摘要:

We performed a phase I study combining gemcitabine and interferon (IFN)-&agr;2b in patients with advanced solid tumors to determine the maximum tolerated dose (MTD) and recommended doses for phase II trials. Five dose levels of gemcitabine (mg/m2)/IFN-&agr;(×106IU) were planned: 500/5, 1000/5, 1000/7, 1000/10 and 1200/10. Gemcitabine was given once weekly and IFN&agr;3 × weekly for 3 consecutive weeks followed by 1 week of rest (28-day cycles). Between February 1997 and June 1999, 21 patients with advanced pancreatic (n=3), ovarian (n=1), renal (n=10) and non-small cell lung cancer (NSCLC;n=7) were enrolled. The MTD was reached at gemcitabine 1000 mg/m2and IFN-&agr;7 × 106IU, with two of three patients having dose-limiting toxicity (thrombocytopenia). The predominant hematologic toxicities (grade 3/4) were neutropenia and thrombocytopenia (13 and five patients, respectively). Three patients had moderate neutropenic fever and one had grade 4 AST/ALT; none required hospitalization. Of the 18 evaluable patients, responses included one partial response (NSCLC) and 10 stable diseases (eight renal cancer). We conclude that the recommended phase II study regimen is gemcitabine 1000 mg/m2and IFN-&agr;5×106IU, every 28 days. The results, particularly those in metastatic renal carcinoma, are encouraging and worthy of further evaluation in phase II trials.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

We undertook a prospective study to evaluate the role of the combination of fludarabine and cyclophosphamide in patients with low-grade non-Hodgkin's lymphoma. Twenty-seven patients with low-grade non-Hodgkin's lymphoma were treated with i.v. fludarabine (30 mg/m2) and cyclophosphamide (250 mg/m2) on days 1–3. Cycles were given at 4-week intervals for a maximum of six courses. Fourteen patients (52%) were previously untreated, 13 patients (48%) had been treated with at least one chemotherapy regimen before. Of the 27 patients, 11 (41%) obtained a complete and 13 (48%) a partial remission, thus the overall response rate was 89%. The remission rate in untreated patients was slightly higher than in pretreated patients (93 versus 85%). The toxicity was mild, no treatment-related mortality occurred. Neutropenia was the most common side effect, grade 4 neutropenia of rather short duration was observed in less than 7% of the cycles. At the end of the treatment, the mean CD4+count was 155/μl and the mean CD8+count 204/μl. Severe infections did not occur. These results show that the combination of fludarabine and cyclophosphamide in the doses used in this study is an effective regimen with manageable toxicity in low-grade non-Hodgkin's lymphoma.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

AP 5280 is a novel polymer-conjugated platinum anticancer agent currently undergoing phase I clinical trials. It is pharmaceutically formulated as a lyophilized product containing 200 mg platinum per dosage unit. The aim of this study was to determine the reconstitution and dilution fluid of choice, and to investigate the stability and compatibility of AP 5280 in solution under different storage conditions and with several container materials. Furthermore, the hemolytic potential of AP 5280 infusion solution was investigatedin vitro. AP 5280 slowly released small platinum species in all solutions, although this release was enhanced in normal saline. Accordingly, 5% dextrose in water (D5W) was selected for reconstitution and dilution of AP 5280. Container material [glass or polyvinylchloride (PVC)] did not influence the stability of AP 5280 in solution. Storage at refrigerated temperature (2–8°C) marginally decreased the release rate of liberated platinum. The infusion solutions are compatible with the PVC infusion system and do not cause hemolysisin vitro. In conclusion, AP 5280 lyophilized product should be reconstituted and diluted to infusion concentration with D5W, and administered within 8 h after preparation to ensure that less than 1.0% of the total platinum concentration is present as liberated platinum.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The purpose of this investigation was to evaluate the efficacy and toxicity of 6 months' treatment with the combination of epirubicin and docetaxel in metastatic breast cancer. Thirty-eight women (mean age 51 years, range 35–72) with metastatic breast cancer were treated with a regimen of epirubicin 75 mg/m2and docetaxel 75 mg/m2every 3 weeks, given 4 times if progression was seen upon evaluation after 4 courses or 8 times in responding/stable patients. The patients received 285 cycles of combination treatment and two treatments with docetaxel or epirubicin alone. When neutropenia with fever was observed, further cycles were given with dose reduction. The median cumulative docetaxel dose was 462 mg/m2(range 199–600) and that of epirubicin 476 mg/m2(range 199–740). The overall response rate was 54% (95% CI 37–71), with a median duration of response of 14.8 months (95% CI 8.8–27.8). Median time to progression was 12 months, median survival 26 months. Neutropenia below 0.5×109/l occurred following 113 (39%) of the total of 285 cycles given; 21 patients (55%) were hospitalized for febrile neutropenia. We conclude that dose tailoring is required in treatment with an epirubicin and docetaxel regimen to avoid grade 3/4 adverse effects in a significant number of patients treated for metastatic breast cancer.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

