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1. |
Toxicity and disposition of TLC ELL-12 (liposomal antitumor ether lipid) in Sprague-Dawley rats |
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Anti-Cancer Drugs,
Volume 14,
Issue 3,
2003,
Page 183-191
Rupinder Bhamra,
Lois Bolcsak,
Patricia Roberts,
Rachel Stevens,
Christopher Cavanaugh,
Christine Swenson,
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摘要:
TLC ELL-12 is a liposomal formulation of the antineoplastic L-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine [L-ET-18-OCH3(EL)]. The purpose of these studies was to characterize the toxicity and disposition of [N-methyl-14C] L-ET-18-OCH3administered as TLC ELL-12. Rats received TLC ELL-12 by i.v. infusion into a tail vein as a single 12.5 or 62.5 mg/kg dose or as five daily doses at 12.5 mg/kg (cumulative dose of 62.5 mg/kg). Whole blood and tissue samples were collected over 24 h, and assayed for total and EL-specific radioactivity. The amounts of radioactivity in urine, bile, injection site and carcass were determined for up to 48 h. TLC ELL-12 was well tolerated in male and female rats in single doses up to 37.5 mg/kg. The minimum lethal dose was 112.5 mg/kg. Doses of 12.5 mg/kg (no observed adverse effects) and 62.5 mg/kg (approximate maximum tolerated dose) were chosen for further study. The pharmacokinetics of EL given as TLC ELL-12 were non-linear with a disproportionate increase in AUC at the higher dose. Daily dosing at 12.5 mg/kg did not result in accumulation in the blood. The highest concentrations of EL at 24 h after dosing were in the spleen and liver. Virtually no radioactivity was recovered in the urine or bile of rats, most remaining in the carcass and injection site (tail). After a 12.5 mg/kg dose of TLC ELL-12, the levels of EL in the blood and most tissues examined were well above the levels that inhibit tumor growthin vitroand may therefore be therapeutically active.
ISSN:0959-4973
出版商:OVID
年代:2003
数据来源: OVID
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2. |
Interaction of 5-aza-2′-deoxycytidine and depsipeptide on antineoplastic activity and activation of 14-3-3σ, E-cadherin and tissue inhibitor of metalloproteinase 3 expression in human breast carcinoma cells |
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Anti-Cancer Drugs,
Volume 14,
Issue 3,
2003,
Page 193-202
Jacynthe Gagnon,
Sepideh Shaker,
Mélanie Primeau,
Annie Hurtubise,
Richard Momparler,
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摘要:
Genes that suppress tumorigenesis can be silenced by epigenetic events, such as aberrant DNA methylation and modification of chromatin structure. Inhibitors of DNA methylase and histone deacetylase (HDAC) can potentially reverse these events. The aim of this study was to determine thein vitroantineoplastic activity of 5-aza-2′-deoxycytidine (5-AZA-CdR), a potent inhibitor of DNA methylase, in combination with depsipeptide (depsi), an inhibitor of HDAC, on human breast carcinoma cells. We observed a synergistic antineoplastic interaction between 5-AZA-CdR and depsi in their capacity to inhibit colony formation of Hs578T and MCF-7 breast carcinoma cells. In order to understand the molecular mechanism of this interaction, we investigated the effect of these drugs on the activation of the 14-3-3σ, E-cadherin and tissue inhibitor of metalloproteinase 3 (TIMP3) cancer-related genes, which were reported to be silenced by aberrant methylation in many breast tumor cell lines. 14-3-3σ was reported to produce G2cell cycle arrest following DNA damage. E-cadherin and TIMP3 function as suppressors of tumor metastasis. Semi-quantitative RT-PCR was used to determine the effect of the co-administration of 5-AZA-CdR and depsi on four breast carcinoma cell lines for the reactivation of these genes. We observed a synergistic activation of E-cadherin by the combination in Hs578T, MDA-MB-231 and MDA-MB-435 tumor cells. For 14-3-3σ, we demonstrated an additive to synergistic activation by the combination for Hs578T and MDA-MB-435 tumor cells, respectively. In the MCF-7 tumor cells, the drug combination produced a synergistic activation of TIMP3. The association between the synergistic antineoplastic activity and the synergistic activation of the target genes in this study suggests that the mechanism of anticancer activity of 5-AZA-CdR, in combination with depsi, is probably related to their enhanced activation of different types of tumor suppressor genes that have been silenced by epigenetic events.
