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1. |
Phase II trial of gemcitabine as prolonged infusion in metastatic breast cancer |
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Anti-Cancer Drugs,
Volume 10,
Issue 7,
1999,
Page 625-632
Peter Schmid,
Konstantin Akrivakis,
Bernd Flath,
Yvonne Grosse,
Orhan Sezer,
Hans-Günter Mergenthaler,
Kurt Possinger,
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摘要:
Gemcitabine is an active agent in the treatment of metastatic breast cancer. The phosphorylation of gemcitabine into the active gemcitabine triphosphate (dFdCTP) is catalyzed by deoxycytidine kinase. This enzyme is saturated at plasma concentrations achieved after an infusion over 30 min. Therefore accumulation of higher intracellular dFdCTP concentrations, which may result in an enhanced antineoplastic activity, cannot be achieved by higher dosage, but only by prolonged infusion time. In a previous phase I trial the maximum tolerated dose of gemcitabine given as a 6 h i.v. infusion was 250 mg/m2. The objective of this phase II trial was to determine the efficacy and safety of gemcitabine as prolonged infusion in patients with metastatic breast cancer. Twenty patients [median age 50.4 years, range 35–63 years; performance status EORTC 0 (17 patients), 1 (two patients), 2 (one patient)] with metastatic breast cancer were treated with 250 mg/m2gemcitabine as infusion over 6 h on days 1, 8 and 15 q3 weeks for up to six courses (median 3.9 courses). Treatment was first line for four patients, second line for five patients and third line or higher for 11 patients. Metastatic sites were liver in 14 patients, bone in 12 patients, lung in eight patients and lymph nodes in nine patients. Nine patients presented two metastatic sites, three patients three and five patients four. All patients were evaluable for response and toxicity. One patient (5%) achieved a complete remission (CR) and four patients (20%) a partial remission (PR) (one patient with CR of visceral metastases but stable bone metastases), for an overall response rate of 25% (five of 20). In addition, six patients (30%) had stable disease and nine (45%) failed to respond to the treatment. Time to progression ranged from 2 to 23 months with a median of 6.3 months. Hematologic toxicity was mild with leukopenia grade 3 in only three patients (15%) and no grade 3 thrombocytopenia. Moderate elevations of liver enzymes (three patients grade 3), nausea and vomiting (two patients grade 2), and mild alopecia were observed, but only one patient had to be withdrawn due to toxicity. In conclusion gemcitabine as prolonged infusion is an effective treatment in metastatic breast cancer. Toxicity, especially myelosuppression, is surprisingly mild. Therefore, gemcitabine seems to be ideal for combination therapies.
ISSN:0959-4973
出版商:OVID
年代:1999
数据来源: OVID
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2. |
KW‐2149‐induced pulmonary toxicity is not prevented by corticosteroidsa phase I and pharmacokinetic study |
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Anti-Cancer Drugs,
Volume 10,
Issue 7,
1999,
Page 633-640
D Schrijvers,
G Catimel,
M Highley,
FJP Höppener,
L Dirix,
E Bruijn,
J Droz,
AT Oosterom,
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摘要:
KW-2149 is a new, semisynthetic,C-7-N-Substituted, mitomycin C analog showing antitumor activity bothin vitroandin vivo, equal or superior to mitomycin C. In a phase I study, KW-2149 was administered as an i.v. bolus injection every 21 days and at a dose of 100 mg/m2pulmonary toxicity was dose limiting. Animal studies have indicated since that KW-2149-induced pulmonary toxicity can be prevented by pretreatment with corticosteroids. This paper presents the results of a further phase I study of KW-2149 with corticosteroid pretreatment. Patients were treated with oral dexamethasone 8 mg every 12 h, starting 24 h before KW-2149 administration, for 5 days. KW-2149 was given as an i.v. bolus injection every 21 days. Seventeen patients were treated with a total of 48 courses. Six patients received 60 mg/m2and 11 patients 75 mg/m2. Two courses were not evaluable for toxicity. Significant lung toxicity was observed in at least three patients treated with a dose of 75 mg/m2KW-2149 and pulmonary toxicity was therefore considered the dose-limiting toxicity at 75 mg/m2. No other important side effects were noted. One partial response was observed in a patient with colorectal cancer. Pretreatment with dexamethasone failed to suppress KW-2149-induced lung toxicity.