We carried out a retrospective evaluation of thymidylate synthase (TS) expression in tumor tissue, and its relation to outcome and response to treatment. The treatment consisted of chemotherapy with tegafur and uracil (UFT). The study group comprised 245 patients with curatively resected Dukes' stage B or C colorectal cancer who were postoperatively enrolled in a controlled study and assigned to receive UFT or no adjuvant chemotherapy. TS expression in tumor tissue was evaluated immunohistochemically with the use of recombinant human TS-specific antibody. Results were as follows. There was no relation between TS expression and the rate of 5-year disease-free survival. Similar results were obtained in both colonic and rectal tumors. The rate of 5-year disease-free survival was significantly higher in the UFT group than in the group receiving no adjuvant chemotherapy (p=0.0055). The difference in survival became more marked among patients whose tumors had diffuse TS expression (p=0.0027). There was no difference in survival between the treatment groups among patients whose tumors had focal TS expression. We conclude that, although unrelated to outcome, TS activity may be useful in predicting the response to adjuvant chemotherapy with UFT in patients with curatively resected Dukes' stage B or C colorectal cancer.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Why some women are at increased risk for the development of endometrial carcinoma while taking the antiestrogen tamoxifen (Tam) for breast cancer treatment or prevention is unknown. Various strains of rodents display differences in sensitivity to compounds with estrogenic activity, but whether differences in Tam sensitivity exist in rodent strains has not been investigated. In the present study, we investigated whether rat strain differences in reproductive tract sensitivity to Tam and estrogen exist between Fischer 344 (F344) and Sprague Dawley (SD) rats. Immature (21–23 day;n=6/group), ovariectomized F344 and SD rats were treated with vehicle (control), 17&bgr;-estradiol (E2) [1×10−6to 1.0 μg/kg body weight (BW)] or 4-OH tamoxifen (4-OHT) (1×10−4to 10 mg/kg BW) for 2 days and then sacrificed on day 3. Reproductive tracts were collected, weighed, and examined for changes in histomorphology and expression of ER&agr;and nuclear receptor co-regulators (SRC1, p300, CARM1, GRIP1, SPA, REA and Uba3). Treatment with E2(1×10−5 μg/kg BW) increased (p<0.05) uterine epithelial cell height in F344 but not SD rats, demonstrating increased sensitivity of the F344 strain to E2. Conversely, treatment with 1×10−3 mg/kg BW 4-OHT increased (p<0.05) uterine weight and epithelial cell height in SD but not F344 rats, demonstrating that the SD strain is more sensitive to the antiestrogen. Northern and Western blot and immunohistochemical analysis revealed that ER&agr;expression levels in the SD and F344 uterus were not different. Expression of receptor co-regulators was higher in the uterus compared to the vagina regardless of strain and higher CARM1 expression was seen in SD uterus compared to F344 rats. Understanding differences in Tam sensitivity may help us to better understand why some women develop endometrial cancer while taking Tam and be beneficial in treatment decisions for breast cancer patients.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The receptors for luteinizing hormone-releasing hormone (LHRH) are found in 80% of human ovarian carcinomas. These receptors can be used for targeted chemotherapy with cytotoxic analogs of LHRH, such as AN-207, consisting of 2-pyrrolinodoxorubicin (AN-201) linked to [D-Lys6]LHRH. We investigated the effects of AN-207 and AN-201 on thein vivogrowth of LHRH receptor-positive ES-2 human ovarian cancers. The effects of the treatment on mRNA and protein levels of human epidermal growth factor (EGF) receptors (EGFR and HER-2) in ovarian tumors were determined by RT-PCR and immunoblotting. In Experiment 1, nude mice bearing ES-2 ovarian tumors were injected i.v. with 250 nmol/kg doses of AN-207, AN-201, the carrier [D-Lys6]LHRH, an unconjugated mixture of AN-201 and [D-Lys6]LHRH or vehicle. AN-207 caused a significant (p<0.01) 59.5% inhibition in tumor growth while its components were ineffective. In Experiment 2, mice with large ES-2 tumors were treated with AN-207 or AN-201 at 250 nmol/kg. Again, AN-207, but not AN-201, inhibited tumor growth. In Experiment 3, the site of action of AN-207 was investigated. The blockade of LHRH receptors with Cetrorelix partially suppressed the antitumor effect of AN-207. Treatment with AN-207 significantly (p<0.01) decreased the expression of mRNA for EGFR, and HER-2 by 27 and 34%, respectively, as compared to controls and reduced the receptor protein levels of EGFR and HER-2 by 35 and 36%, respectively (p<0.05). The results indicate that cytotoxic LHRH analog AN-207 could be considered for chemotherapy of ovarian cancers expressing LHRH receptors.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The use of cisplatin as a potential radiosensitizer in nasopharyngeal carcinoma (NPC) has produced encouraging results in clinical trials. In order to provide information on improving the design of clinical treatments, we investigated the effect of cisplatin dose, and the time interval and sequence between administration of cisplatin and radiation on cell survival of two NPC cell lines, CNE1 and SUNE1. When cisplatin was applied first, an exposure time of 24 h resulted in up to 2.6-fold increase in cell death and 7-fold increase in radiation effect (cell survival after cisplatin/cell survival after cisplatin plus radiation) in the cisplatin–radiation combination treatment compared to the cells treated with cisplatin for 4 h. When radiation was applied first, a shorter interval time of 4 h followed by cisplatin treatment resulted in up to 3-fold increase in cell death and a 3-fold enhanced radiation effect over longer time intervals of 24 h. By changing the order of radiation and cisplatin treatment alone, a 2-fold difference in radiation effect was observed. The differential cytotoxicity was partially explained by the alterations in cell cycle distribution. Our results indicate the importance of scheduling the radiation and cisplatin combination regimens on the survival of NPC cells.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

