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1. |
Preclinical pharmacokinetics of paclitaxel and docetaxel |
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Anti-Cancer Drugs,
Volume 9,
Issue 1,
1998,
Page 1-17
Alex Sparreboom,
Olaf van Tellingen,
Willem Nooijen,
Jos Beijnen,
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摘要:
The taxanes paclitaxel and docetaxel represent a novel class of antlneoplastic agents. A major problem of both drugs is their low aqueous solubility and the design of suitable formulations has been a difficult step In the process of therapeutic development. The formulations currently used are mixtures of Cremophor EL:ethanol for paclitaxel (TaxolR) and Tween 80:ethanol for docetaxel (TaxotereR), but many new approaches have been tested or are under investigation. Paclitaxel and docetaxel have a similar mechanism of action, which is based on promotion of tubulin assembly and inhibition of microtubule disassembly. Pharmacokinetic studies revealed a marked non-linearity of paclitaxel In mice, which appeared to result exclusively from Cremophor EL, the major component present in the pharmaceutical formulation. An almost linear pharmacokinetic behavior was observed In the case of docetaxel. The reported plasma protein binding of both compounds ranged from 76 to 97% In different animal species. Paclitaxel and docetaxel widely distribute into most tissues of mice and rats, including tumor tissue, but only low concentrations were detected in the central nervous system. Despite the great similarity in the chemical structures of paclitaxel and docetaxel, their metabolic profile is very distinct. Furthermore, whereas paclitaxel metabolism is largely species dependent, docetaxel metabolism is similar across species in both isolated hepatic microsomal fractions and In vivo models. For both taxanes, hepatobiliary excretion is the major pathway of elimination and a major fraction of the dose is excreted in feces as parent drug or hydroxylated metabolites
ISSN:0959-4973
出版商:OVID
年代:1998
数据来源: OVID
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2. |
Continuing the fight against advanced colorectal cancer: new and future treatment options |
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Anti-Cancer Drugs,
Volume 9,
Issue 1,
1998,
Page 18-28
Harry Bleiberg,
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摘要:
The benefit of chemotherapy in the treatment of advanced colorectal cancer has now been clearly demonstrated with several studies reporting advantages in terms of overall survival, quality of life and effective palliation following chemotherapy plus supportive care in comparison to supportive care alone. However, the survival benefit achieved with the current 5-fluorouracil (5-FU)-based regimens is modest and thus investigations are ongoing to identify more effective agents with novel mechanisms of action. The three new agents likely to have the greatest impact in the near future are the thymidylate synthase inhibitor ZD1694 (TomudexR), the topoisomerase I inhibitor irinotecan (CamptoR) and the new platinum compound, oxaliplatin (L-OHPR). Promising response rates of 26 and 20% have been reported with ZD1694 in patients with advanced colorectal cancer in phase II and III studies, respectively. In a European phase II study, irinotecan has achieved response rates of 19% in chemotherapy-naive patients and 18% in pretreated patients with advanced disease. Oxaliplatin has mainly been investigated in combination with continuous infusion 5-FU, with response rates of 29-58%. Other agents currently in development include monoclonal antibodies (e.g. 17-1A and MN-14), protein synthesis inhibitors (e.g. RA 700) and angiogenesis inhibitors (e.g. PF 4).
ISSN:0959-4973
出版商:OVID
年代:1998
数据来源: OVID
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3. |
Vorozole (Rivizor™): an active and well tolerated new aromatase inhibitor for the treatment of advanced breast cancer patients with prior tamoxifen exposure |
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Anti-Cancer Drugs,
Volume 9,
Issue 1,
1998,
Page 29-35
Robert Paridaens,
Jose Roy,
Marianne Nooij,
Jan Klijn,
Stephen Houston,
Louk Beex,
Jefferson Vinholes,
Eva Tomiak,
Ann Vreckem,
Christine Langenaeken,
Martine Glabbeke,
Martine Piccart,
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摘要:
Vorozole (Rivizor™) is a potent and stereospecific inhibitor of aromatase having shown promising endocrine effects in phase I studies. In the present trial, 27 postmenopausal patients with advanced breast cancer, measurable lesions, presumably hormone responsive (ER or PR+, or ER? with disease-free survival longer than 1 year, or prior documented response to tamoxifen), were treated with vorozole one tablet 2.5 mg daily. All had been previously treated with tamoxifen as adjuvant (two patients) or for advanced disease (24 patients), or both (one patient). Objective remissions were observed in eight patients (30%) with two complete responses (CR) and six partial responses (PR) lasting for a median of 14.3 months (range 6.8-40.6); nine stabilizations were also recorded (median 7.9 months; range 3.7-40.1). Median time to progression for the 27 patients was 5.9 months. Sites of response were skin (three patients), lymph nodes (two patients), lung (two patients) and chest wall plus lymph nodes (one patient). Treatment was very well tolerated: mild hot flushes (four patients), gastrointestinal complaints (four patients) and no significant toxicity (common toxicity criteria grade above 2) or drug-related severe adverse event. It is concluded that vorozole is an active second-line endocrine treatment, deserving consideration for randomized comparison with other agents such as aminoglutethimide, megestrol acetate or medroxyprogesterone acetate.
ISSN:0959-4973
出版商:OVID
年代:1998
数据来源: OVID
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4. |
A phase I clinical and pharmacological study of oral 9-nitrocamptothecin, a novel water-insoluble topoisomerase I inhibitor |
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Anti-Cancer Drugs,
Volume 9,
Issue 1,
1998,
Page 36-44
Claire Verschraegen,
Ethan Natelson,
Beppino Giovanella,
John Kavanagh,
Andrzej Kudelka,
Ralph Freedman,
Creighton Edwards,
Karen Ende,
John Stehlin,
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摘要:
9-nitrocamptothecin (9NC) is a water-insoluble topoisomerase I inhibitor with a broad antitumor activity in animal models. To determine the maximum tolerated oral dose (MTD), a phase I study was performed in patients with advanced cancer refractory to conventional chemotherapy. 9NC was administered orally with escalating doses to cohorts of five patients beginning at 1 mg/m2/day for five consecutive days every week for 4 weeks. Increments were 0.5 mg/m2/day for each cohort. Toxicity was evaluated in 28 patients diagnosed with various malignancies. Seven patients received 1 mg/m2/day for 28 weeks; 10 patients, 1.5 mg/m2/day for 68 weeks; and 26 patients, 2 mg/m2/day for 159 weeks. At 1.5 mg/m2/day or higher, the dose-limiting toxicity was hematologic, with grade 4 anemia in eight (29%); neutropenia in seven (25%) and thrombocytopenia in five (18%). Grade 2 or higher toxic effects occurred at each dose level: nausea and vomiting in 15 (54%), diarrhea in nine (32%), chemical cystitis in seven (25%), neutropenic sepsis in six (21%) and weight loss in five (18%) (N=28). Responses were observed after 2-8 weeks of therapy in five patients with pancreatic, breast, ovarian and hematologic tumors. Fourteen patients had a disease stabilization and one patient received treatment up to 18 months. The MTD of 9NC given orally has been estimated at 1.5 mg/m2/day for five consecutive days weekly. 9NC may be tolerated for sustained periods of time, but has the potential for significant hematologic, gastrointestinal and urinary bladder toxicity. Significant antitumor activity was observed, warranting further clinical investigations.
ISSN:0959-4973
出版商:OVID
年代:1998
数据来源: OVID
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5. |
Mechanism of transient dyspnea induced by pegylated-liposomal doxorubicin (Doxil™) |
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Anti-Cancer Drugs,
Volume 9,
Issue 1,
1998,
Page 45-50
Keith Skubitz,
Amy Skubitz,
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摘要:
While mucositis and hand-foot syndrome are the main limiting toxicities of pegylated-liposomal doxorubicin, a small proportion of patients develop transient dyspnea at the initiation of drug infusion. Of the first 35 patients in a phase II study of pegylated-liposomal doxorubicin, three developed dyspnea, two low back pain and two pain at the site of tumor, within 1-5 min after starting the pegylatedliposomal doxorubicin infusion. The symptoms resolved within 5-15 min of stopping the infusion. In each case, the infusion was restarted without adverse effect. The mechanism of these symptoms is unclear. Because the dyspnea was reminiscent of that seen with hemodialysis neutropenia, complete blood counts were obtained in four of these patients approximately 2 min after the onset of symptoms. In all four patients, relative neutropenia was present (ANC 35, 3,24 and 46% of pretreatment) that resolved by the end of the pegylated-liposomal doxorubicin infusion. Pegylated-liposomal doxorubicin stimulated neutrophil adhesion to human umbilical vein endothelial cells In vitro at concentrations predicted to be present in plasma during the initiation of treatment. Thus, pegylated-liposomal doxorubicin can induce an increase in neutrophil adhesion directly. We conclude that one mechanism of pegylated-liposomal doxorubicin- induced acute dyspnea is a transient sequestration of neutrophils in the pulmonary circulation, resulting in a decrease in compliance and associated dyspnea. In the patients In this study, these symptoms were transient, mild and not life threatening. Pegylated-liposomal doxorubicin is generally well tolerated and we do not routinely use premedications in patients receiving pegylated-liposomal doxorubicin.
ISSN:0959-4973
出版商:OVID
年代:1998
数据来源: OVID
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6. |
Use of anex vivoATP luminescence assay to direct chemotherapy for recurrent ovarian cancer |
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Anti-Cancer Drugs,
Volume 9,
Issue 1,
1998,
Page 51-57
Christian Kurbacher,
Ian Cree,
Howard Bruckner,
Ursula Brenne,
Jutta Kurbacher,
Karin Müller,
Tonja Ackermann,
Tobias Gilster,
Lucas Wilhelm,
Heike Engel,
Peter Mallmann,
Peter Andreotti,
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摘要:
Chemotherapy for recurrent ovarian carcinoma (ROC) produces response rates of 10-80% depending on the prevalence of platinum resistance. Most patients relapse within 1 year and median progression-free survival (PFS) is generally no more than 6 months. Previous pretherapeutic chemosensitlvity assays mostly failed to improve the outcome of patients with ROC. Newly developed ATP assays show promising retrospective correlation with clinical outcome. We report here the first results of ATP assay-directed chemotherapy in patients with ROC. Therapy was selected by the ATP tumor chemosensitivity assay (ATP-TCA) in a prospective open-label pilot trial for ROC. Objective response rate (ORR), PFS and overall survival (OAS) of the first 25 evaluable patients were retrospectively compared with those of 30 others having similar characteristics who were treated empirically within the same period. The actuarial median observation times were 80 weeks for the ATP-TCA group and 83.5 weeks for the control group, respectively. In the control group, a 37% ORR [two complete responses (CR) and nine partial responses (PR)] was followed by a median PFS of 20 weeks and a median OAS of 69 weeks, mainly related to the use of single-agent chemotherapy. The ORR in the ATP-TCA group was 64% (eight CR and eight PR) (p=0.04) with the majority of responses (11 of 16) achieved with novel combinations. The median PFS in this group was 50 weeks (p=0.003) and the median OAS was 97 weeks (p=0.145). Survival of responding patients was similar in both groups. Chemotherapy guided by the ATP-TCA produced a greater benefit with regard to both ORR and PFS in platinum-refractory patients. ATP-TCA-directed chemotherapy for ROC compares favorably with chemotherapy chosen by a clinician and often leads to the choice of novel drug combinations. These promising results now warrant confirmation by prospective randomized trials.
ISSN:0959-4973
出版商:OVID
年代:1998
数据来源: OVID
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7. |
Cytotoxicity and intracellular biotransformation ofN-benzyladriamycin-14-yalerate (AD 198) are modulated by changes in 14-O-acyl chain length |
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Anti-Cancer Drugs,
Volume 9,
Issue 1,
1998,
Page 58-66
Leonard Lothstein,
Patrick Rodrigues,
Trevor Sweatman,
Mervyn Israel,
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摘要:
N-benzyladriamycin-14-valerate (AD 198) is pharmacologically superior to Adriamycin (ADR) based upon comparable cytotoxicity, decreased cardiotoxicity and the ability of AD 198 to circumvent multidrug resistance conferred by either Pglycoprotein overexpression or reduced topoisomerase II activity. AD 198, however, suffers from systemic lability of the 14-O-valerate moiety to enzymatic and non-enzymatic cleavage to yieldN-benzyladriamycin (AD 288), which is more similar to ADR in activity. The purpose of this study was to determine whether stability of the ester linkage could be achieved while preserving the favorable characteristics of AD 198 by using a series ofN-benzylated ADR congeners containing 14-O-acyl substitutions of incrementally shorter carbon chain lengths. Results from this study indicate that the linear five-carbon valerate substitution is the minimum length necessary to circumvent P-glycoprotein and prevent inhibition of topoisomerase II activity. In addition, although AD 198 is not a pro-drug of AD 288, intracellular 14-O-acyl cleavage appears to contribute to the cytotoxicity of AD 198.