ISSN:0959-4973
出版商:OVID
年代:2003
数据来源: OVID
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3. |
Metabolism of paclitaxel in mice |
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Anti-Cancer Drugs,
Volume 14,
Issue 3,
2003,
Page 203-209
Heleen Bardelmeijer,
Ingrid Oomen,
Michel Hillebrand,
Jos Beijnen,
Jan Schellens,
Olaf van Tellingen,
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摘要:
Previous mass balance studies in humans and mice have shown that the fecal and urinary recovery of paclitaxel and known metabolites (3′p-hydroxypaclitaxel, 6&agr;-hydroxypaclitaxel and 3′p,6&agr;-dihydroxypaclitaxel) was not complete. Obviously this discrepancy is caused by the existence of other yet unknown metabolites.Mdr1a/1b−/−mice excrete very low quantities of unchanged paclitaxel. We have therefore used these mice receiving i.v. [3H]paclitaxel to further study the metabolic fate of paclitaxel. The major part of the radiolabel, being 70%, was excreted in the feces. A lipophilic sample, containing about 70% of the radioactivity present in the feces sample, was obtained by diethyl ether extraction. The aqueous residue containing about 30% of the radioactivity was further extracted using methanol. The high-performance liquid chromatography (HPLC) chromatograms of the lipophilic and aqueous sample revealed two and five putative new metabolites of paclitaxel, respectively. The HPLC fractions containing substantial amounts of radioactivity were subjected to tandem mass spectrometry. Two novel monohydroxylated paclitaxel structures were identified, which are probably 2m-hydroxypaclitaxel and 19-hydroxypaclitaxel, structures previously identified in rats. Including these metabolites, about 60% of the mass balance of paclitaxel could be quantified.
ISSN:0959-4973
出版商:OVID
年代:2003
数据来源: OVID
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4. |
Magnolol induces apoptosis in human leukemia cells via cytochromecrelease and caspase activation |
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Anti-Cancer Drugs,
Volume 14,
Issue 3,
2003,
Page 211-217
Wen-Bin Zhong,
Chih-Yuan Wang,
Kuo-Jang Ho,
Fung-Jou Lu,
Tien-Chun Chang,
Wen-Sen Lee,
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摘要:
Magnolol, isolated from the stem bark ofMagnolia officnalis, was found to inhibit proliferation of human HL-60 cells and Jurkat T leukemia cells via inducing apoptosis in a dose- and time-dependent manner. By contrast, magnolol did not cause apoptosis in neutrophils and peripheral blood mononuclear cells of healthy donors. Apoptosis was determined by detection of DNA fragmentation in gel electrophoresis, morphological alternations by flow cytometry, quantification of phosphatidylserine externalization by Annexin V labeling and oligonucleosomal DNA content by TUNEL labeling. Activation of caspase-9, -3 and -2, and the proteolytic cleavage of poly(ADP-ribose) polymerase were found during apoptosis induced by magnolol. In addition, both pan-caspase and selective caspase-9 inhibitor blocked magnolol-induced apoptosis. The apoptosis could also be partially attenuated by caspase-3 and -2 inhibitors. Magnolol induced the reduction of mitochondrial transmembrane potential and the release of cytochromecinto cytoplasm. In conclusion, our findings indicate that magnolol-induced apoptotic signaling is carried out through mitochondria alternations to caspase-9 and that then the downstream effector caspases are activated sequentially. Magnolol could be a potentially effective drug for leukemia with low toxicity to normal blood cells and it merits further investigation.
ISSN:0959-4973
出版商:OVID
年代:2003
数据来源: OVID
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5. |
Synthetic chenodeoxycholic acid derivative HS-1200-induced apoptosis of p815 mastocytoma cells is augmented by co-treatment with lactacystin |
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Anti-Cancer Drugs,
Volume 14,
Issue 3,
2003,
Page 219-225
Su Seo,
Eun Jun,
Sung Jung,
Ki-Ho Kim,
Young Lim,
Bong Park,
Jae-Kon Kim,
Sungeun Lee,
Hongsuk Suh,
Nam Kim,
Young Yoo,
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摘要:
The antitumor activity of a synthetic chenodeoxycholic acid derivative, HS-1200, on the p815 mastocytoma cell line was investigated. We present several lines of evidence indicating that HS-1200 at 35 μM induced apoptosis of p815 cells. Reduction of mitochondrial membrane potential, the release of cytochromecto cytosol, activation of caspase-3, nuclear condensation, production of poly(ADP-ribose) polymerase cleavage, generation of DNA fragmentation and nuclear condensation were demonstrated. Importantly, HS-1200 inhibited proteasome activity. Next, the combination treatment of HS-1200 or a proteasome inhibitor lactacystin was undertaken. Although the single treatment of 20 μM HS-1200 or 1 μM lactacystin induced apoptosis slightly, the combination treatment of them augmented prominently the extent of apoptosis. The combination therapy of HS-1200 and lactacystin could be potentially a therapeutic strategy reducing the extent and severity of treatment-related toxicity.
