摘要:

Pancreatic cancer, one of the most frequently reported gastrointestinal tumors, has a 5-year survival of less than 5%. Despite representing only 2-3% of the total cancer incidence, it is the fifth leading cause of cancer death. This is because it is commonly only diagnosed at an advanced stage. Until recently the traditional therapy for patients with advanced disease was palliative 5-fluorouracil (5-FU)-based chemotherapy. However, the novel antinucleoside gemcitabine (Gemzar®) has demonstrated a survival benefit over 5-FU, and an improvement in disease-related symptoms and quality of life in patients with advanced disease. This review presents an overview of the clinical studies of gemcitabine, either alone or in combination, with other chemotherapeutic agents and/or radiation therapy, in the treatment of these patients. A comparison of these studies is made with those using alternative treatment regimens. The data suggest that gemcitabine in combination with biomodulated 5-FU should be considered the standard palliative treatment to which other new drug combinations or combined modality chemoradiation regimens should be compared.

ISSN:0959-4973    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Thalidomide caused severe malformations in babies born to mothers taking the drug for morning sickness in the late 1950s and early 1960s. It is now known that these teratogenic effects are due to potent anti-angiogenic and immunomodulatory actions. These properties have lead to the testing of thalidomide in a number of infective, inflammatory and malignant conditions. Promising activity has been reported in myeloma, AIDS-related Kaposi's sarcoma, renal cell carcinoma and glioblastoma multiforme. A review is presented of the history of thalidomide and its recent development with an emphasis on applications in malignant disease.

ISSN:0959-4973    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The marine ecosystem is more and more acknowledged as a source of potential anticancer agents. After the identification of a potential substance several hurdles have to be overcome before a marine candidate can enter the clinic. Amongst these are the establishment of a method which ensures sufficient supply and, which is the focus of this review, the development of a clinically useful pharmaceutical formulation. General issues with respect to the pharmaceutical development of marine anticancer agents will be discussed, which will be illustrated by highlighting aspects of the pharmaceutical development and clinical use of some representative compounds.

ISSN:0959-4973    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The objective of this study was to compare the quantitative excretion of paclitaxel and metabolites after i.v. and oral drug administration. Four patients received 300 mg/m2paclitaxel orally 30 min after 15 mg/kg oral cyclosporin A, co-administered to enhance the uptake of paclitaxel. Three weeks later these and three other patients received 175 mg/m2paclitaxel by i.v. infusion. Blood samples, urine and feces were collected up to 48-96 h after administration, and analyzed for paclitaxel and metabolites. The area under the plasma concentration-time curve of paclitaxel after i.v. administration (175 mg/m2) was 16.2±1.7 μM·h and after oral administration (300 mg/m2) 3.8±1.5 μM·h. Following i.v. infusion of paclitaxel, total fecal excretion was 56±25%, with the metabolite 6α-hydroxypaclitaxel being the main excretory product (37±18%). After oral administration of paclitaxel, total fecal excretion was 76±21%, of which paclitaxel accounted for 61±14%. In conclusion, after i.v. administration of paclitaxel, excretion occurs mainly in the feces with the metabolites as the major excretory products. Orally administered paclitaxel is also mainly excreted in feces but with the parent drug in highest amounts. We assume that this high amount of parent drug is due to incomplete absorption of orally administered paclitaxel from the gastrointestinal tract.