An i.v. formulation of rubitecan (9-nitrocamptothecin) was evaluated in five human solid tumor xenograft models. Rubitecan in IDD-P™, a particulate suspension of the insoluble analog, produced significant tumor growth delay in athymic nude mice bearing A375 melanoma, and MX-1 breast, SKMES non-small-cell lung, Panc-1 pancreatic and HT29 colon carcinomas. The activity of i.v. rubitecan was similar or somewhat superior to those of i.p. regimens with the reference drugs, irinotecan and topotecan. Tumor sensitivity to rubitecan in IDD-P was MX-1>A375>SKMES >Panc-1>HT29. Some complete regression responses were seen with MX-1, A375 and SKMES tumors treated with 2.5 mg/kg on a schedule of two 5-day dosing cycles separated by 2 drug-free days. In nude mice, the MTD of rubitecan in IDD-P lies between 2 and 2.5 mg/kg on this schedule; antitumor efficacy was achieved with doses between 2.5 and 1.25 mg/kg. Dosing with 6.6 mg/kg rubitecan in IDD-P on intermittent schedules (4- or 7-day intervals) was tolerated, but less efficacious, when tested in the A375 model. The good responses obtained with rubitecan in IDD-P suggest it could be used clinically in circumstances where an i.v. formulation offers advantages to oral or aerosol formulations.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID