Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: KEGG:D02165 (Docetaxel)
 1,764 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate the clinical usefulness of taxanes as antitumor agents, we compared the antitumor spectrum of taxanes with those of conventional antitumor agents against 88 fresh gastric cancer specimens by MTT assay. At cut-off concentrations of 100 micrograms/ml for taxotere (Docetaxel, DOC) and 300 micrograms/ml for taxol (Paclitaxel, PAC), both agents showed a higher efficacy rate than mitomycin C (MMC), cisplatin (CDDP) and 5-fluorouracil (5-FU) against the gastric cancer specimens. The patterns of antitumor activity of DOC and PAC were independent from those of the conventional agents, while the patterns of antitumor activity of the taxanes significantly correlated with each other. Conventional agent antitumor activity patterns tended to correlate with the patterns of other conventional agents. In conclusion, taxanes may be useful for clinical application against gastric cancer due to their different antitumor spectrum as compared to conventional agents.
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PMID:No cross-resistance of taxotere and taxol to conventional chemotherapeutic agents against gastric cancers as detected by MTT assay. 1292 47

Taxol (paclitaxel) and Taxotere (docetaxel) are considered as two of the most important anti-cancer chemotherapy drugs. The cytotoxic action of these drugs has been linked to their ability to inhibit microtubule depolymerization, causing growth arrest and subsequent cell death. Studies by a number of laboratories have also linked suppression of mitogen activated protein kinase (MAPK) signaling to enhanced Taxol toxicity. The present study examined the interactions of the semi-synthetic taxane Taxotere with MEK1/2 inhibitors in epithelial tumor cells. Concurrent treatment of MDA-MB-231 mammary and DU145 prostate carcinoma cells with Taxotere and MEK1/2 inhibitor resulted in protection from the anti-proliferative effects of Taxotere in MTT assays. In contrast, in MCF-7 mammary cells, concurrent Taxotere and MEK1/2 inhibitor treatment weakly enhanced the anti-proliferative effects of the taxane. Sequential treatment of MDA-MB-231 and MCF-7 cells with Taxotere followed by MEK1/2 inhibitor also enhanced the anti-proliferative effects of the taxane in MTT assays. However, no enhancement was observed in DU145 or PC-3 cells. Colony formation assays, including isobologram analyses, provided a more definitive demonstration that MCF-7 and MDA-MB-231 cells were sensitized to the toxic effects of Taxotere by U0126. Similar data were observed using Laulimalide, which binds to tubulin at a different site to Taxotere. The enhancement in Taxotere anti-proliferative effects by U0126 correlated with increased cell killing, 48-72h after treatment of cells that was blocked by inhibition of caspase 9, but not caspase 8, function. This observation was associated with prolonged suppression of ERK1/2 and AKT activity, without alteration in either p38 or JNK1/2 activity. Collectively these findings demonstrate that sequential administration of Taxotere followed by MEK1/2 inhibition can lead to increased cell death and loss of reproductive capacity in some, but not all, human tumor cells.
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PMID:Sequence dependent exposure of mammary carcinoma cells to Taxotere and the MEK1/2 inhibitor U0126 causes enhanced cell killing in vitro. 1468 75

