|
1. |
Ecteinascidin 743: a novel anticancer drug with a unique mechanism of action |
|
Anti-Cancer Drugs,
Volume 13,
Issue 6,
2002,
Page 545-555
Gregory Aune,
Takahisa Furuta,
Yves Pommier,
Preview
|
PDF (314KB)
|
|
摘要:
Ecteinascidin 743 (Et743) is an interesting compound in phase II/III clinical trials. Its chemistry is complex, its mechanism of action is original and it is active in human cancers, such as sarcomas refractory to conventional chemotherapy. The present review describes the discovery of the drug, its specific interactions with DNA and its reversible alkylation mechanism with guanineN2in the DNA minor groove. Et743 is a selective transcription inhibitor, which has the unique characteristic of poisoning transcription-coupled nucleotide excision repair. Understanding the molecular pharmacology of Et743 should help in deciding which patients should receive Et743 treatments and which agents should be most useful in association.
ISSN:0959-4973
出版商:OVID
年代:2002
数据来源: OVID
|
2. |
Selective cytotoxicity of gemcitabine in bladder cancer cell lines |
|
Anti-Cancer Drugs,
Volume 13,
Issue 6,
2002,
Page 557-566
RT Kilani,
Y Tamimi,
S Karmali,
J Mackey,
EG Hanel,
KK Wong,
RB Moore,
Preview
|
PDF (359KB)
|
|
摘要:
We have examined the cytotoxic effect of gemcitabine in intravesical therapy using anin vitroco-cultured spheroid model composed of transitional cell carcinoma (TCC) and fibroblasts from both human and rat species. Immunohistochemistry analysis of the co-cultured spheroids, using cytokeratin-13 and vimentin antibodies against TCC and fibroblasts, respectively, showed the central location of fibroblasts within the spheroid, whereas TCC formed the peripheral layers. Spheroids composed of human TCC and fibroblasts (MGH-U3/CRL-1120 or RT-112/CRL-1120) as well as rat TCC and their corresponding fibroblasts (AY-27/RF-Ed1) displayed the same drug tolerance profile after an exposure of 0, 1, 3, 5, 7 and 14 days. As confirmed by time-lapse photography, MTT essay and vital dye staining, gemcitabine selectively killed the human and rat bladder cancer cell lines, but did not affect un-transformed human and rat fibroblast lines.
ISSN:0959-4973
出版商:OVID
年代:2002
数据来源: OVID
|
3. |
Among substituted 9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4,5,8-tetraones, the lead antitumor triptycene bisquinone TT24 blocks nucleoside transport, induces apoptotic DNA fragmentation and decreases the viability of L1210 leukemic cells in the nanomolar range of daunorubicinin vitro |
|
Anti-Cancer Drugs,
Volume 13,
Issue 6,
2002,
Page 567-581
Elisabeth Perchellet,
Bonnie Sperfslage,
Yang Wang,
Xiaodong Huang,
Masafumi Tamura,
Duy Hua,
Jean-Pierre Perchellet,
Preview
|
PDF (382KB)
|
|
摘要:
In contrast to their inactive parent compound triptycene (code name TT0), several new synthetic analogs (TT code number) have antileukemic activities and remain effective in daunorubicin (DAU)-resistant tumor sublinesin vitro. Among variously substituted 9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4,5,8-tetraones, a total of six lead antitumor compounds have been identified, and their code names are TT2, TT13, TT16, TT19, TT21 and TT24. These active antitumor triptych structures have bisquinone functionality, and various bromo, methoxy, methylamino and/or dimethylamino substitutions with or without longer alkyl chains on the amino function. Like the anthracycline quinone antibiotic DAU, these triptycene (TT) bisquinones also inhibit DNA synthesis and induce DNA cleavage in relation with their cytotoxic activities, but have the additional advantage of blocking the cellular transport of purine and pyrimidine nucleosides, an effect which DAU cannot do. As demonstrated by intact chromatin precipitation and agarose gel electrophoresis, the ability of TT bisquinones and DAU to induce DNA fragmentation is biphasic with a peak that shifts to lower concentrations with increasing times of drug exposure. The most effective lead antitumor compound, TT24, induces DNA cleavage in the same concentration-dependent manner as DAU at 24 h (similar peak in response to 1.6 μM) and is nearly equipotent to DAU against L1210 tumor cell viability at day 4 (IC50values of TT24 and DAU: 48 and 25 nM, respectively). The mechanism by which TT24 induces DNA fragmentation is inhibited by actinomycin D, cycloheximide, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, benzyloxycarbonyl-Ile-Glu-Thr-Asp-fluoromethyl ketone,N-tosyl-L-phenylalanine chloromethyl ketone and ZnSO4, suggesting that TT bisquinones trigger apoptosis by caspase and endonuclease activation. Since TT24 is cytotoxic in the nanomolar range of DAU, but might have a more versatile mechanism of action than DAU in wild-type and multidrug-resistant tumor cells, this new class of DNA-damaging quinone antitumor drugs inhibiting nucleoside transport might be valuable to develop new means of polychemotherapy.