ISSN:0959-4973
出版商:OVID
年代:2003
数据来源: OVID
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6. |
Red blood cells: a neglected compartment in topotecan pharmacokinetic analysis |
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Anti-Cancer Drugs,
Volume 14,
Issue 3,
2003,
Page 227-232
Walter Loos,
Hans Gelderblom,
Jaap Verweij,
Desirée van Boven-van Zomeren,
Kees Nooter,
Gerrit Stoter,
Alex Sparreboom,
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摘要:
Previously, a gender dependency of topotecan was found in the pharmacokinetics in the plasma compartment. Here, we prospectively studied the red blood cell (RBC) partitioning of topotecan and evaluated its consequences for overall drug disposition. Blood samples were obtained from 12 patients receiving cisplatin followed by i.v. topotecan. Topotecan pharmacokinetic analysis was performed in whole blood, plasma and RBCs. Significantly slower clearance was noted in females (n=7) compared to males (n=5) for lactone and total topotecan in plasma (p<0.0001), and for total drug in RBCs (p=0.027), but not in whole blood. In addition, no gender-dependent differences were observed in the terminal half-lives of topotecan in any of the compartments. The area under the curve ratios for RBC total to plasma lactone were 2.53±0.0640 and 2.13±0.442 in males and females, respectively. Hence, topotecan displays preferential affinity for RBCs compared to plasma, although these cells do not act as a depot in which drug accumulates over time. RBCs thus play a principal role in the distribution kinetics of topotecan and have a major impact on its plasma pharmacokinetics. The data warrant a change from current practice in pharmacokinetic studies with this agent and provide further evidence that, in general, the choice of the appropriate assay matrix should be rationally based.
ISSN:0959-4973
出版商:OVID
年代:2003
数据来源: OVID
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7. |
Weekly docetaxel in patients with pretreated metastatic breast cancer: a phase II trial |
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Anti-Cancer Drugs,
Volume 14,
Issue 3,
2003,
Page 233-238
U. Mey,
M. Gorschlüter,
C. Ziske,
R. Kleinschmidt,
A. Glasmacher,
I.G.H. Schmidt-Wolf,
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摘要:
Docetaxel has consistently demonstrated its high activity as an antineoplastic agent in the treatment of metastatic breast cancer. However, 90% of patients receiving the recommended dose of 100 mg/m2every 3 weeks will develop grade 3 or 4 neutropenia. Recent data suggest that the safety profile of a weekly docetaxel regimen compared favorably with the standard 3-week schedule. Thus, we initiated a phase II study to assess the efficacy and toxicity of weekly docetaxel in pretreated patients with metastatic breast cancer. Twenty patients with advanced, anthra-cycline-refractory breast cancer were included in this phase II trial. Docetaxel was administered at a starting dose of 40 mg/m2, repeated once a week for 3 consecutive weeks followed by a 1-week rest period (1 cycle). Patients were evaluated for tumor response every 8 weeks (after every other cycle). Therapy was continued for a maximum of six courses in patients showing tumor response or stable disease. Twenty patients received a total of 204 weekly infusions of docetaxel. The mean number of treatments was 10.2 (range 1–18). Eighteen patients were assessable for response. Five patients achieved a partial response and six patients showed either stable disease or a minor response. Seven patients had disease progression. The median survival was 7.8 months. Grade 3/4 leukopenia occurred in two patients. No other grade 3 or 4 hematologic toxicities were observed. The following grade 3/4 non-hematologic toxicities were seen: nausea/vomiting (one patient), infection (one patient), mucositis (two patients) and diarrhea (one patient). Three patients withdrew from the study due to dose-limiting toxicities (one due to severe neutropenia and two due to mucositis). We conclude that administration of docetaxel at a dose of 40 mg/m2was effective and well tolerated even in heavily pretreated patients with metastatic breast cancer. This regimen is associated with only mild myelosuppression.
