摘要:

Neovastat (Æ-941) is an antiangiogenic drug isolated from marine cartilage. It interferes with several steps associated with the development of angiogenesis through its ability to induce endothelial cell apoptosis, and to inhibit matrix metalloproteinase activities and vascular endothelial growth factor-mediated signaling pathways, suggesting that Neovastat behaves as a multifunctional antiangiogenic drug. Neovastat is orally bioavailable, and shows significant antitumor and antimetastatic properties in animal models. An excellent safety profile with few side effects has been monitored in more than 800 patients who have been exposed to Neovastat, some of whom for more than 4 years. This indicates that Neovastat is suitable for long-term use, either alone or in combination with other anticancer therapies. Accordingly, Neovastat is currently under evaluation in three pivotal clinical studies with two phase III clinical trials in patients with lung and renal carcinoma, and a phase II clinical trial in patients with multiple myeloma is ongoing.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

In the last two decades the prognosis of colorectal cancer has improved for two reasons: (i) the proportion of patients with localized disease has increased and treatment has been standardized, and (ii) new chemotherapeutic agents have led to a longer life expectancy for patients with advanced disease. In this review the current insights in disease etiology and treatment of localized and disseminated colorectal cancer are discussed.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The purpose of this study was to evaluate the pharmacokinetics and toxicity of docetaxel in continuous hyperthermic perfusion peritoneal chemotherapy (CHPPC) after cytoreductive surgery for peritoneal involvement of gynecological malignancies, mainly ovarian cancer. Eighteen patients, with a mean age of 64 years (range 51–80), underwent cytoreductive surgery and subsequent CHPPC with 75 mg/m2docetaxel at 41–43°C. One patient was treated twice. In eight cases, peritoneal fluid and blood samples were obtained for pharmacokinetic analysis. Death occurred in two heavily pretreated elderly patients with a high volume i.p. tumor recurrence, probably reflecting poor patient selection (mortality rate 10.5%). Other complications, mainly minor, were recorded after 63% of the procedures. Hematological docetaxel-induced toxicity was limited, while the incidence of wound complications was relatively high and probably caused by the direct exposure of the wound to docetaxel during CHPPC. The maximal i.p. versus plasma concentration ratio ranged from 17 to 95 (average 45), while the i.p. versus systemic exposure ratio varied between 105 and 555 (average 207). We conclude that the use of docetaxel in CHPPC following cytoreductive surgery seems feasible and results in a high i.p. versus systemic exposure ratio. The AUC for the peritoneal cavity is on average 13–27 times higher after i.p. administration of 75 mg/m2during CHPPC than the AUC achieved in the systemic compartment after i.v. administration of the recommended dose of 100 mg/m2, while docetaxel-induced systemic toxicity is highly limited.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Gemcitabine, a pyrimidine analog active in non-small cell lung cancer (NSCLC), is widely used with cisplatin. The potential activity of the combination has not been fully assessed: gemcitabine is not used at its maximum tolerated dose (MTD) and cisplatin shows a clearly dose-related toxicity. This trial was designed to assess the MTD and dose-limiting toxicity (DLT) of low-dose cisplatin and increasing gemcitabine dose. Chemotherapy: cisplatin 50 mg/m2on day 1, gemcitabine starting at 1400 mg/m2on days 1 and 8 every 21 days. Subsequent levels were increased by 200 mg/m2. Forty-two patients with metastatic NSCLC were enrolled (37 males; median age 61 years; squamous cell carcinoma 19 patients; performance status 2, in 13 patients; 18 patients had significant weight loss). MTD was found to be 2600 mg/m2because of DLT in three of six patients: two neutropenic fever and one massive bleeding. Overall toxicity was generally mild consisting mainly of neutropenia. Asthenia was the most common non-hematological effect. Overall response rate was 19 out of 41 patients (46.3%) and median survival was 31 weeks. We conclude that the recommended dose for a phase II dose is gemcitabine 2400 mg/m2days 1 and 8 as a 30-min infusion when given with cisplatin 50 mg/m2.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Capecitabine is a novel fluoropyrimidine carbamate which is selectively activated after oral administration to 5-fluorouracil (5-FU) by a sequential triple enzyme pathway in liver and tumor cells. The cytotoxic activity of the metabolized 5-FU depends on thymidylate synthase (TS) inhibition, leading to defective DNA synthesis. Capecitabine has shown promising activity in all tumor types sensitive to 5-FU and is therefore investigated in many clinical trials. Since we observed an increase of mean corpuscular volume (MCV) of red blood cells under therapy with capecitabine, the current investigation aimed to quantitate this effect and to elucidate the underlying mechanisms. A total of 154 patients suffering from advanced cancer received capecitabine (2500 mg/m2/day for 14 days every 21 days) either as monotherapy, or in combination with other antineoplastic agents or biological response modifiers. During 3 consecutive cycles of therapy a complete blood cell count including the red cell indices MCV, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration was performed before each application of capecitabine. In addition, vitamin B12, folic acid and homocysteine were determined to define their role in increasing MCV. Restaging was performed after 9 weeks. Within 9 weeks, a statistically significant increase of MCV (without other hematologic abnormalities or clinical symptoms) could be observed (p<0.0001). Vitamin B12, folic acid and homocysteine levels did not change significantly during the observation period. When comparing the different increases of MCV during 9 weeks (ΔMCV) with respect to tumor response, ΔMCV tended to higher values in patients with tumor remission or stable disease than in patients with tumor progression. We conclude that serum levels within the normal range rule out severe deficiencies of vitamin B12, folic acid or homocysteine as an account of macrocytemia. We therefore hypothesize that an increased MCV (without concomitant anemia) in patients receiving capecitabine might be due to the 5-FU-induced TS inhibition also in erythroid precursor cells. Whether this increase in MCV might serve as a surrogate marker for tumor response has to be evaluated in further investigations.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

A phase I trial of flavopiridol administered as a 1-h i.v. infusion schedule was explored. Fifty-five patients were treated with flavopiridol at doses ranging from 12 to 78 mg/m2daily for 5, 3 and 1 day every 3 weeks. Pharmacokinetic and pharmacodynamic analysis was performed together with analysis of a promoter polymorphism of theUGT1A1gene. Peak concentrations and areas under the time–concentration curve of flavopiridol were linear within the doses studied. Estimated clearance was 13.8±4.9 l/h/m2(mean±SD), volume of distribution at steady-state was 64.9±43.4 l/m2and elimination half-life was 5.2±4.9 h. Forty-nine of the 55 patients were genotyped for the promoter polymorphism. We found five (10%) homozygous and 11 (22%) heterozygous patients forUGT1A1*28, which alters the reference sequence (TA)6TAA to the variant (TA)7TAA by an extra TA dinucleotide insertion within the TATA box. One patient was heterozygous for the sequence of five TA repeats, (TA)5TAA. The remaining 32 patients did not have theUGT1A1*28allele (homozygous for the reference sequence). Associations of theUGT1A1promoter genotype with either the pharmacokinetic parameters or diarrhea (occurrence and severity) were not observed in this study. The pharmacogenetic analyses did not support that theUGT1A1promoter polymorphism could affect flavopiridol pharmacokinetics and alter the incidence and severity of diarrhea induced by the drug.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

In our institution, 103 glioblastoma multiforme (GBM) patients aged from 55 to 83 years were treated since November 1994 as follows. All patients underwent surgical intervention (gross total resection,n=35; subtotal resection,n=38; stereotactic biopsy,n=30). Subsequently all patients were offered radiotherapy and chemotherapy with CCNU. Results were as follows: 101 patients started radiotherapy, 93 patients completed it (96% of the patients aged <65 years and 85% of the patients ≥65 years). All patients received at least 1 cycle of chemotherapy (median 3 cycles). Chemotherapy-associated toxicity was generally mild, more pronounced in females and did not increase with age. Median time to progression was 10.5±3.2 months for the patients <65 years and 5.1±1 months for patients ≥65 years. median overall survival was 17.5±3.8 months in patients <65 years and 8.6±1 months in patients ≥65 years (p<0.0001). In multivariate analysis, age and female sex remained independent prognostic factors. Our data indicate that a treatment concept including concomitant radio- and chemotherapy is feasible even in elderly patients with GBM.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The primary objective of this study was to determine the maximum tolerable dose (MTD) and dose-limiting toxicity (DLT) for bolus 5-fluorouracil (5-FU) administered on a biweekly schedule and in combination with fixed doses of leucovorin (LV) and oxaliplatin. The secondary objectives were to evaluate the toxicity profile and antitumor activity of this regimen for pre-treated patients with advanced colorectal cancer. A total of 26 patients with documented fluoropyrimidine-resistant, advanced colorectal cancer were enrolled into this phase I study. Fixed dose of oxaliplatin (85 mg/m2) was delivered as an i.v. infusion over 2 h, followed by LV (20 mg/m2) and 5-FU bolus every 2 weeks. The starting dose of 5-FU was 600 mg/m2, which was then incremented by 100 mg/m2for each dose level. The DLT was determined for the first two treatment cycles, while toxicity and efficacy were evaluated throughout treatment. Six dose levels were tested. The MTD of 5-FU was deemed to be 1000 mg/m2since dose-limiting fatigue was noted for three of the five-patient cohort during the first two cycles of chemotherapy at dose level 6. The most frequent treatment-related toxicities during the study were neutropenia, vomiting, diarrhea, fatigue and neuropathy. In an intent-to-treat analysis, the objective response rate was 30.8% (95% confidence interval 11.8–49.8%) for the 26 patients. The combination of bolus 5-FU/LV and oxaliplatin every 2 weeks is a feasible and effective treatment at the recommended dosages. A phase II study, to more-precisely define activity and toxicity, is ongoing.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Thioredoxin (Trx) expression is increased in several human primary cancers and the Trx/Trx reductase (TrxR) system therefore provides an attractive target for cancer drug development. Novel organotellurium antioxidants, especially a primitive analog of vitamin E (compound 1d) and compounds 7, 9 and 10—all carrying highly functionalized 4-(dialkylamino)phenyltelluro groups to secure high antioxidative capacity—were found to inhibit TrxR with IC50values in the low micromolar range. Whereas antioxidant 1d also inhibited the growth of MCF-7 human breast cancer cells in culture at a similar level (IC50=1.8 μM), the other TrxR inhibitors were inactive in concentrations below about 10 μM.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

We evaluatedin vitrothe inhibitory effect ofcis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate,N4]-chlorideplatinum(II) monohydrochloride monohydrate (DPR) on colony formation by granulocyte/macrophage (CFU-GM) peripheral blood progenitor cells, representing a method to quantitate the toxicity of drugs to the hematopoietic system, and human leukemic cell lines. The results were compared with those obtained exposing cells to cisplatin and carboplatin. Our data showed that while DPR had a significantly better cytotoxic activity than cisplatin and carboplatin against HL60 and K562, and than carboplatin against Molt 4 cells, it showed 12 and 43 times less inhibitory effect on CFU-GM than cisplatin and carboplatin, respectively. These results suggest that the myelosuppressive activity of DPR could be lower than that of cisplatin and carboplatin, and, furthermore, that leukemic cells represent a preferential target for its cytotoxic activity compared to normal committed hemopoietic progenitor cells. All our results speak in favor of a better therapeutic index for DPR than for the other platinum compounds considered here.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID