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991.
Mace L Rothenberg Bonnie LaFleur Donna E Levy Mary Kay Washington Sherry L Morgan-Meadows Ramesh K Ramanathan Jordan D Berlin Al B Benson Robert J Coffey 《Journal of clinical oncology》2005,23(36):9265-9274
PURPOSE: The clinical objective of this trial was to evaluate gefitinib in patients with metastatic colorectal cancer that had progressed despite prior treatment. Serial tumor biopsies were performed when possible and analyzed for activation of the epidermal growth factor receptor (EGFR) signaling pathway. Serial serum samples were measured for amphiregulin and transforming growth factor-alpha (TGFalpha). PATIENTS AND METHODS: One hundred fifteen patients were randomly assigned to receive gefitinib 250 or 500 mg orally once a day. One hundred ten patients were assessable for clinical efficacy. Biologic evaluation was performed on paired tumor samples from 28 patients and correlated with clinical outcome. RESULTS: Median progression-free survival was 1.9 months (95% CI, 1.8 to 2.1 months) and 4-month progression-free survival rate was 13% +/- 5%. One patient achieved a radiographic partial response (RR = 1%; 95% CI, 0.01% to 5%). Median survival was 6.3 months (95% CI, 5.1 to 8.2 months). The most common adverse events were skin rash, diarrhea, and fatigue. In the biopsy cohort, expression of total or activated EGFR, activated Akt, activated MAP-kinase, or Ki67 did not decrease following 1 week of gefitinib. However, a trend toward decreased post-treatment levels of activated Akt and Ki67 was observed in patients with a PFS higher than the median, although these did not reach the .05 level of significance. CONCLUSION: Gefitinib is inactive as a single agent in patients with previously treated colorectal cancer. In tumor samples, gefitinib did not inhibit activation of its proximal target, EGFR. Trends were observed for inhibition of downstream regulators of cellular survival and proliferation in patients achieving longer progression-free survival. 相似文献
992.
Robert T. Dorr MD Mary Ann Raymond Terry H. Landowski Nicholas O. Roman Shoji Fukushima 《Journal of gastrointestinal cancer》2005,36(1):15-28
Imexon is an aziridine-containing small molecule currently in Phase I clinical trials. This agent has been shown to bind to thiols and increase intracellular oxidants, inducing apoptosis in hematologic cancer cells. Pancreatic cancers are known to be sensitive to oxidation, suggesting this disease may be an appropriate target for this agent. The current report examines the activity of imexon in pancreatic cells. Imexon induced concentration-dependent and time-dependent apoptosis in a panel of six human pancreatic carcinoma cell (PCC) lines. The mean IC50 (SD) for growth inhibition by the SRB assay was 200 (101) µM for a 48 h exposure with a range of 64–358 µM. Cell killing was schedule-dependent, favoring exposure times ≥48 h. Imexon-treated MiaPaCa-2 cells underwent non-lethal growth arrest following exposure to concentrations ≤200 µM for 48 h. When concentrations were increased to 300 µM for ≥48 h, the MiaPaCa-2 cells arrested in G2 phase and activated caspases 3, 8, and 9 were detected. After a 72 h exposure to the IC80 concentration of imexon, cells exhibited a loss of mitochondrial membrane potential detected by CMXRos staining. However, there was no loss of reduced cellular thiols unless very high concentrations of ≥400 µM were used. In contrast, reactive oxygen species (ROS) were elevated in a dose-dependent fashion, starting at very low imexon concentrations. Imexon also significantly inhibited MiaPaCa-2 tumor growth in SCID mice at 100 mg/kg/d for 9 d. The tumor growth inhibition (% T/C) was 27% of control, and the tumor growth delay was 21 d, indicating an active agent by NCI standards. The levels of imexon that are cytotoxic in human PCC’s are achievable based on the preliminary results of the ongoing Phase I trial. Imexon appears to be active against PCCs in vitro and has an entirely novel mechanism of action involving G2 arrest, accumulation of ROS, and the induction of apoptosis. 相似文献
993.
