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1. |
Determination of camptothecin analogs in biological matrices by high-performance liquid chromatography |
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Anti-Cancer Drugs,
Volume 11,
Issue 5,
2000,
Page 315-324
Walter Loos,
Peter de Bruijn,
Jaap Verweij,
Alex Sparreboom,
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摘要:
Several analogs of the topoisomerase I inhibitor camptothecin (CPT) have been introduced in clinical practice in the last decade. All CPT analogs are sensitive to a pH-dependent reversible conversion between a pharmacologically active lactone form and its inactive, lactone ring-opened, carboxylate form. The reversible conversion is also dependent on the, sometimes species-dependent, protein binding properties of the two forms, resulting in different lactone to carboxylate plasma ratios for the various analogs. Pharmacokinetic analysis of the CPT analogs is helpful in understanding the pharmacodynamic outcome of drug treatment, in clinical as well preclinical studies. Measurement of these analogs is habitually complicated by the chemical instability of the lactone moiety and necessitates a rapid centrifugation of the blood sample, preferably at the bedside of the patient, to collect the plasma supernatant. Since the lactone forms of these drugs are able to diffuse across cell membranes, including those of the red blood cells, rapid collection and processing is even necessary in the case where only the total concentrations of the CPT analogs are to be measured. Sample pretreatment procedures of the CPT analogs topotecan, irinotecan, 9-aminocamptothecin and lurtotecan are summarized and discussed in this review.
ISSN:0959-4973
出版商:OVID
年代:2000
数据来源: OVID
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2. |
Phase II trial of gemcitabine in patients with pretreated advanced soft tissue sarcomas |
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Anti-Cancer Drugs,
Volume 11,
Issue 5,
2000,
Page 325-329
E Späth-Schwalbe,
I Genvresse,
A Koschuth,
A Dietzmann,
R Grunewald,
K Possinger,
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摘要:
Because of the low number of active cytotoxic drugs and their limited activity, the evaluation of new anti-cancer agents for their activity in soft tissue sarcomas is a continuing need. The objectives of this prospective phase II trial of gemcitabine were to estimate the response rate and to define the toxicities of prolonged infusions of low-dose gemcitabine in patients with pretreated advanced soft tissue sarcomas. Patients were eligible if they had a histologic diagnosis of unresectable, recurrent or metastatic, progressive soft tissue sarcoma, and if they had been treated with at least one prior chemotherapy consisting of an anthracycline- and/or ifosfamide-containing regimen. Gemcitabine was administered as a 360 min infusion on days 1, 8 and 15 of a 28 day cycle. The initial dose of gemcitabine was 200 mg/m2in all patients. Dose escalation to 250 mg/m2was allowed in the case of stable disease and good tolerability of the drug. All 18 patients (median age 58 years) who enrolled were treated with gemcitabine, and all were assessable for toxicity, response and survival. Only two of these 18 patients had an objective response to a previous palliative chemotherapy. A median of 3 cycles (range 1-7) of gemcitabicin were administered. Two (11%) of the patients had a partial response lasting 5 and 6 months, respectively. Both of these patients had only lung metastases. Whereas one of these patients had a transient partial response to the foregoing chemotherapy (consisting of ifosfamide and doxorubicin), the other patient has been progressive on these drugs. One additional patient, progressive on ifosfamide and doxorubicin, had an objective response of greater than 50% confined to the lungs and stable local recurrence for 6 months. Six patients had stable disease for 3-6 months and nine patients had disease progression. The median survival was 8 months. Treatment generally was well tolerated with six patients having transient grade 3 non-hematologic toxicity, four having grade 3 neutropenia, and one having grade 4 neutropenia and thrombocytopenia. Gemcitabine, given as a prolonged infusion at a low dose level, has a favorable toxicity profile and displays antitumor activity in patients with intensively pretreated, advanced soft tissue sarcomas.
ISSN:0959-4973
出版商:OVID
年代:2000
数据来源: OVID
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3. |
Inter-relationships of paclitaxel disposition, infusion duration and Cremophor EL kinetics in cancer patients |
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Anti-Cancer Drugs,
Volume 11,
Issue 5,
2000,
Page 331-337
Lia van Zuylen,
Luca Gianni,
Jaap Verweij,
Klaus Mross,
Eric Brouwer,
Walter Loos,
Alex Sparreboom,
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摘要:
Cremophor EL (CrEL) is a castor oil surfactant used as a vehicle for formulation of a variety of poorly water-soluble agents, including paclitaxel. Recently, we found that CrEL can influence the in vitro blood distribution of paclitaxel by reducing the free drug fraction, thereby altering drug accumulation in erythrocytes. The purpose of this study was to investigate the clinical pharmacokinetics of CrEL, and to examine inter-relationships of paclitaxel disposition, infusion duration and CrEL kinetics. The CrEL plasma clearance, studied in 17 patients for a total of 28 courses, was time dependent and increased significantly with prolongation of the infusion duration from 1 to 3 to 24 h (p<0.03). An indirect response model, applied based on use of a Hill function for CrEL concentration-dependent alteration of in vivo blood distribution of paclitaxel, was used to fit experimental data of the 3 h infusion (r2=0.733; p=0.00001). Simulations for 1 and 24 h infusions using predicted parameters and CrEL kinetic data revealed that both short and prolonged administration schedules induce a low relative net change in paclitaxel blood distribution. Our pharmacokinetic/pharmacodynamic model demonstrates that CrEL causes disproportional accumulation of paclitaxel in plasma in a 3 h schedule, but is unlikely to affect drug pharmacokinetics in this manner with alternative infusion durations.
ISSN:0959-4973
出版商:OVID
年代:2000
数据来源: OVID
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4. |
1,4-Anthraquinone: an anticancer drug that blocks nucleoside transport, inhibits macromolecule synthesis, induces DNA fragmentation, and decreases the growth and viability of L1210 leukemic cells in the same nanomolar range as daunorubicinin vitro |
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Anti-Cancer Drugs,
Volume 11,
Issue 5,
2000,
Page 339-352
Elisabeth Perchellet,
Molly Magill,
Xiaodong Huang,
Dawn Dalke,
Duy Hua,
Jean-Pierre Perchellet,
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摘要:
1,4-Anthraquinone (AQ) was synthesized and shown to prevent L1210 leukemic cells from synthesizing macromolecules and growingin vitro. In contrast, its dihydroxy-9,10-anthraquinone precursor, quinizarin, was inactive. The antitumor activity of AQ was compared to that of daunorubicin (DAU), which is structurally different from AQ but also contains a quinone moiety. AQ is equipotent to DAU against L1210 tumor cell proliferation (IC50: 25 nM at day 2 and 9 nM at day 4) and viability (IC50: 100 nM at day 2 and 25 nM at day 4), suggesting that its cytostatic and cytotoxic activities are a combination of drug concentration and duration of drug exposure. Since AQ does not increase but rather decreases the mitotic index of L1210 cells at 24 h, it is not an antitubulin drug but might arrest early stages of cell cycle progression. Like DAU, a 1.5-3 h pretreatment with AQ is sufficient to inhibit the rates of DNA, RNA and protein syntheses (IC50: 2 μM) determined over 30-60 min periods of pulse-labeling in L1210 cellsin vitro. In contrast to DAU, which is inactive, a 15 min pretreatment with AQ has the advantage of also inhibiting the cellular transport of both purine and pyrimidine nucleosides (IC50: 2.5 μM) over a 30 s periodin vitro. Hence, AQ may prevent the incorporation of [3H]adenosine and [3H]thymidine into DNA because it rapidly blocks the uptake of these nucleosides by the tumor cells. After 24 h, AQ induces as much DNA cleavage as camptothecin and DAU, two anticancer drugs producing DNA strand breaks and known to, respectively, inhibit topoisomerase I and II activities. However, the concentration-dependent induction of DNA cleavage by AQ, which peaks at 1.6-4 μM and disappears at 10-25 μM, resembles that of DAU. The mechanism by which AQ induces DNA cleavage is inhibited by actinomycin D, cycloheximide and aurintricarboxylic acid, suggesting that AQ activates endonucleases and triggers apoptosis. The abilities of AQ to block nucleoside transport, inhibit DNA synthesis and induce DNA fragmentation are irreversible upon drug removal, suggesting that this compound may rapidly interact with various molecular targets in cell membranes and nuclei to disrupt the functions of nucleoside transporters and nucleic acids, and trigger long-lasting antitumor effects which persist after cessation of drug treatment. Because of its potency and dual effects on nucleoside transport and DNA cleavage, the use of bifunctional AQ with antileukemic activity in the nM rangein vitromight provide a considerable advantage in polychemotherapy to potentiate the action of antimetabolites and sensitize multidrug-resistant tumor cells.