ISSN:0959-4973
出版商:OVID
年代:1999
数据来源: OVID
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3. |
Phase II trial of neoadjuvant chemotherapy in early‐stage small cell cervical cancer |
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Anti-Cancer Drugs,
Volume 10,
Issue 7,
1999,
Page 641-646
Ting-Chang Chang,
Suei Hsueh,
Chyong-Huey Lai,
Chih-Jen Tseng,
Kam-Fai Lee,
Kuan-Gen Huang,
Hung-Hsueh Chou,
Yung-Kwei Soong,
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摘要:
Clinical complete response (CR) to chemotherapy is not uncommon in small cell carcinoma. To understand its pathologic response, we conducted a phase II trial with neoadjuvant chemotherapy followed by hysterectomy in patients with small cell cervical cancer and reviewed all reported cases receiving neoadjuvant chemotherapy followed by hysterectomy through a MEDLINE search. From December 1993 to December 1997, the enrolled patients were treated with two to three courses of vincristine, adriamycin and cyclophosphamide alternating with cisplatin and etoposide (VAC/PE) before hysterectomy. Another three courses of chemotherapy were added after surgery. A total of seven patients was enrolled. Clinical CR was observed in six patients, but microscopic residual tumor was present in all. Lymphatic permeation, scattered residual tumor clusters and residual superficial invasive adenocarcinoma over the cervix presented in five cases, and another had a metastatic pelvic node with no residual cervical tumor. Three of these seven patients have been alive with no evidence of disease for 16.2, 45.2 and 56.6 months, respectively. The other four died from disease 10.3–23.6 months after diagnosis. These findings indicate the discrepancy between clinical and pathologic responses in small cell cervical cancer after chemotherapy and emphasize the necessity of local treatment.
ISSN:0959-4973
出版商:OVID
年代:1999
数据来源: OVID
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4. |
Effects of mutations in the F361 to R364 region of topoisomerase I (Topo I), in the presence and absence of 9‐aminocamptothecin, on the Topo I‐DNA interaction |
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Anti-Cancer Drugs,
Volume 10,
Issue 7,
1999,
Page 647-654
Christopher Pond,
Xi-Guang Li,
Eric Rubin,
Louis Barrows,
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摘要:
Steady-state levels and rates of DNA binding and release of wild-type and mutant topoisomerase I (Topo I) proteins were quantified by surface plasmon resonance analysis. The proteins were constructed and expressed as GST fusion proteins. The Topo I mutations analyzed were F361S, R362L and R364G, all altering a highly conserved region of wild-type eukaryotic Topo I. The R362L and R364G mutations resulted in much lower steady-state levels of DNA binding than wild-type. This was due to a large increase in thekd. The F361S mutation increased the steady-state levels of the protein-DNA interaction by increasing theka2-fold, while having little effect on thekd. The F361S mutation has been shown to confer resistance to camptothecin and its analogs. The camptothecin analog 9-aminocamptothecin decreased greatly the overall kdof the wild-type Topo I, but had little effect on the F361S mutant. Both the wild-type and the F361S mutant exhibited decreased steady-state levels in the presence of the drug, and this was attributable to decreased association.
ISSN:0959-4973
出版商:OVID
年代:1999
数据来源: OVID
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5. |
Comparison of DX‐8951f and topotecan effects on tumor colony formation from freshly explanted adult and pediatric human tumor cells |
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Anti-Cancer Drugs,
Volume 10,
Issue 7,
1999,
Page 655-662
Richard Lawrence,
Elzbieta Izbicka,
Robert De Jager,
Akiko Tohgo,
Gary Clark,
Steven Weitman,
Eric Rowinsky,
Daniel Von Hoff,
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摘要:
DX-8951f, which shows great therapeutic potential, was tested in the human tumor cloning system in adult and pediatric tumor types against which topotecan has been active. In 47 tumors from adults, DX-8951f had definite cytotoxic activity in a concentration-dependent manner with both 1 h and continuous exposures. Topotecan was minimally effective using a 1 h exposure and showed concentration-dependent inhibition with continuous exposure. In head-to-head comparisons at 1 h exposure against adult tumors, DX-8951f was significantly more effective at 0.1 and 1.0 μg/ml than topotecan. In head-to-head comparisons (continuous exposure), 1.0 μg/ml DX-8951f was more effective than topotecan at 1.0 μg/ml in adult tumors, including three of four head and neck, one of two kidney, two of five liver, six of 10 non-small cell lung, five of eight ovarian, four of eight prostate tumors, and in single specimens of breast, mesothelioma, colon and small cell lung tumors. With continuous exposure, DX-8951f and topotecan were equally effective at equimolar concentrations. The maximum tolerated dose for DX-8951f is 3 times that of topotecan, so higher doses of DX-8951f could be administered to patients. DX-8951f is a promising new antineoplastic agent with significant activity against tumors taken directly from patients.