Xavier Leleu Ga?lle Le Friec Thierry Facon Laurence Amiot Renée Fauchet Bernadette Hennache Valérie Coiteux Ibrahim Yakoub-Agha Sylvain Dubucquoi Hervé Avet-Loiseau Claire Mathiot Régis Bataille Jean-Yves Mary 《Clinical cancer research》2005,11(20):7297-7303
Serum beta2-microglobulin, the light chain of the HLA class I molecular complex, remains one of the best survival prognostic factors in multiple myeloma, but other HLA class I molecules might be of interest in monoclonal gammopathies. In this study, we evaluate total soluble HLA class I (HLA-Is) and soluble HLA-G (HLA-Gs) in 103 patients with newly diagnosed multiple myeloma, 30 patients with monoclonal gammopathy of undetermined significance (MGUS), and 30 healthy subjects, studying their prognostic value in multiple myeloma. In multiple myeloma patients, HLA-Is and HLA-Gs median values were 0.8 microg/mL and 28 ng/mL, respectively. Median HLA-Is concentration was higher in stage II and III multiple myeloma patients than in stage I multiple myeloma, MGUS, and control patients. Median HLA-Gs was significantly lower in healthy controls than in MGUS and multiple myeloma patients. A high level of HLA-Is (> or =2.1 microg/mL) was predictive of short survival (P = 0.017). For each given level of beta2-microglobulin, the relative risk of death was higher for patients with HLA-Is > or = 2.1 microg/mL than in patients with a lower level (P = 0.047). HLA-Gs, a marker of monoclonal gammopathy, was of no prognostic value, but the addition of HLA-Is to beta2-microglobulin produced an efficient prognostic score (P < 0.0001). HLA-Is is a new marker of multiple myeloma tumor load and provides additional survival prognostic information to beta2-microglobulin. 相似文献
994.
Robert W Weber Steven O'Day Madalene Rose Regina Deck Patricia Ames James Good John Meyer Robert Allen Sharon Trautvetter Molly Timmerman Scott Cruickshank Mary Cook Rene Gonzalez Lynn E Spitler 《Journal of clinical oncology》2005,23(35):8992-9000
PURPOSE: The objective of this study was to further investigate the efficacy and safety of low-dose outpatient chemobiotherapy in patients with unresectable metastatic melanoma. PATIENTS AND METHODS: Thirty-one patients with histologically confirmed unresectable measurable metastatic melanoma were enrolled onto an open-label, multicenter phase II study. The treatment regimen consisted of oral temozolomide followed by subcutaneous biotherapy with granulocyte macrophage colony-stimulating factor, interferon-alfa, and recombinant interleukin-2 (rIL-2). RESULTS: Twenty-eight patients (90%) had M1c disease, and 58% had three or more sites of metastasis. Four patients (13%), all with M1c disease, had a complete response, and four patients had a partial response. The median progression-free survival was 4.9 months and the median overall survival was 13.1 months. Two patients (6%) developed CNS metastasis as the first site of disease progression, and 7 (23%) of 30 experienced CNS progression after receiving chemobiotherapy. A total of 112 cycles of therapy were administered. Toxicity occurred in 78% of the cycles and was grade 1 or 2 in the majority of cases and easily managed. Grade 4 toxicity occurred in 3% of the cycles. CONCLUSION: This low-dose chemobiotherapy combination produces clinical responses in patients with metastatic melanoma, even in those with M1c disease, is well tolerated, and allows home dosing. It offers a reasonable alternative to high-dose regimens, such as high-dose biochemotherapy or rIL-2 requiring prolonged periods of hospitalization, or single agent outpatient regimens, such as dacarbazine, which is usually not effective in patients with M1c disease. Furthermore, it may protect against the development of brain metastases. 相似文献
995.
Objectives: To develop a set of explicit and operationalisable indicators of appropriate prescribing and assess their face validity using
clinical pharmacists practising in secondary and primary care.
Method: Appropriateness indicators were derived from the literature, applied to data in the hospital clinical records of all newly
prescribed long-term drugs for 50 randomly selected patients, further refined and then applied to another 25 randomly selected
patients. A pre-piloted postal questionnaire was sent to 200 hospitals and primary care pharmacists, asking them to assess
the indicators as to their importance for the assessment of appropriateness of long-term prescribing initiated in hospitals.
Results: Fourteen indicators were developed and piloted. Of the 16 original indicators, 5 were discarded, as they were unable to be
operationalised, and 2 were subdivided to reflect the routinely available data. Eighty-six pharmacists with individual patient-focussed
clinical duties took part in the assessment of the face validity (response rate 43%). Eleven indicators achieved a median
importance rating of 1 (very important), and three indicators a median importance rating of 2 on a 5-point scale. The three
most important indicators overall were ‘indication included in discharge summary’, ‘questionable high-risk therapeutic combination’
and ‘hazardous drug-drug combination’.
Conclusion: It was possible to develop and operationalise 14 indicators of the appropriateness of long-term prescribing commenced in
hospital practice, all of which were considered to have face validity by an expert panel of clinical pharmacists. The development
of these explicit indicators highlighted the incompleteness of the patient’s record. Further work is needed to assess their
validity and reliability, before their use in research or audit can be recommended. 相似文献
996.