ISSN:0959-4973
出版商:OVID
年代:2000
数据来源: OVID
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5. |
Growth inhibitory effect of a new camptothecin analog, DX-8951f, on various drug-resistant sublines including BCRP-mediated camptothecin derivative-resistant variants derived from the human lung cancer cell line PC-6 |
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Anti-Cancer Drugs,
Volume 11,
Issue 5,
2000,
Page 353-362
Mineko Ishii,
Michio Iwahana,
Ikuo Mitsui,
Megumi Minami,
Setsuko Imagawa,
Akiko Tohgo,
Akio Ejima,
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摘要:
DX-8951f, a new water-soluble camptothecin (CPT) derivative, has been reported to show potent antitumor effects against various tumorsin vitroandin vivo. We further evaluated the cytotoxic effect of DX-8951f against eight drug-resistant sublines derived by stepwise exposure of human oat cell carcinoma PC-6 to various drugs. In paclitaxel-, adriamycin-, vincristine- and etoposide-resistant cells, overexpression of P-glycoprotein (P-gp) and a correlative reduction in drug accumulation and typical drug-sensitivity pattern were confirmed. The etoposide-resistant line with the highest P-gp level was cross-resistant also to SN-38, CPT-11 and topotecan (TPT), but not to 9-aminocamptothecin (9-AC), CPT and DX-8951f. SN-38- and CPT-11-resistant cells, of which topoisomerase I activities and levels were similar to those of the parent cells, showed cross-resistance clearly to TPT, 9-AC and mitoxantrone, but hardly to DX-8951f. In these two resistant sublines, the intracellular topotecan level was significantly lower than that in parental PC-6 and the reduced accumulation was found to be mediated by breast cancer resistant protein (BCRP). The cisplatin-resistant variant, which had a 2-fold increase in glutathione content, showed no cross-resistance and the 5-fluorouracil-resistant variant, which had a 50% decrease in glutathione content, exhibited collateral sensitivity to most of the other anticancer agents including DX-8951f. We concluded that DX-8951f showed a potent cytotoxic effect on various types of drug-resistant cells.
ISSN:0959-4973
出版商:OVID
年代:2000
数据来源: OVID
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6. |
Antiproliferative activityin vitroof new malatoplatinum(II) complexes |
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Anti-Cancer Drugs,
Volume 11,
Issue 5,
2000,
Page 363-368
Adam Opolski,
Janina Kuduk-Jaworska,
Joanna Wietrzyk,
Elzbieta Wojdat,
Katarzyna Waszkiewicz,
Anna Romaniewska,
Czeslaw Radzikowski,
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摘要:
The results of studies on antiproliferative activityin vitroof nine new platinum(II) complexes against cells of eight human and six murine neoplastic cell lines are described. New complexes with the anionic rest originating from enantiomeric forms of hydroxydicarboxylic malic acid were synthesized to obtain agents with increased water solubility and decreased toxicity. Three compounds, coded 1-3, with ethylenediamine as a neutral ligand, showed cytotoxic activity against 12 out of 14 target cell lines. Their cytotoxic activity was similar or even slightly higher than that of the reference carboplatin. The remaining six compounds, coded 4-9, with 1-alkylimidazole as a neutral ligand, revealed rather low cytotoxic activity, and only against the cells of the human bladder cancer cell line Hu1703He, ovarian cancer cell line OAW-42 and mouse leukemia P388. Most of them appeared to be negative against all other cell lines. No compounds, including reference carboplatin, showed any cytotoxicity against the cells of the T47D human breast cancer cell line or B16F-10 mouse melanoma cell line. The results obtained are in accordance with common opinion, i.e. that the presence of neutral amine ligands with NH groups is required for the cytotoxic activity of platinum complexes. Compounds with a primary amine (ethylenediamine) showed higher cytotoxic activityin vitrothan complexes with a tertiary amine (1-alkylimidazole).
ISSN:0959-4973
出版商:OVID
年代:2000
数据来源: OVID
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7. |
Bovine seminal ribonuclease attached to nanoparticles made of polylactic acid kills leukemia and lymphoma cell linesin vitro |
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Anti-Cancer Drugs,
Volume 11,
Issue 5,
2000,
Page 369-376
Martin Michaelis,
Josef Matousek,
Jens-Uwe Vogel,
Tomas Slavik,
Klaus Langer,
Jaroslav Cinatl,
Jörg Kreuter,
Dirk Schwabe,
Jindrich Cinatl,
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摘要:
Bovine seminal ribonuclease (BS-RNase) is a protein with a number of biological effects. It shows antitumoral, aspermatogenic, antiembryonic, immunosuppressive and antiviral properties. The cytotoxic effects appear to be specific for tumor cells as non-malignant cells seem to be unaffectedin vitro. Unfortunately, thein vivoapplication of BS-RNase so far was successful only when it was administered intratumorally. Therefore, the objective of the present investigation was to improve the properties of BS-RNase by attachment to nanoparticles made of polylactic acid (PLA-NP) using an adsorption method. This preparation was testedin vitroagainst leukemia (MOLT-4) and lymphoma (H9) cell lines sensitive and resistant to cytarabine. No difference between the nanoparticle preparation and pure BS-RNase was found in these tests. To examine thein vivoeffects, the preparations were tested for their aspermatogenic and antiembryonal efficacy compared to the pure BS-RNase as a rapid test for antitumoral activity. The aspermatogenic and antiembryonal effects were enhanced by the nanoparticle preparation. Consequently, BS-RNase loaded adsorptively to PLA-NP holds promise for thein vivouse as an antitumoral agent. Further research will investigate the efficacy of this preparations in anin vivotumor model.
ISSN:0959-4973
出版商:OVID
年代:2000
数据来源: OVID
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8. |
Toxicity and DNA binding of dextran-doxorubicin conjugates in multidrug-resistant KB-V1 cells: optimization of dextran size |
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Anti-Cancer Drugs,
Volume 11,
Issue 5,
2000,
Page 377-384
Wing Lam,
Chung-Hang Leung,
Hing-Leung Chan,
Wang-Fun Fong,
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摘要:
We previously showed that conjugating doxorubicin to very large 70-500 kDa dextran decreased its removal rate from P-glycoprotein (P-gp) over-expressing, multidrug-resistant KB-V1 cells. Furthermore these conjugates could act synergistically with other cancer drugs. In the drug-sensitive 3-1 clone, but not in the V1 subclone which was 300-fold more resistant to free doxorubicin, conjugation led to a size-related decrease in toxicity. Here we identified the optimal size of dextran for avoiding P-gp-mediated efflux and yet preserving as much as possible doxorubicin toxicity. Chemically reduced, intracellularly stable 3.4-10 kDa conjugates were prepared. Confocal microscopy and fluorescence quenching experiments showed that these conjugates entered nuclei and interacted with DNA. In 3-1 cells, but not in V1 cells, cytotoxicity of conjugates decreased 14- to 45-fold linearly related to log size of the carrier (r=0.95). In V1 cells toxicity of the 10 kDa conjugate exceeded that of free doxorubicin. After conjugation the equilibrium binding constant of the DNA-drug complex (KA) decreased only by up to 3-fold. In 3-1 cells, but not in V1 cells, DNA binding kinetics was an important factor and toxicity could be linearly correlated to 1/KAof conjugate (r=0.94). Drug accumulation decreased with an increase in dextran size but drug removal was decreased only in V1 cells. It appeared that drug uptake was also sensitive to dextran conjugation. In V1 cells drug removal was sensitive to the P-gp inhibitor verapamil or energy starvation. Ratios of V1/3-1 toxicity, drug accumulation and drug removal correlated linearly with log dextran size. When these ratios equaled 1, dextran sizes were estimated to be 32, 103 and 21 kDa, respectively.
