There was no pharmacokinetic-sequence interaction between C and P in this study. A clear dose-response relation with respect to response rate and survival was observed. The pharmacokinetic parameter P-T > or = 0.1 mumol/L was related to improved survival in this study.

Purpose: Paclitaxel and carboplatin are frequently used in advanced ovarian cancer following cytoreductive surgery. Threshold models have been used to predict paclitaxel pharmacokineticpharmacodynamics, whereas the time above paclitaxel plasma concentration of 0.05 to 0.2 Amol/L (t C > 0.05-0.2 ) predicts neutropenia.The objective of this study was to build a population pharmacokinetic-pharmacodynamic model of paclitaxel/carboplatin in ovarian cancer patients. Experimental Design: One hundred thirty-nine ovarian cancer patients received paclitaxel (175 mg/m 2 ) over 3 h followed by carboplatin area under the concentration-time curve 5 mg/mL*min over 30 min. Plasma concentration-time data were measured, and data were processed using nonlinear mixed-effect modeling. Semiphysiologic models with linear or sigmoidal maximum response and threshold models were adapted to the data. Results: One hundred five patients had complete pharmacokinetic and toxicity data. In 34 patients with measurable disease, objective response rate was 76%. Neutrophil and thrombocyte counts were adequately described by an inhibitory linear response model. Paclitaxel t C > 0.05 was significantly higher in patients with a complete (91.8 h) or partial (76.3 h) response compared with patients with progressive disease (31.5 h; P = 0.02 and 0.05, respectively).Patients with paclitaxel t C > 0.05 > 61.4 h (mean value) had a longer time to disease progression compared with patients with paclitaxel t C > 0.05 < 61.4 h (89.0 versus 61.9 weeks; P = 0.05).Paclitaxel t C > 0.05 was a good predictor for severe neutropenia (P = 0.01), whereas carboplatin exposure (C max and area under the concentration-time curve) was the best predictor for thrombocytopenia (P < 10 -4 ). Conclusions: In this group of patients, paclitaxel t C > 0.05 is a good predictive marker for severe neutropenia and clinical outcome, whereas carboplatin exposure is a good predictive marker for thrombocytopenia.

Summary The anti-pan carcinoma monoclonal antibody (MAb) 323/A3, linked to E. coli-derived pglucuronidase (GUS) was used to study the tumour-site-selective activation of the prodrug Epirubicinglucuronide (Epi-glu). Epi-glu was isolated from the urine of patients treated with Epirubicin (Epi) by reversed phase chromatography on a silica-C18 column. Epi-glu was stable in human blood and was not converted into Epi by A2780, MCF-7, or

Circulating concentrations of 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D and 25-hydroxyvitamin D were measured in 21 anephric subjects. 13 subjects had no therapy with vitamin D, dihydrotachysterol or lα-hydroxyvitamin D₃. In 7 subjects of this group 1,25-dihydroxyvitamin D was undetectable ( < 5 pmol/l). In the other 6 patients concentrations ranged from 10 to 43 pmol/l (reference value 111 ± 33 pmol/l). All subjects taking high doses of vitamin D showed detectable 1,25-dihydroxyvitamin D concentrations in the same range. Dihydrotachysterol therapy caused spuriously high ‘1,25-dihydroxyvitamin D’ values, probably by interference of a metabolite of dihydrotachysterol in our assay. In subjects on vitamin D or dihydrotachysterol therapy 25-hydroxyvitamin D concentrations were significantly elevated (314 ± 146 nmol/l and 98 ± 19 nmol/l, respectively; reference value 52 ± 22 nmol/l). Concentrations of 24,25-dihydroxyvitamin D were only measured in subjects without vitamin D₂ intake. In general very low but detectable concentrations were found. One subject on a high dose of vitamin D₃ showed a 24,25-dihydroxyvitamin D₃ concentration of 10.2 nmol/l (reference value 4.4 ± 2.9 nmol/l). Our results therefore confirm earlier reports on extrarenal synthesis of 24,25-dihydroxyvitamin D and suggest that there may be extrarenal production of 1,25-dihydroxyvitamin D as well.

Background:Despite therapeutic advances, the prognosis of patients with metastatic soft tissue sarcoma (STS) remains extremely poor. The results of a recent clinical phase II study, evaluating the protective effects of the semisynthetic flavonoid 7-mono-O-(β-hydroxyethyl)-rutoside (monoHER) on doxorubicin-induced cardiotoxicity, suggest that monoHER enhances the antitumour activity of doxorubicin in STSs.Methods:To molecularly explain this unexpected finding, we investigated the effect of monoHER on the cytotoxicity of doxorubicin, and the potential involvement of glutathione (GSH) depletion and nuclear factor-κB (NF-κB) inactivation in the chemosensitising effect of monoHER.Results:MonoHER potentiated the antitumour activity of doxorubicin in the human liposarcoma cell line WLS-160. Moreover, the combination of monoHER with doxorubicin induced more apoptosis in WLS-160 cells compared with doxorubicin alone. MonoHER did not reduce intracellular GSH levels. On the other hand, monoHER pretreatment significantly reduced doxorubicin-induced NF-κB activation.Conclusion:These results suggest that reduction of doxorubicin-induced NF-κB activation by monoHER, which sensitises cancer cells to apoptosis, is involved in the chemosensitising effect of monoHER in human liposarcoma cells.