The omega-6 polyunsaturated fatty acid gamma-linolenic acid (GLA; 18:3n-6) has raised recent interest as novel anti-cancer agent as it possesses effective tumoricidal properties while not inducing damage to normal cells or creating harmful systemic side effects. The taxane docetaxel (Taxotere) is currently one of the most active microtubule-interfering agents for breast cancer. Despite this encouraging therapeutical potential, the clinical use of taxanes involves problems related to the solubility, toxicity and development of drug resistance, which may be partially dependent on the expression of HER-2/neu oncogene. Current trends in the treatment of human tumors are for drug combinations that result in improved responses as well as the ability to use less toxic concentrations of the drugs. Here, we examined the cytotoxic effects of GLA in combination with docetaxel against estrogen-dependent (MCF-7) and estrogen-independent (MDA-MB-231 and SK-Br3) human breast carcinoma cell lines. The cells were exposed simultaneously to GLA and docetaxel or sequentially to GLA followed by docetaxel for 24 h. Cytotoxicity was evaluated by the MTT assay, and the nature of the interactions between GLA and docetaxel (antagonism, additivity, and synergism) was analyzed by median effect and isobologram analyses. Interaction assessment showed that concurrent exposure to GLA plus docetaxel for 24 h resulted in synergism for MCF-7 and MDA-MB-231 cells, whereas an additive effect was observed in SK-Br3 cells. When exposure to GLA (24 and 48 h) was followed sequentially by docetaxel (24 h) a synergistic effect was observed in MDA-MB-231 and SK-Br3 cells, whereas an additive effect was found in MCF-7 cells. GLA-mediated increase in docetaxel cytotoxicity was only marginally abolished by Vitamin E, a lipid peroxidation inhibitor. Moreover, simultaneous exposure to GLA and docetaxel in the presence of the anti-oxidant Vitamin E also resulted in synergism, suggesting a limited influence of the oxidative status of GLA in achieving potentiation of docetaxel-induced cytotoxicity. Further experiments showed that GLA markedly decreased the expression of p185HER-2/neu oncoprotein in MCF-7 breast cancer cells (</=85%), and RT-PCR analysis revealed that HER-2/neu mRNA was selectively decreased in a concentration-dependent manner following GLA treatment. Therefore, our results show that the fatty acid GLA enhances the cytotoxicity of docetaxel in human breast cancer cells by mechanisms other than lipoperoxidation, and that GLA-induced transcriptional repression of HER-2/neu oncogene might be one component of the mechanisms of this interaction.
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PMID:Omega-6 polyunsaturated fatty acid gamma-linolenic acid (18:3n-6) enhances docetaxel (Taxotere) cytotoxicity in human breast carcinoma cells: Relationship to lipid peroxidation and HER-2/neu expression. 1513 62

The microtubule stabilizing agent peloruside A binds to a unique site on the tubulin alpha,beta-heterodimer compared to taxoid site drugs such as paclitaxel (Taxol), docetaxel (Taxotere), epothilone A, and discodermolide. Because the binding sites differ, peloruside A may be able to synergize with these taxoid site drugs when added in combination to cultured cells. Ovarian carcinoma cells (1A9) and myeloid leukemic cells (HL-60) were treated with different concentrations of peloruside A and taxoid site drugs, both compounds given singly and in combination in the nanomolar range, and the antiproliferative activity, G2/M blocking potency, and microtubule stabilizing activity of the treatments assessed. Cell proliferation was monitored using the MTT cell proliferation assay, cell cycle block was determined by flow cytometry, and stabilization of the tubulin polymer was assessed by Western blotting for beta-tubulin distributions in supernatant and pellet fractions of cell lysates. A combination index (CI) was calculated from the equation CI = D1/Dx1 + D2/Dx2 in which D1 and D2 are the concentrations of drug 1 and drug 2 that in combination give the same response as drug 1 alone (Dx1) or drug 2 alone (Dx2). A CI of less than 1 indicates synergy, equal to 1, additivity, and greater than 1, antagonism. Confidence intervals for each CI value were obtained using a bootstrapping procedure. In cell proliferation assays, statistically significant synergy was found between peloruside A and paclitaxel and epothilone A. Combinations of these two taxoid site drugs, however, also showed synergy in their effects on cell proliferation. These results confirm that peloruside A, when added in combination with other microtubule stabilizing agents, acts synergistically to enhance the antimitotic action of the drugs, but also highlight the complexity of drug interactions in intact cells.
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PMID:Peloruside A synergizes with other microtubule stabilizing agents in cultured cancer cell lines. 1739 39