ISSN:0959-4973
出版商:OVID
年代:2000
数据来源: OVID
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9. |
Effects of Combretastatin A-4 prodrug against a panel of malignant human B-lymphoid cell lines |
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Anti-Cancer Drugs,
Volume 11,
Issue 5,
2000,
Page 385-392
Sanaa Nabha,
Nathan Wall,
Ramzi Mohammad,
George Pettit,
Ayad Al-Katib,
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摘要:
Combretastatin A-4 (CA-4) is one of a family of compounds isolated from the South African willow treeCombretum caffrum. CA-4 was found to be active against murine melanoma and a variety of other human solid tumors. For the first time, we report the effect of CA-4 against a panel of malignant human B-lymphoid cell lines [early pre-B acute lymphoblastic leukemia (Reh), diffuse large cell lymphoma (WSU-DLCL2), chronic lymphocytic leukemia (WSU-CLL) and Waldenstrom's macroglobulinemia (WSU-WM)]. Our results indicate, using the prodrug form of CA-4, a concentration-dependent growth inhibition in all tested cell lines, although WSU-DLCL2was more sensitive. Exposure to 4 nM CA-4 for 96 h induced 77% growth inhibition in Reh, 86% in WSU-CLL and 92% in WSU-WM. When used against the WSU-DLCL2cell line, this same concentration of CA-4 was completely toxic. Morphological examination showed CA-4 induced the formation of giant, multinucleated cells, a phenomenon commonly found in mitotic catastrophe. Only minimal numbers of cells showing characteristics of apoptosis were detected. In WSU-DLCL2cells, CA-4 (3 nM) induced the highest apoptosis (5%) after 48 h, while the percentage of dead cells was approximately 47%. Exposure of Reh, WSU-CLL, WSU-WM and WSU-DLCL2cells for 24 h to 5 nM CA-4 induced 19, 28, 57 and 75% G2/M arrest, as determined by flow cytometry, respectively. Based on these preliminary studies, we believe that mitotic catastrophe is the predominant mechanism by which CA-4 induces cell death rather than apoptosis. Further studies to elucidate the mechanisms of CA-4 activityin vitroandin vivoare currently under investigation in our laboratory.
ISSN:0959-4973
出版商:OVID
年代:2000
数据来源: OVID
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10. |
Intraperitoneal injection of dextran sulfate as an anti-adherent drug for the prevention of peritoneal metastasis of cancer shows low toxicity in animals |
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Anti-Cancer Drugs,
Volume 11,
Issue 5,
2000,
Page 393-399
Akeo Hagiwara,
Chouhei Sakakura,
Morio Shirasu,
Takeshi Togawa,
Yoshinobu Sonoyama,
Junshin Fujiyama,
Yoshimasa Ebihara,
Tadao Itoh,
Hisakazu Yamagishi,
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摘要:
Intraperitoneal dextran sulfate with a mean molecular weight of 5×105has been developed for use in an anti-adherent therapy against peritoneal carcinomatosis. The present study examined acute toxicity of i.p. injection of dextran sulfate in mice and rabbits. The 10, 50 and 90% lethal dose values are 0.213 (0.146-0.252), 0.336 (0.291-0.405) and 0.530 mg/g (0.431-0.873 mg/g: 95% confidence interval) in mice, respectively. These are markedly larger than the efficacious dose of 0.005-0.01 mg/g obtained previously. Death or symptoms of intoxication were seen within 3 days after administration of toxic doses. Rabbits received i.p. injection of dextran sulfate at 0.02 mg/g, which was close to the efficacious dose. At 2, 4, 6, 8 and 13 days after administration, blood was taken for biochemical and hematological analyses. Dextran sulfate at 0.02 mg/g induced no remarkable abnormal findings. These results suggest that the i.p. dextran sulfate is safe as an anti-adherent agent against peritoneal metastasis of cancer.
ISSN:0959-4973
出版商:OVID
年代:2000
数据来源: OVID
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