Jayaprakash Aravindakshan Valérie Paquet Mary Gregory Julie Dufresne Michel Fournier David J Marcogliese Daniel G Cyr 《Toxicological sciences》2004,78(1):156-165
There is limited information on the physiological consequences associated with exposure to xenoestrogens under field conditions. The objectives of this study were to determine the presence of estrogenic chemicals in the St. Lawrence River and their effects on male reproduction in the spottail shiner (Notropis hudsonius). Hepatic vitellogenin (VTG) mRNA levels in immature shiners indicate extensive estrogenic contamination spanning almost 50 km both upstream and downstream from the island of Montreal. Stages of spermatogenesis were assessed in fish captured at sites having varying levels of estrogenic contamination. In control fish, 95% had testis of either stage IV (50%) or stage V (45%) of spermatogenesis. At Ile Dorval, where VTG mRNA levels are moderate, fish had testes of stage III (38%) and IV (45%) and only 15% of fish were at spermatogenic stage V. In contrast, at Ilet Vert and Ile Beauregard, located in the sewage effluent plume from the City of Montreal and where hepatic VTG mRNA levels are high in fish, none of the fish were at stage V and 8% of fish at Ilet Vert were at stage II of development. Sperm concentration and various motility parameters were significantly lower in shiners from Ilet Vert as compared with those from Iles de la Paix (reference). Histological analyses of testes revealed that more than one-third of the fish captured at sites with the highest estrogenic contamination displayed intersex, a condition in which ovarian follicles were developing within the testis. These data indicate that there is significant estrogenic contamination in the St. Lawrence River that is associated with impaired reproductive function in male fish. 相似文献
997.
Bergamottin (BG) and 6',7'-dihydroxybergamottin (DHB) are the most abundant furanocoumarins present in grapefruit juice and have been proposed as major intestinal CYP3A4 inhibitors contributing to grapefruit juice-drug interactions. The relative contribution of BG versus DHB to the interaction potential is unclear, in part due to inconsistencies in the literature regarding inhibitory potency. To resolve these inconsistencies, the inhibitory kinetics of each furanocoumarin toward CYP3A4 catalytic activity were systematically characterized using representative probes from two distinct CYP3A4 substrate subgroups (testosterone and midazolam). With human intestinal microsomes, DHB was a substrate-independent reversible (Ki, approximately 0.8 microM) and mechanism-based (KI, approximately 3 microM; kinact, 0.3-0.4 min(-1)) inhibitor of CYP3A4. In contrast, BG was a substrate-dependent reversible inhibitor, with a Ki (13 microM) using midazolam that was 8-fold greater than that using testosterone, but a substrate-independent mechanism-based inhibitor (KI, approximately 25 microM; kinact, approximately 0.35 min(-1)). Similar trends resulted with cDNA-expressed CYP3A4, only the KI values for BG were approximately 10-fold lower than with microsomes. This seemed to reflect a much greater degree of microsomal protein binding by BG compared with DHB. Differential inhibition kinetics and binding properties between BG and DHB could account in part for the apparent in vitro inconsistencies in the literature. Results also emphasize the importance of appropriate substrate selection when designing inhibition studies involving dietary constituents. 相似文献
998.
Thomas C Dowling Mahiyar Arjomand Emil T Lin Loyd V Allen Mary Lynn McPherson 《American journal of health-system pharmacy》2004,61(23):2541-2544
PURPOSE: The bioavailability of a single, topically applied, 200-mg dose of ketoprofen (delivered in a ketoprofen 20% gel) relative to a single 50-mg oral dose in healthy volunteers was studied. METHODS: This was an open-label crossover study. The subjects were randomized to receive an oral 50-mg ketoprofen capsule or a single topical dose of ketoprofen 20% in a poloxamer-lecithin organogel (PLO). Treatment was followed by a one-week washout period. Blood samples were collected at intervals up to 10 hours after administration, and plasma ketoprofen concentrations were determined by high-performance liquid chromatography with ultraviolet or mass spectrometry detection. Noncompartmental pharmacokinetic values were obtained after each dose, and relative bioavailability was calculated. RESULTS: Eight healthy volunteers enrolled in and completed the study. Topical absorption of ketoprofen was highly variable among the subjects over the 10-hour sampling period. The median oral maximum plasma concentration (Cmax) exceeded the topical Cmax by nearly 200-fold (4.15 versus 0.021 microg/mL) (p = 0.001). The median relative bioavailability of topical ketoprofen was 0.48%, with individual subjects' values ranging from 0.18% to 2.1%. CONCLUSION: The relative bioavailability of ketoprofen was low and highly variable when the drug was administered as a single dose in a PLO-based ketoprofen 20% gel. 相似文献
999.
1000.