摘要:

Protein kinase C (PKC) plays a pivotal role in signal transduction involved in the control of cell proliferation, differentiation and apoptosis. Interference with such signaling pathways may result in altered tumor cell response to antineoplastic drugs. We investigated the effects of two selective PKC inhibitors as single agents and in combination with cisplatin in cell lines derived from squamous cell carcinomas of the head and neck (SCCHN). Safingol (Saf) is directed against the regulatory domain, whereas chelerythrine (Che) interacts with the catalytic domain of PKC. In six SCCHN cell lines (UM-SCC 11B, 14A, 14C and 22B, 8029NA, and a 5-fold cisplatin-resistant subline 8029DDP). PKC activities ranged between 1 and 158 IU/1×107cells, and they were inversely proportional to the amount of cellular epidermal growth factor receptor. Using the colorimetric MTT assay, PKC inhibitors Saf and Che showed comparable dose-dependent growth inhibition. The 50% inhibitory concentrations (IC50) were between 3.8–8.6 μM for Saf and 8.5–13.6 μM for Che with no relationship to PKC activity or cisplatin sensitivity of the respective cell lines. Combinations of cisplatin (IC50 = 0.4–5.8 μg/ml) and either PKC inhibitor (5 μM Saf, 10 μM Che) led to a significant decrease of cisplatin IC50values in most cell lines. However, comparison with theoretical additive dose–response curves showed additive rather than synergistic effects for both PKC inhibitors.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Pharmacokinetics after high-dose (HD) etoposide (Eto) (40 mg/kg i.v. once as 4-h infusion, one patient 20 mg/kg i.v. as 4-h infusion, for 3 consecutive days) were studied in 31 children and young adults (age 0.8–23.7 years, median: 8.0 years) undergoing bone marrow transplantation after different conditioning regimens. Blood samples were collected until 97 h after the end of infusion. The population analysis of the first part of data (112 samples/21 patients, well documented) served to establish the pharmacokinetic model. The same data combined with the second part of data (50 samples/10 patients, ‘intention to treat’) then served to calculate the final population model. Data were best described by a three-compartment model witht1/2&agr;=0.28 h±3.2%,t1/2&bgr;=3.6 h±16.9% andt1/2&ggr;=44.2 h±56.5%, respectively (meangeom±CVgeom). Clearance (CL) was 15.5 ml/min/m2±30.6% (meangeom±CVgeom) and thus at the lower range of data reported in the literature. The fraction of unbound Eto (fu) was 7.0% (4.3–11.9%) [median (range)], with high intra-individual variability. An increase infuwith increasing total Eto was observed. The question of a principally lower Eto CL in children, as compared to adults, after HD treatment remains open.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID