Phase I clinical and pharmacokinetic study of titanocene dichloride in adults with advanced solid tumors.

This Phase I dose-escalation clinical trial of a lyophilized formulation of titanocene dichloride (MKT4) was conducted to determine the maximum tolerated dose, the dose-limiting toxicity (DLT), and pharmacokinetics of titanium (Ti) after a single i.v. infusion of MKT4. Forty patients with refractory solid malignancies were treated with a total of 78 courses. Using a modified Fibonacci scheme, 15 mg/m2 initial doses of titanocene dichloride were increased in cohorts of three patients up to level 11 (560 mg/m2) if DLT was not observed. The maximum tolerated dose was 315 mg/m2, and nephrotoxicity was DLT. Two minor responses (bladder carcinoma and non-small cell lung cancer) were observed. The pharmacokinetics of plasma Ti were assessed in 14 treatment courses by atomic absorption spectroscopy. The ratio for the area under the curve(0-infinity) in plasma and whole blood was 1.2. The following pharmacokinetic parameters were determined for plasma, as calculated in a two-compartment model: biological half-life t1/2beta in plasma was 22.8+/-11.2 h (xh +/- pseudo-SD), peak plasma concentration cmax approximately 30 microg/ml at a dose of 420 mg/m2, distribution volume Vss= 5.34+/-2.1 L (xa +/- SD), and a total clearance CItotal = 2.58+/-1.23 ml/min (xa +/- SD). There was a linear correlation between the area under the curve(0-infinity) of Ti in plasma and the titanocene dichloride dose administered with a correlation coefficient r2 of 0.8856. Plasma protein binding of Ti was in the 70-80% range. Between 3% and 16% of the total amount of Ti administered were renally excreted during the first 36 h. The recommended dose for Phase II evaluation is 240 mg/m2 given every 3 weeks with i.v. hydration to reduce renal toxicity.

Synergistic cytotoxic effects of ether phospholipid analogues and ionizing radiation in human carcinoma cells.

BACKGROUND AND PURPOSE: There is growing evidence in recent years that the antiproliferative effects of ionizing radiation may not be exclusively mediated via DNA damage but also by interactions and alterations of cell membrane associated processes. Here, we tested the hypothesis that membrane active cytotoxic ether lipids and analogues may interact with ionizing radiation, enhancing its antiproliferative effects. MATERIALS AND METHODS: The two epithelial tumor cell lines HTB 43 and KB, and the ether lipid resistant subline KBr were treated by a combination of radiation and ether lipids. Cytotoxic effects were measured by colony forming assays and the effects on membrane phospholipids were determined by quantitative thin-layer chromatography of cell lipid extracts. RESULTS: We present evidence that some ether lipids show supra-additive cytotoxic effects with ionizing radiation. These effects seem to depend on the same structural properties of ether lipids that determine their intrinsic cytostatic and cytotoxic activity. Identical growth inhibitory results were achieved when cells were treated before, or 30 min after irradiation. Analysis of major membrane phospholipids revealed no statistically significant differences of phospholipid distribution pattern in cells exposed to both treatment modalities. CONCLUSION: Our data indicate that changes of overall membrane phospholipid composition do not seem to be the mechanism of synergistic antiproliferative activity of ether lipids and ionizing radiation.

Quantification and Comparison of Cell Properties in Cat's Striate Cortex Determined by Different Types of Stimuli.

Direction and orientation tuning elicited by moving bars, flashing bars and a moving noise field were compared in cells in area 17 of the cat. Fourier analysis of tuning curves (SDO-analysis) was applied to quantify the general sensitivity (S) to visual stimulation, tuning strength to direction(D) and orientation (O), as well as the preferred direction (PD) and orientation (PO). Results from SDO-analysis were compared with the commonly used direction index and half-width-at-half-height orientational tuning parameter and it is demonstrated that the commonly used parameters can be replaced and are superseded by the results from SDO-analysis. The comparison of the responses elicited by the different types of stimuli showed that a linear correlation between D (or O) components was mainly found in simple cells, while in most cases no correlation was obtained for complex cells. Since several of the simple cells also showed no linear relationship, a direct mutual prediction of the S, D and O components can only be achieved for approximately 50% of the cortical cells applying commonly used stimulus types. The general responsiveness (S) shows that flashing bar stimuli are at least as effective as moving bars, whereas moving noise stimulates cortical cells more weakly. A moving bar tends to increase the orientation tuning (O) in most cells and with a moving noise stimulus predominantly the directional tuning (D) of complex cells is strongly enhanced. In conclusion, Fourier analysis of tuning curves (SDO-analysis) provides a valuable and simple tool for the quantification of direction and orientation specificity. Motion enhances the cortical response specificity which indicates the involvement of facilitation or inhibition exclusively induced by movement.