ISSN:0959-4973
出版商:OVID
年代:2002
数据来源: OVID
|
4. |
The impact of drug administration sequence and pharmacokinetic interaction in a phase I study of the combination of docetaxel and gemcitabine in patients with advanced solid tumors |
|
Anti-Cancer Drugs,
Volume 13,
Issue 6,
2002,
Page 583-593
H Dumez,
M Louwerens,
A Pawinsky,
ASTh Planting,
MJA de Jonge,
AT Van Oosterom,
M Highley,
G Guetens,
M Mantel,
G De Boeck,
E de Bruijn,
J Verweij,
Preview
|
PDF (142KB)
|
|
摘要:
Our objective was to determine the maximum tolerated dose (MTD) of two administration sequences of docetaxel and gemcitabine in cancer patients, and to describe the pharmacokinetics of both drugs. Patients were treated in a 4-weekly schedule at two dose levels: gemcitabine 800 mg/m2on days 1, 8 and 15, and docetaxel 85 or 100 mg/m2on day 15 (levels I and II). The protocol was amended to a 3-weekly schedule, testing gemcitabine 800 or 1000 mg/m2on days 1 and 8, with docetaxel 85 mg/m2on day 8 given initially (dose levels IIIa and IV). At the recommended dose, an extra cohort of patients initially received gemcitabine (dose level IIIb). Eleven patients were treated with the 4-week schedule; 29% of cycles were delayed predominantly because of hematological toxicity. Four patients developed dose-limiting toxicities (DLTs), predominantly hematological. In the 3-week schedule, 14 patients were treated. At level IV, three of four patients developed DLTs, defining the MTD. With the reverse sequence, three patients received a total of 10 cycles. Overall, nine partial remissions were observed. We conclude the recommended dose for phase II studies is gemcitabine 800 mg/m2on days 1 and 8, combined with docetaxel 85 mg/m2on day 8, on a 3-weekly schedule. Gemcitabine distribution is significantly altered upon docetaxel administration.
ISSN:0959-4973
出版商:OVID
年代:2002
数据来源: OVID
|
5. |
Down-regulation of telomerase activity by anticancer drugs in human ovarian cancer cells |
|
Anti-Cancer Drugs,
Volume 13,
Issue 6,
2002,
Page 595-598
Yasumasa Kunifuji,
Sadao Gotoh,
Tetsuya Abe,
Masayoshi Miura,
Yuji Karasaki,
Preview
|
PDF (92KB)
|
|
摘要:
Maintenance of telomere length is crucial for survival of cells. Telo-merase, an enzyme that is responsible for elongation of shortened telomeres, is active in human germ cells as well as most tumor tissues and experimentally immortalized cells. In contrast, most mature somatic cells in human tissues express undetectable or low telomerase activity, implying the existence of a stringent and negative regulatory mechanism. In this study we report the effects of anticancer drugs on telomerase activity in human cancer cells. In assaying for telomerase activity, we basically followed the original TRAP assay system, but with some modifications. A down-regulation of telomerase activity was found when cells of a human ovarian cancer cell line, A2780, were treated with;cis-diamminedichloroplatinum(II) (CDDP; cisplatin). However, down-regulation of telomerase activity was not found in cells of a cisplatin-resistant cell line, A2780CP, treated with cisplatin. On the other hand, telomerase activity in both the cell lines A2780 and A2780CP was reduced when A2780 or A2780CP was treated with adriamycin, an anthracycline antibiotic having a broad spectrum of antineoplastic activity. The different effects on the telomerase activity of the two types of anticancer drugs may be due the distinct chemical functions of these drugs. The present results may indicate a positive relationship between anticancer effects and down-regulation of telomerase activity by anticancer drugs.