ISSN:0959-4973
出版商:OVID
年代:1999
数据来源: OVID
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6. |
FCE 24517‐resistant MCF‐7 human breast cancer cell lineselection and characterization |
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Anti-Cancer Drugs,
Volume 10,
Issue 7,
1999,
Page 663-670
Carmela Salvatore,
Mario Bigioni,
Elisabetta lafrate,
Maurizio Cianfriglia,
Stefano Manzini,
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摘要:
We have developed a stable line of the human breast carcinoma cell line MCF-7 byin vitrocontinuous exposure to increasing concentrations of the antitumoral alkylating agent FCE 24517 (tallimustine). The selected line, MCF-7/ 245171, was resistant to the selecting agent (RI=10) and to a lesser degree to melphalan, MEN 10710 (a related dystamycin analog), doxorubicin and etoposide, but not tom-AMSA. MCF-7/245171cells did not express the multidrug-resistant phenotype, evaluated in terms of mRNA formdr-1 and gp170 glycoprotein. A significant, albeit modest, increase in the cellular content of glutathione was measured and therefore other resistance mechanism(s) should be operative. We conclude that the MCF-7/245171line is a valuable model to investigate the mechanisms of resistance of FCE 24517 and its derivatives.
ISSN:0959-4973
出版商:OVID
年代:1999
数据来源: OVID
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7. |
Comparative cardiotoxicity of idarubicin and doxorubicin using the isolated perfused rat heart model |
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Anti-Cancer Drugs,
Volume 10,
Issue 7,
1999,
Page 671-676
Denis Platel,
Paul Pouna,
Simone Bonoron-Adèle,
Jacques Robert,
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摘要:
Attempts to reduce the incidence of congestive heart failure following anthracycline therapy include the replacement of the parent compounds (especially doxorubicin) by less cardiotoxic analogs. Among these analogs, idarubicin (4-demethoxy-daunorubicin) was shown to be less cardiotoxic than doxorubicin in phase II clinical trials, but its actual cardiotoxicity has never been evaluated in large series and has never been compared to that of doxorubicin in relevant experimental models. Using the isolated perfused rat heart model, we compared the cardiac effects (developed pressure, contractility and relaxation of the left ventricle) induced by idarubicin to those induced by doxorubicin. Drugs were administered i.v. every other day for 11 days at doses of 1, 2, 2.5 and 3 mg/kg per injection for doxorubicin and 0.5, 0.75 and 1 mg/kg per injection for idarubicin. We confirmed that similar general toxicity symptoms were obtained for a dose ratio of 1:4 (idarubicimdoxorubicin). However, at the maximum tolerated doses of both drugs (3 mg/kg per injection for doxorubicin and 0.75 mg/kg per injection for idarubicin), the cardiac toxicity of idarubicin remained significantly lower than that of doxorubicin. Anthracycline cardiac accumulation was evaluated in parallel and revealed a lower cardiac accumulation of idarubicin, which could explain the reduced cardiac toxicity of this analog. Direct perfusion of the drugs in the isolated hearts of untreated animals revealed that idarubicin was taken up more readily than doxorubicin in the cardiac tissue, despite the fact that it had less deleterious effects on cardiac function. This indicates that idarubicin also had less intrinsic cardiotoxicity than doxorubicin in this model.