ISSN:0959-4973
出版商:OVID
年代:2003
数据来源: OVID
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8. |
Pharmacokinetics of doxorubicin administered i.v. as Myocet (TLC D-99; liposome-encapsulated doxorubicin citrate) compared with conventional doxorubicin when given in combination with cyclophosphamide in patients with metastatic breast cancer |
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Anti-Cancer Drugs,
Volume 14,
Issue 3,
2003,
Page 239-246
Christine Swenson,
Lois Bolcsak,
Gerald Batist,
Troy Guthrie,
Katherine Tkaczuk,
Harold Boxenbaum,
Lauri Welles,
Shein-Chung Chow,
Rupinder Bhamra,
Philip Chaikin,
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摘要:
Myocet (TLC D-99) is a liposomal formulation of the anti-neoplastic drug doxorubicin with an improved therapeutic index compared with conventional doxorubicin. The objective of this study was to assess the plasma disposition of doxorubicin when administered i.v. as TLC D-99 and to compare this to conventional drug. Metabolite (doxorubicinol) plasma levels were also quantitated in both treatment groups. Plasma was collected during the first course of treatment from 10 patients receiving TLC D-99 60 mg/m2and 10 receiving conventional doxorubicin 60 mg/m2, each with cyclophosphamide 600 mg/m2. Samples were assayed for total doxorubicin (all doxorubicin regardless of whether it is encapsulated or not), encapsulated doxorubicin (TLC D-99 group only) and doxorubicinol using high-performance liquid chromatography. Plasma concentrations of total doxorubicin were higher in patients receiving TLC D-99 than in patients receiving conventional doxorubicin. The clearance of total doxorubicin after administration of TLC D-99 was lower (approximately 9-fold) and the volume of distribution at steady state was less (25-fold) than that of doxorubicin after conventional drug. Doxorubicinol was detected in the plasma of all patients in both treatment groups. The mean AUC0−∞of doxorubicinol for patients receiving TLC D-99 (1.5±0.4 μM·h) was not statistically different than that in patients receiving conventional doxorubicin (1.8±0.4 μM·h), although the appearance of the peak doxorubicinol concentration occurred later and was lower in patients receiving TLC D-99. There was a correlation between the plasma AUC0−∞of total doxorubicin and the degree of myelosuppression in patients receiving conventional doxorubicin, but this correlation was not found in patients receiving TLC D-99.
ISSN:0959-4973
出版商:OVID
年代:2003
数据来源: OVID
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9. |
Doxil-induced regression of pleuro-pulmonary metastases in a patient with malignant meningioma |
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Anti-Cancer Drugs,
Volume 14,
Issue 3,
2003,
Page 247-250
Mila Travitzky,
Eugene Libson,
Igor Nemirovsky,
Irit Hadas,
Alberto Gabizon,
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摘要:
Metastatic meningioma is a rare disease, which has no effective chemotherapy. We report on a treatment of this condition with Doxil, a liposomal doxorubicin formulation. A 60-year-old woman with massive pleuro-pulmonary metastases from recurrent cranial meningioma was treated with Doxil (50–37.5 mg/m2) for 18 months with near-complete resolution of metastases and disappearance of pleural fluid. The only significant toxicities observed were stomatitis and hand–foot syndrome, which resolved with dose reduction and increase of dosing intervals. Doxil was cleared very slowly in this patient with a monoexponential half-life of 108 h. The patient remains in near-complete response for 6 months after treatment discontinuation. This is the first report on an effective chemotherapy in a patient with typical metastatic meningioma. The exact mechanism accounting for such an effective drug action is not clear, but may be related to a particularly high microvascular permeability to the liposome carriers in these metastatic lesions.
ISSN:0959-4973
出版商:OVID
年代:2003
数据来源: OVID
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10. |
Merkel cell carcinoma developing after antithymocyte globulin and cyclosporine therapy for aplastic anemia |
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Anti-Cancer Drugs,
Volume 14,
Issue 3,
2003,
Page 251-253
Maki Takabayashi,
Rika Sakai,
Hiroshi Sakamoto,
Youichi Iemoto,
Heiwa Kanamori,
Yoshiaki Inayama,
Yoshiaki Ishigatsubo,
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摘要:
We report a patient who developed Merkel cell carcinoma (MCC) after treatment with antithymocyte globulin and cyclosporine for aplastic anemia. The clinical course was progressive and poor prognosis. Although MCC is relatively rare in second cancers arising after immunosuppressive therapy, patients should be closely monitored for the development of this complication as well as other second malignancies.
ISSN:0959-4973
出版商:OVID
年代:2003
数据来源: OVID
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