Before transplantation, the heart graft is preserved by the use of cold storage in order to limit ischemia-reperfusion stress. However, sustained exposure to low temperature may induce myocardial ultrastructural damage, particularly microtubules (MT) disruption. Previous data suggested that tubulin-binding agents are able to attenuate cold-induced cytoskeleton alterations. Thus, the aim of the present work was to study the influence of docetaxel (DX, a tubulin-binding taxane) on the effects of deep hypothermia (4 degrees C) and of simulated cold ischemia-reperfusion on the MT network and oxidative stress of cardiomyocyte (CM) in monolayer cultures prepared from newborn rat ventricles. The MT network was explored by immunocytochemistry and Western-blotting, the cell stress by tetrazolium dye assay (MTT) and lactate dehydrogenase (LDH) release, and the superoxide production by the dihydroethidium probe (DHE). The MT assembly remained stable after 4 and 8 h of hypothermia. Tubulin acetylation was promoted in CM subjected to 4-h hypothermia. Low temperature reduced the mitochondrial function and increased the basal LDH release. The cold ischemia during 4 and 8 h preserved MT network. Docetaxel promoted MT polymerization and tubulin acetylation in basal and in cold conditions. This drug decreased the release of LDH induced by cold ischemia. Moreover, hypothermia (4 h) significantly raised the anion superoxide production. Docetaxel decreased this oxidative stress in the control CM and in CM submitted to 4 h of hypothermia. These data demonstrated that stabilizing MT with DX exerted a protective effect on CM subjected to hypothermia and to cold ischemia-reperfusion. Tubulin-ligands should be thus considered to improve the tolerance of the heart graft toward stressing conservative conditions.
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PMID:Involvement of microtubules in the tolerance of cardiomyocytes to cold ischemia-reperfusion. 1782 77

Docetaxel (DX) is one of the most effective antineoplastic drugs. Its current clinical administration is limited because of its hydrophobicity and serious side effects. A polymer/DX conjugate is designed and successfully prepared to solve these problems. It is monomethoxy-poly(ethylene glycol)-block-poly(L-lactide)/DX (MPEG-PLLA/DX). It was synthesized by reacting DX with carboxyl-terminated copolymer MPEG-PLLA, which was prepared by reacting succinic anhydride with hydroxyl-terminated copolymer monomethoxy-poly(ethylene glycol)-block-poly(L-lactide) (MPEG-PLLA). Its structure and molecular weight was confirmed by (1)H NMR and GPC. The MPEG-PLLA/DX micelles in aqueous solution were prepared using a solvent displacement method and characterized by dynamic light scattering for size and size distribution, and by transmission electron microscopy for surface morphology. Its antitumor activity against HeLa cancer cells evaluated by MTT assay showed that it had a similar antitumor activity to pure DX at the same drug content.
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PMID:Synthesis, self-assembly in water, and cytotoxicity of MPEG-block-PLLA/DX conjugates. 1828 38

Docetaxel (DTX) is one of the most active chemotherapeutic agents for treating metastatic breast cancer. Its aqueous solubility is very low, hence the available formulation of DTX for clinical use consists of high concentrations of tween80, which has been associated with several hypersensitivity reactions. To reduce the systemic toxicity of DTX as well as to avoid the use of tween80, in this study DTX was chemically conjugated with human serum albumin via a succinic spacer. A high-performance liquid chromatography method was developed for the determination of DTX-albumin conjugate. T47D and SKOV3 cells were used for the evaluation of the in vitro cytotoxicity of the conjugate by MTT assay. Studies were then done on balb/c mice to elucidate the tissue distribution of conjugates after intravenous administration. The albumin-conjugated formulation of DTX with the particle size of 90-110 nm showed enhanced solubility and in vivo characteristics and significantly higher cytotoxicity against tumor cells, for example, IC50 of 6.30 +/- 0.73 nM for T47D cell line compared to free DTX with IC50 of 39.4 +/- 1.75 nM. Conjugation also maintained DTX plasma level at 16.19% up to 2 h after injection compared with 2.51% for Taxotere, hence increasing the chance of nanoparticles uptake by tumor cells.
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PMID:Docetaxel-albumin conjugates: preparation, in vitro evaluation and biodistribution studies. 1897 21

The aim of this study was to investigate the effect of liposomes on docetaxel-induced lipid oxidization and membrane damage in human hepatoma cells. Cytotoxicity of free docetaxel and docetaxel-containing liposomes was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay in human hepatoma cell lines HepG2 and SMMC-7721. To the cell lines, blank liposomes prepared with soybean phosphatidylcholine (SPC), dimyristoylphosphocholine (DMPC), and dioleoylphosphocholine (DOPC) did not show any significant toxicity below a 0.02-mg/mL phospholipid concentration. On the other hand, free docetaxel showed IC(50) values of 9.13 x 10(-6) +/- 1.54 x 10(-5) and 1.58 x 10(-2) +/- 2.71 x 10(-2) mg/mL in HepG2 cells and SMMC-7721 cells, respectively, after of 24 hours of incubation. IC(50) values of docetaxel-encapsulating liposomes, measured in terms of total docetaxel concentration, were at least 1.5-fold higher than those of free docetaxel. SPC liposomes reduced cellular damage caused by free docetaxel, as evidenced by the attenuation of docetaxel-induced lactate dehydrogenase (LDH) leakage by over 11% after liposome encapsulation at each dosage. Docetaxel-induced oxidative membrane damage was monitored by the formation of the lipid peroxidation product, malondialdehyde (MDA), and the antioxidative property of SPC liposome was monitored by the suppression of superoxide dismutase (SOD). These data demonstrated that free docetaxel facilitated MDA formation and suppressed SOD, and that these membrane-damaging effects were reduced by SPC liposomes.
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PMID:Liposomes modulate docetaxel-induced lipid oxidization and membrane damage in human hepatoma cells. 1923 43