ISSN:0959-4973
出版商:OVID
年代:2002
数据来源: OVID
|
6. |
Antitumor activity of a new orally active organotin compound: a preliminary study in murine tumor models |
|
Anti-Cancer Drugs,
Volume 13,
Issue 6,
2002,
Page 599-604
Federica Barbieri,
Maurizio Viale,
Fabio Sparatore,
Gennaro Schettini,
Anna Favre,
Cristina Bruzzo,
Federica Novelli,
Angela Alama,
Preview
|
PDF (98KB)
|
|
摘要:
The toxicity and antitumor activity of the novel organotin compound triethyltin(IV)lupinylsulfide hydrochloride (IST-FS 29), administered by the oral route, have been evaluated against three transplantable murine tumor models: P388 lymphocytic leukemia, B16F10 melanoma and 3LL Lewis lung carcinoma. Mild and reversible signs of acute toxicity such as behavioral symptoms, weight loss and histological alterations were mainly reported at the highest single dose of 28 mg/kg. Conversely, lower concentrations of compound ranging from 7 to 21 mg/kg did not result in major toxic effects, even after repeated dosing. The antitumor activity studies showed that fractionation dosing, rather than single bolus administration, over 1 week, might prove more active and better tolerated by allowing the achievement of the highest therapeutic total dose of IST-FS 29 (42 mg/kg). Indeed, repeated administrations of IST-FS 29 resulted in marked significant improvement of antitumor activity against B16F10 (50% of tumor volume inhibition,p = 0.0003) and, to a greater extent, 3LL (90% of tumor volume inhibition,p = 0.0001) tumors. These results indicate that IST-FS 29 might be a suitable candidate as an orally administrable anticancer drug and support its further development in human tumor xenografts.
ISSN:0959-4973
出版商:OVID
年代:2002
数据来源: OVID
|
7. |
Prevention and treatment of peritoneal carcinomatosis in experimental investigations with CPT-11 and oxaliplatin |
|
Anti-Cancer Drugs,
Volume 13,
Issue 6,
2002,
Page 605-614
A Hribaschek,
M Pross,
R Kuhn,
S Krüger,
K Ridwelski,
W Halangk,
C Boltze,
H Lippert,
Preview
|
PDF (377KB)
|
|
摘要:
Following surgical resection of colorectal carcinoma, local recurrence in the tumor bed or in the mesentery remains a frequently encountered problem. Currently there are no recognized standard therapy protocols for the prevention of local recurrence or the treatment of peritoneal carcinomatosis. The aim of our trial was to investigate whether CPT-11 and oxaliplatin could decrease i.p. tumor growth in a basic experimental animal model. Experiments were performed on three groups of animals plus controls. In the first group, the cytostatic agents were applied directly following tumor cell implantation into the peritoneal cavity. In the second group, early postoperative i.p. chemotherapy (days 5, 10 and 15 following surgery) was administered. In the third group, late i.p. chemotherapy (days 15, 20 and 25 after tumor cell transfer) was administered with the intention of reducing a manifest peritoneal carcinomatosis. The trial also set out to describe any side effects observed following i.p. administration. The results indicated that CPT-11 and oxaliplatin were highly effective in reducing i.p. tumor spread after direct i.p intraoperative application. Intraperitoneal administration of CPT-11 or oxaliplatin also decreased i.p. tumor growth after early i.p. chemotherapy. CPT-11 was a little more effective with lower side effects. However, it was clear that it was not possible to treat a manifest peritoneal carcinomatosis in this way.