ISSN:0959-4973
出版商:OVID
年代:1998
数据来源: OVID
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8. |
The potent microtubule-stabilizing agent (+)-discodermolide induces apoptosis in human breast carcinoma cells—preliminary comparisons to paclitaxel |
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Anti-Cancer Drugs,
Volume 9,
Issue 1,
1998,
Page 67-76
Raghavan Balachandran,
Ernst Haar,
Manda Welsh,
Stephen Grant,
Billy Day,
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摘要:
(+)–Discodermolide, a sponge–derived natural product, stabilizes microtubules more potently than paclitaxel despite the lack of any obvious structural similarities between the drugs. It competitively inhibits the binding of paclitaxel to tubulin polymers, hypernucleates microtubule assembly more potently than paclitaxel, and inhibits the growth of paclitaxel–reslstant ovarian and colon carcinoma cells. Because paclitaxel shows clinical promise for breast cancer treatment, its effects in a series of human breast cancer cells were compared to those of (+)–discodermolide. Growth inhibition, cell and nuclear morphological, and electrophoretic and flow cytometric analyses were performed on (+)–discodermolide–treated MCF–7 and MDAMB231 cells. (–f)–Discodermolide potently inhibited the growth of both cell types (IC50<2.5 nM) at concentrations similar to those observed with paclitaxel. Complete inhibition of growth occurred with 10 nM or greater of each drug and was not reversed by removal. (+)–Discodermolide–treated cells exhibited condensed and highly fragmented nuclei. Flow cytometric comparison of cells treated with either drug at 10 nM, a concentration well below that achieved clinically with paclitaxel, showed both caused cell cycle perturbation and induction of a hypodiploid cell population. (+)–Discodermolide caused these effects more extensively and at earlier time points. The timing and type of high molecular weight DNA fragmentation induced by the two agents was consistent with induction of apoptosis. The results suggest that (+)–discodermolide has promise as a new chemotherapeutic agent against breast and other cancers.
ISSN:0959-4973
出版商:OVID
年代:1998
数据来源: OVID
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9. |
Induction of apoptosis in human leukemic U937 cells by tetrandrine |
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Anti-Cancer Drugs,
Volume 9,
Issue 1,
1998,
Page 77-81
Yuen-Liang Lai,
Yu-Jen Chen,
Tsu-Yen Wu,
Sheng-Yuan Wang,
Kuo-Hua Chang,
Chong-Hung Chung,
Mong-Liang Chen,
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摘要:
Tetrandrine, a calcium channel antagonist, is a plant alkaloid possessing various pharmacological activities including anti-tumor activity. We studied tetrandrine to determine whether or not this anti-tumor effect occurs through induction of apoptosis. Tetrandrine inhibited both proliferation and clonogenicity of human leukemic U937 cells at an optimal concentration of 2.5 μg/ml. This growth inhibition was dose and time dependent, and accompanied with evidence of apoptotic changes. The characteristic morphological changes of apoptosis were observed in U937 cells under light microscopy and DNA fragmentation was noted by gel electrophoresis. Moreover, flow cytometric detection of surface phosphatidyl serine expression of U937 cells after treatment with tetrandrine confirmed the induction of apoptosis in these cells. The induction of apoptosis by tetrandrine would appear to proceed via non-Ca2+-dependent pathways.
ISSN:0959-4973
出版商:OVID
年代:1998
数据来源: OVID
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10. |
Enhancement of chemosensitivity toward anticancer drugs by high expression of caspase-1 in NIH 3T3 cells |
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Anti-Cancer Drugs,
Volume 9,
Issue 1,
1998,
Page 82-87
Takaki Hiwasa,
Hisashi Tokita,
Shigeru Sakiyama,
Akira Nakagaware,
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摘要:
It has been well documented that caspase-1 (interleukin-1/Jconverting enzyme, ICE) and its related cysteine proteinases such as caspase-3 (CPP32, apopain) and caspase-2 (ICH-1L) play important roles in apoptosis. In the present study, these genes were inserted into an inducible eukaryotic expression vector, pMSG, and transfected into NIH 3T3 mouse f ibroblasts. The expression of caspases-1 and -3 was effectively induced by treatment with dexamethasone (Dex). The expression of caspase-2 was elevated in the transfected cells without treatment with Dex but was not further stimulated by Dex. High expression of these proteases alone induced neither apoptosis-like cell death nor any morphological change. However, the expression of caspase-1 but not of caspase-2 or -3 enhanced chemosensitivity toward cytotoxic anticancer drugs such as aclarubicin, epirubicin, adriamycin, nimustine and ifosfamide. It is thus concluded that caspase-1 mediates cytotoxic effects of these drugs.
ISSN:0959-4973
出版商:OVID
年代:1998
数据来源: OVID
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