were balanced with 26 patients with SVG lesions treated with the bare-metal Express stent (BMS) in the preceding period. Angiographic follow-up was performed after 6 months, clinical follow-up after 6 and 12 months. RESULTS: There were no statistically significant differences regarding clinical, procedural and angiographic parameters pre and post intervention. Binary restenoses occurred significantly less in the Taxus group compared with the BMS group (0% vs 34.6%; p=0.016). This translated into a significantly lower occurrence of major adverse cardiac events (death, Q-wave myocardial infarction, repeat target vessel revascularization) in the Taxus group compared with the BMS group at the 6-month (0% vs 26.9%, p=0.039) and 12-month follow-up (7.7% vs 38.5%, p=0.045). Multivariate predictors for freedom of binary restenosis were the reference diameter pre intervention and treatment with Taxus stents. Meta-analysis including 280 DES and 256 BMS patients revealed an odds ratio of 0.34 (95% confidence interval 0.21-0.54) for MACE and 0.26 (95% confidence interval 0.16-0.44) for target vessel revascularizations, both favoring DES. CONCLUSIONS: We conclude that the use of the slow-release Taxus-Express stent has the potential to be superior regarding angiographic and clinical outcome compared with its bare-metal counterpart for treatment of SVG lesions within a 12-month follow-up. A large, randomized trial including a long follow-up period is now required to prove the results of the meta-analysis.

Aged↗
PubMed2006

Is late stent thrombosis in drug-eluting stents a real clinical issue? A single-center experience and review of the literature.

BACKGROUND: Randomized studies have not found an increased rate of late stent thrombosis (LAST) in drug-eluting stents (DES) compared with bare metal stents (BMS) but those studies were statistically not powered to show such a difference. At the same time there is an increasing number of reports of LAST in DES patients in the current literature. PATIENTS AND METHODS: We tried to describe the incidence of LAST in an unselected DES and BMS patient population. All patients who underwent stenting in our hospital between October 2003 and March 2006 were included in the study (n=1377). A total of 424 (30.1%) patients were treated with only BMS stents, 520 (37.8%) with paclitaxel-eluting stents (PES), 384 (27.9%) with sirolimus-eluting stents (SES) and 49 (3.6%) with BMS and DES. Long-term follow-up of all patients was used to determine the incidence of LAST as defined by angiographically proven stent thrombosis associated with acute symptoms more than 30 days after stent implantation. Followup was between 1 month and 2 years 7 months (mean 12 months). Patients treated with DES were younger (66+/-11 years) than BMS patients (72+/-10 years; p<0.001) and more often had diabetes (24.2% vs 17.4%; p < 0.001). A previous PCI had been performed in 27.1% of DES patients vs 13.9% of BMS patients (p < 0.001). RESULTS: There were 9 cases of LAST: 2 with SES (at 6 and 11 months after implantation), 6 with PES (at 6, 9 (2x), 10, 16 and 26 months), and one with BMS (at 22 months). All patients with LAST presented with STEMI and without an angina history that suggested restenosis. Two cases were related to complete cessation of antiplatelet therapy, one because of patient non-compliance (SES), one after aspirin was stopped for orthopedic surgery (BMS). Two cases occurred within 1 month of cessation of clopidogrel therapy and while these patients were on aspirin therapy. Five cases occurred on aspirin monotherapy 2, 3, 4, 10 and 20 months, respectively after planned cessation of clopidogrel. None of the cases occurred under dual antiplatelet therapy. All patients underwent primary PCI; none died. CONCLUSION: Angiographically proven LAST occurred in our unselected patient population with an incidence of 0.84% in patients treated with DES and 0.21% in BMS patients within a mean follow-up of 12 months (p = 0.36). LAST may indeed occur in clinically stable patients while on aspirin monotherapy. Since LAST led in all patients to STEMI it seems to be a serious clinical issue that prompts further investigation and discussion of length of dual platelet therapy.

Aged↗
PubMed2005

Differential gene expression in a paclitaxel-resistant clone of a head and neck cancer cell line.

The anti-neoplastic drug paclitaxel (taxol), which is known to block cells in the G2/M phase of the cell cycle through stabilization of microtubules, is meanwhile commonly used for chemotherapy of advanced head and neck cancer. Chemotherapy is primarily used in order to preserve laryngeal and/or pharyngeal structures. Although paclitaxel generally seems to be a powerful agent, it failed to reach a loco-regional tumor control in a sufficient percentage of patients. In order to investigate molecular resistance mechanisms, we have established a paclitaxel-resistant subline originating from the larynx carcinoma cell line HLaC79, which seemed to be partially dependent on taxol. The original and the descendant cell line were characterized by growth inhibition assays. We used western blotting and the cDNA subtraction (SSH) technique to identify genes differentially expressed in the taxol-resistant cell clone. cDNA subtraction revealed increased expression of six genes, including clathrin heavy chain, alpha3-tubulin, a neuroblastoma-specific Thymosin beta, the ribosomal protein L7a, HLA-B associated transcript 3 and collagen IIIalpha1 in the taxol-resistant cell line. Furthermore, western blots showed an overexpression of MDR-1 in the taxol-resistant clone, while alpha- and beta-tubulins and p48/IRF9 were expressed in equal amounts in both cell lines.

Biomarkers, Tumor↗
PubMed2006

Localization of Golgi 58K protein (formiminotransferase cyclodeaminase) to the centrosome.

In vertebrate cells, the centrosome consists of a pair of centrioles and surrounding pericentriolar material. Using anti-Golgi 58K protein antibodies that recognize formiminotransferase cyclodeaminase (FTCD), we investigated its localization to the centrosome in various cultured cells and human oviductal secretory cells by immunohistochemistry. In addition to the Golgi apparatus, FTCD was localized to the centrosome, more abundantly around the mother centriole. The centrosome localization of FTCD continued throughout the cell cycle and was not disrupted after Golgi fragmentation, which was induced by colcemid and brefeldin A. Centriole microtubules are polyglutamylated and stable against tubulin depolymerizing drugs. FTCD in the centrosome may be associated with polyglutamylated residues of centriole microtubules and may play a role in providing centrioles with glutamate produced by cyclodeaminase domains of FTCD.

Ammonia-Lyases↗