ISSN:0959-4973    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

A phase I study was conducted in patients with stage IIIB or IV non-small cell lung cancer to determine the maximum tolerated dose (MTD) of irinotecan combined with a fixed schedule of docetaxel and carboplatin with recombinant human granulocyte colony stimulating factor (rhG-CSF) (nartograstim) support. Docetaxel was given at 60 mg/m2on day 1 with carboplatin. The dose of carboplatin was calculated using the Calvert formula to achieve an estimated AUC of 5.0 mg/ml·min. Irinotecan was administered at a starting dose of 40 mg/m2on day 1 and increased in increments of 10 mg/m2. rhG-CSF was given at 1 μg/kg on days 5-15. Cycles were repeated every 3 weeks. Between February 1998 and March 1999, 22 patients were enrolled in this phase I study. Five patients were chemotherapy naive. The MTD of irinotecan was 60 mg/m2. Diarrhea was considered to be the dose-limiting toxicity. The irinotecan dose intensity of 16.7 mg/m2/week was low compared with other irinotecan-containing regimens. The overall response rate was 38.1% and median survival was 278 days. Irinotecan 50 mg/m2in combination with 60 mg/m2docetaxel and carboplatin on day 1 with rhG-CSF support is recommended for phase II study. The response rate and survival data in this phase I study are encouraging.

ISSN:0959-4973    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Topical treatment of skin metastases with a cytotoxic agent is attractive for its easy self-administration and absence of major systemic interference. Miltefosine exerts its cytotoxicity by acting on cell membrane phospholipids and can be administered topically. Twenty breast cancer patients with progression of skin metastases were treated with a 6% solution of miltefosine, which was topically administered once daily during the first week and twice daily thereafter. Sixteen out of 20 patients also had metastatic disease at other sites. Concomitant systemic treatment when ongoing for at least 2 months prior to study entry was permitted, and consisted of chemotherapy and hormonal therapy in seven and nine patients, respectively. Prior palliative cytotoxic and hormonal therapy had been administered to 11 and 19 patients, respectively. No grade 3 and 4 toxicity occurred. Miltefosine therapy was discontinued in two patients due to nausea and in one patient due to skin toxicity. Grade 1 and 2 adverse skin reactions, and nausea and vomiting were seen in 11 and two patients, respectively. In 18 patients evaluable for response, four partial responses were noted (response rate 22%), while seven patients had stable disease. Three partial responses were observed in patients in whom the skin lesions were smaller than 1.5 cm2. Median duration of respons was 2.5 months and median time to progression for all patients was 1.9 months. In this study topically applied miltefosine for metastatic skin lesions of breast cancer showed modest activity in a relatively heavily pretreated patient population, without serious systemic toxicity.

ISSN:0959-4973    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

F 11782 is a newly identified catalytic inhibitor of topoisomerases I and II, without any detectable interaction with DNA. This study aimed to establish whether its catalytic inhibition of topoisomerase II was mediated by mechanisms similar to those identified for the bisdioxopiperazines.In vitrocombinations of F 11782 with etoposide resulted in greater than additive cytotoxicity in L1210 cells, contrasting with marked antagonism for combinations of etoposide with either ICRF-187 or ICRF-193. All three compounds caused a G2/M blockade of P388 cells after an 18-h incubation, but by 40 h polyploidization was evident only with the bisdioxopiperazines. Gel retardation data revealed that only F 11782, and not the bisdioxopiperazines, was capable of completely inhibiting the DNA-binding activity of topoisomerase II, confirming its novel mechanism of action. Furthermore, unlike ICRF-187 and ICRF-193, the cytotoxicity of F 11782 appeared mediated, at least partially, by DNA damage induction in cultured GCT27 human teratoma cells, as judged by a fluorescence-enhancement assay and monitoring p53 activation. Finally, the majorin vivoantitumor activity ofF 11782 against the murine P388 leukemia (i.v. implanted) and the B16 melanoma (s.c. grafted) contrasted with the bisdioxopiperazines' general lack of activity. Overall, F 11782 and the bisdioxopiperazines appear to function as quite distinctive catalytic topoisomerase II inhibitors.