ISSN:0959-4973
出版商:OVID
年代:1999
数据来源: OVID
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8. |
Variable expression of the folylpolyglutamate synthetase gene at the level of mRNA transcription in human leukemia cell lines sensitive, or made resistant, to various antifolate drugs |
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Anti-Cancer Drugs,
Volume 10,
Issue 7,
1999,
Page 677-684
Yuzuru Takemura,
Hiroyuki Kobayashi,
Hayato Miyachi,
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摘要:
We investigated the expression of the folylpolyglutamate synthetase (FPGS) gene at the mRNA level in MOLT-3 and K562 human leukemia cell lines sensitive, or made resistant, to methotrexate (MTX) and/or trimetrexate (TMQ), or raltitrexed (ZD1694). Northern blot analysis demonstrated approximately 3-fold higher FPGS mRNA expression in K562 cells than that in MOLT-3 cells, being consistent with graded polyglutamation capacities of these cell lines. A slight increase in the expression of the FPGS gene was observed in the TMQ-resistant MOLT-3 cells (MOLT-3/TMQ800); moreover, sequential development of MTX resistance in the TMQ-resistant cells (MOLT-3/TMQ800-MTX10000) resulted in a further enhancement of FPGS mRNA expression despite of decreased polyglutamation capacity in this subline. Another MTX-resistant subline with impaired reduced folate carrier (MOLT-3/MTX10000) also showed overexpression of FPGS mRNA. Conversely, both raltitrexed-resistant sublines (MOLT-3/ZD1694·C and K562/ZD1694·C) displayed a moderately decreased expression of FPGS mRNA. These findings did not correspond to the virtual absence of ZD1694 polyglutamates inside the former cells nor to possibly intact polyglutamation capacity in the latter cells. These results indicate that FPGS mRNA expression may predict cellular ability to produce polyglutamate metabolites of antifolate drugs in the sensitive cells, but does not necessarily reflect FPGS function at the enzyme level in the antifolate-resistant tumor cells.
ISSN:0959-4973
出版商:OVID
年代:1999
数据来源: OVID
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9. |
Synthesis of [99mTc]ethyjenedicysteine‐colchicine for evaluation of antiangiogenic effect |
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Anti-Cancer Drugs,
Volume 10,
Issue 7,
1999,
Page 685-692
Fereshteh Zareneyrizi,
David Yang,
Chang-Sok Oh,
Seyfettin Ilgan,
Dong-Fang Yu,
Wayne Tansey,
Chun-Wei Liu,
E Kim,
Donald Podoloff,
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摘要:
Angiogenesis is in part responsible for tumor growth and the development of metastasis. Radiolabeled angiongenesis inhibitors would be useful to assess tumor microvasculature density. Colchicine (COL), a potent antiangiogenic agent, is known to inhibit microtubule polymerization and cell arrest at metaphase. This study aimed to develop99mTc-labeled COL (EC-COL) using ethylenedicysteine (EC) as a chelator to assess tumor microvascular density. EC was conjugated to trimethylcolchicinic acid usingN-hydroxysuccinimide and 1-ethyl-3-dimethylaminopropyl carbodiimide as coupling agents with a yield of 50–60%.In vivostability was analyzed in rabbit serum at 0.5–4 h. Tissue distribution and planar imaging studies of [99mTc]EC-COL were evaluated in breast tumor-bearing rats at 0.5, 2 and 4 h. The data was compared to that using [99mTc]EC (control). The radiochemical yield of [99mTc]EC-COL was greater than 95%. [99mTc]EC-COL was stable in rabbit serum.In vivobiodistribution of [99mTc]EC-COL in breast tumor-bearing rats showed increased tumor-to-blood (0.52 ± 0.12 to 0.72 ± 0.07) and tumor-to-muscle (3.47 ± 0.40 to 7.97 ± 0.93) ratios as a function of time. Conversely, tumor-to-blood values showed a time-dependent decrease with [99mTc]EC over the same time period. Planar images confirmed that the tumors could be visualized clearly with [99mTc]EC-COL from 0.5 to 4 h. [99mTc]EC-COL may be useful to assess antiangiogenic and therapeutic effects during chemotherapy.
ISSN:0959-4973
出版商:OVID
年代:1999
数据来源: OVID
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