We have previously reported the synergistic cytotoxic effects of Docetaxel (TXT) and S-1 in gastric cancer in vitro and in vivo, and the combination regimen is now under phase III clinical trail. In this study, to elucidate whether the rapamycin, the inhibitor of the mTOR (mammalian target of rapamaycin), can enhance the potentiation of TXT and 5-fluorouracil (5-Fu) in gastric carcinoma cells. Rapamycin inhibited the growth of TMK-1, MKN-28, MKN-45 and MKN-74 cell lines by MTT assay, and it demonstrated the cytostatic effects as G1 arrest shown by flowcytometry. However, the cytotoxic effects of 5-Fu, TXT and cisplatin were enhanced by 2 to 4 times with the concomitant administration of rapamycin. To clarify the mechanism of the potentiation, the expression changes of the enzymes relating DNA metabolism and cell growth signal transduction pathways were examined by western blot analysis. Interestingly, the expression of thymidilate synthase was markedly decreased by the administration of rapamycin in TMK-1 cells in a time- and dose-dependent manner. Moreover, rapamycin decreased the phosphorylation of 4E-BP1, the phosphorylation of ERK1/2 and enhanced the phosphorylation of c-Jun NH2-terminal kinase, and the activation of caspase of apoptotic pathways in combination with TXT. These results strongly indicate that the mTOR inhibitor can enhance the potentiation of TXT and 5-Fu or S-1 and can serve as a new therapeutic tool for advanced and recurrent gastric cancer patients.
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PMID:Rapamycin enhances chemotherapy-induced cytotoxicity by inhibiting the expressions of TS and ERK in gastric cancer cells. 1985 12

Docetaxel, a member of the taxane family, induces antitumor effects in patients with advanced gastric cancer. However, toxicity at therapeutic doses can be severe, resulting in discontinuation of therapy. It is possible that dose reduction due to adverse events may decrease the cytotoxic efficacy of docetaxel. PSK, a protein-bound polysaccharide, has been used as a chemoimmunotherapy agent in the treatment of cancer in Asia for over 30 years. In the present study, we investigated the enhancing effects of PSK on the cytotoxicity of docetaxel in human gastric cancer through non-immunological actions both in vitro and in vivo. The sensitization effects of PSK on docetaxel were evaluated by MTT assay using human gastric cancer cell lines in vitro. In addition, to elucidate the molecular mechanism, we analyzed the activation of NF-kappaB and the subsequent production of the antiapoptotic molecule survivin in combined treatment with docetaxel and PSK. Accordingly, TMK-1 xenograft growth in SCID mouse was used to evaluate the in vivo efficacy, and the survivin expression in xenografts was also investigated by immunohistochemistry. In vitro, PSK enhanced docetaxel-induced growth inhibition in TMK-1 cells. The docetaxel-induced NF-kappaB activation was inhibited by adding PSK in a dose-dependent manner. Furthermore, the expression of survivin, which is transcriptionally regulated by NF-kappaB, was also inhibited by treatment with PSK. In SCID mouse, PSK significantly inhibited growth of TMK-1 subcutaneous xenografts in combination with low-dose docetaxel, and decreased the docetaxel-induced survivin expression in TMK-1 xenografts. Our data suggest that PSK enhanced the efficacy of docetaxel against human gastric cancer both in vitro and in vivo, at least in part, by downregulating NF-kappaB activation and survivin expression induced by low-dose docetaxel.
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PMID:PSK enhances the efficacy of docetaxel in human gastric cancer cells through inhibition of nuclear factor-kappaB activation and survivin expression. 2012 79


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