ISSN:0959-4973    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

We evaluated thein vitrocytotoxicity of topotecan (TPT), versus cisplatin, etoposide (VP-16) and paclitaxel (PTX) in four squamous cell cancer cell lines of the cervix uteri and vulva. Four established human squamous cancer cell lines from the cervix uteri (A-431, Ca Ski and C-33) and vulva (CAL-39) were used. The cytotoxic effects of the agents were examined using the ATP-Tumor Chemosensitivity Assay (ATP-TCA). In addition to the single agents, the following combinations were tested: TPT+cisplatin, TPT+VP-16 and TPT+PTX. Three cell lines (C-33, Ca Ski and CAL-39) were highly sensitive to TPT, but one cell line (A-431) was less sensitive. Furthermore, the cytotoxic activity of TPT was superior to that of cisplatin in Ca Ski and C-33 cells, but inferior in CAL-39 and A-431. TPT was also more active than VP-16 in CAL-39 and Ca Ski. On the other hand, the cytotoxic activity of TPT was weaker than PTX in C-33, CAL-39 and A-431. TPT increased the cytotoxic activity of cisplatin and VP-16 in C-33, Ca Ski and A-431. However, synergistic features were observed only in A-431 cells. TPT also enhanced the cytotoxic activity of PTX in A-431 and Ca Ski. In CAL-39 and C-33, however, increased cytotoxic activity occurred only at higher drug concentrations, whereas antagonism was observed at lower drug concentrations. In conclusion, our results suggest that TPT has a significant cytotoxic effect on most squamous cell cancer cell lines which may be superior to cisplatin, VP-16 and PTX in some instances. Furthermore, TPT is likely to potentiate the cytotoxic activity of these agents in individual cell lines tested.

ISSN:0959-4973    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

In a systematic effort to identify a potent anticancer agent against human ovarian cancer, we synthesized 15 oxovanadium(IV) complexes, and examined their cytotoxic activity against human ovarian cancer cell lines PA-1, SKOV-3, ES-2 and OVCAR-3 using a MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyletetrazolium bromide]-based assay. The apoptosis-inducing ability of the oxovanadium compounds was evaluated by the two-color flow cytometric terminal deoxynucleotidyl transferase-based assay that labels 3′-hydroxyl ends of fragmented DNA (TUNEL) assay and confocal laser scanning microscopy. Notably, all eight oxovanadium complexes of 1,10 phenanthroline exhibited significant cytotoxicity and induced apoptosis within 24 h. Themono-chelated, VO(NO2-phen) andbis-chelated, VO(Me2-phen)2, VO(Cl-phen)2and VO(NO2-phen)2complexes were the most potent oxovanadium compounds, and killed target cancer cells at low micromolar concentrations. The marked differences in the cytotoxic activity of oxovanadium(IV) complexes containing different heterocyclic ancillary ligands suggest that the cytotoxic activity of these compounds is determined by the identity of the five-member bidentate ligands, as well as the nature of the substituents on the heterocyclic aromatic rings. Our results presented herein provide experimental evidence that oxovanadium compounds induce apoptosis in human ovarian cancer cells. The lead compounds, VO(Me2-phen)2and VO(NO2-phen)2, may be useful in the treatment of ovarian cancer.

ISSN:0959-4973    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

We have previously confirmed thein vitroactivity of cisplatin and carboplatin against human melanoma cell lines. Both drugs are important components in the chemotherapy used in our service for advanced metastatic melanoma. In this communication we report thein vitroactivity of oxaliplatin against human melanoma cell lines in comparison with cisplatin and carboplatin. Oxaliplatin was found to be active against C32 and G361 cell lines with IC50values of 49.48 and 9.07 μM (1 h exposure), 9.47 and 1.30 μM (4 h exposure), and 0.98 and 0.14 μM (24 h exposure), respectively. The cytotoxic activity of oxaliplatin in thisin vitrosystem appears to be significantly superior to that of carboplatin. Its activity becomes comparatively closer to that of cisplatin as exposure time increases. Indeed at a 24 h exposure oxaliplatin appears to be significantly more active than cisplatin against the G361 cell line (p=0.0343). Oxaliplatin merits evaluation in the clinic both as a single agent and in combination with other drugs active against melanoma.

ISSN:0959-4973    

出版商:OVID    

年代:2000

数据来源: OVID