ISSN:0959-4973
出版商:OVID
年代:2002
数据来源: OVID
|
8. |
Efficacy and tolerability of an aminopterin–albumin conjugate in tumor-bearing rats |
|
Anti-Cancer Drugs,
Volume 13,
Issue 6,
2002,
Page 615-623
Paul Kremer,
Gernot Hartung,
Ulrike Bauder-Wüst,
Hans-Hermann Schrenk,
Andreas Wunder,
Stefan Heckl,
Uwe Zillmann,
Hannsjörg Sinn,
Preview
|
PDF (146KB)
|
|
摘要:
The antifolate aminopterin (AMPT) was developed before methotrexate (MTX), but was not clinically established or generally used due its increased toxicity compared to MTX. Recently, we reported on the increased metabolism of albumin conjugates such as methotrexate–albumin (MTX–SA) in malignant tumors and the feasibility of using albumin as a carrier for drug targeting. Consequently, AMPT was covalently bound to serum albumin (AMPT–SA) at a 1:1 molar ratio. Biodistribution, tolerability and efficacy of this novel conjugate were studied in Walker-256 (W-256) carcinoma-bearing rats. As compared to native albumin, the same biodistribution and plasma clearance were found for AMPT–SA, which achieved 20.1% tumor uptake (estimated uptake per g tumor 6.4%) within 24 h after i.v. administration in rats. In a randomized study, AMPT–SA, repeatedly i.v. injected, was compared with low-molecular-weight AMPT. Depending on the molar concentration, the maximum tolerated dose (MTD) of AMPT covalently bound to SA was twice that of unbound AMPT (three repeated injections of 1.0 mg AMPT–SA/kg body weight versus three repeated injections of 0.5 mg AMPT/kg body weight;p=0.0006). Efficacy was studied at the level of the MTD and MTD/2, and demonstrated that AMPT–SA was significantly more active. At the MTD/2 in W-256 carinoma-bearing rats, AMPT–SA achieved a 100% volume reduction and an optimal volume reduction during treatment/control (T/C) of 8.3% compared to a 53% volume reduction of AMPT and a T/C of 16.5% (p=0.032). Tumor relapses were reduced and occurred later in the AMPT–SA group (two tumor recurrences for AMPT–SA versus seven for AMPT;p=0.05). In this comparative study, the AMPT–SA conjugate showed high antitumor activityin vivoand a favorable toxicity compared to low-molecular-weight AMPT. These effects are attributed to the albumin carrier which seems to be an effective tool for selective tumor drug targeting.
ISSN:0959-4973
出版商:OVID
年代:2002
数据来源: OVID
|
9. |
Use of an ATP-based chemosensitivity assay to design new combinations of high-concentration doxorubicin with other drugs for recurrent ovarian cancer |
|
Anti-Cancer Drugs,
Volume 13,
Issue 6,
2002,
Page 625-630
Federica Di Nicolantonio,
Michael Neale,
Louise Knight,
Alan Lamont,
Geraldine Skailes,
Richard Osborne,
Rosanne Allerton,
Christian Kurbacher,
Ian Cree,
Preview
|
PDF (145KB)
|
|
摘要:
Liposomal doxorubicin (Caelyx/Doxil) has been shown to be active in around 20% of recurrent ovarian cancers. As yet, there is little clinical data on combinations of existing agents with liposomal doxorubicin, despite considerable clinical experience with soluble doxorubicin in combination. In this study, we have used an ATP-based tumor chemosensitivity assay to determine the relative efficacy of high concentrations of doxorubicin tested in combination with cisplatin, treosulfan, 5-fluorouracil (5-FU) or vinorelbine against cells obtained from recurrent ovarian tumor tissue. The results show little enhancement of the efficacy of high concentrations of doxorubicin by 5-FU, cisplatin, or treosulfan. However, vinorelbine+liposomal doxorubicin showed additive inhibition, and this combination is worthy of further testing in clinical trials.
ISSN:0959-4973
出版商:OVID
年代:2002
数据来源: OVID
|
10. |
Non-linear pharmacokinetics of irinotecan in mice |
|
Anti-Cancer Drugs,
Volume 13,
Issue 6,
2002,
Page 631-635
Elisabeth Rouits,
Sylvie Guichard,
Pierre Canal,
Etienne Chatelut,
Preview
|
PDF (97KB)
|
|
摘要:
Irinotecan (CPT-11) is a topoisomerase I inhibitor used in the treatment of metastatic colorectal cancer. Its conversion by carboxyl esterases is necessary to form the active metabolite SN-38. The aims of the study were to evaluate the linearity of CPT-11 pharmacokinetics and the influence of the schedule of administration of CPT-11 in mice, using a population pharmacokinetic approach with the NON-linear Mixed Effects Model (NONMEM) program. Mice were treated using two doses and two schedules of administration [10 mg/kg/day (daily×5)×2 or 50 mg/kg/day on days 1 and 12]. Plasma concentrations of both CPT-11 and SN-38 were determined by HPLC. A pharmacokinetic model based on both immediate conversion of CPT-11 to SN-38 for a fraction of the administered dose and saturable process for the remaining fraction fitted the data well. Refinements of the model allowed us to evaluate both the impacts of the dose and the schedule of administration on the pharmacokinetic parameters. We conclude that the pharmacokinetics of CPT-11 is not linear in mice. Extrapolation of both pharmacokinetic and pharmacodynamic preclinical results to humans may be limited by species particularities for this drug.
ISSN:0959-4973
出版商:OVID
年代:2002
数据来源: OVID
|
|