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Fostriecin is a novel antitumor antibiotic. In vitro studies showed that fostriecin inhibits DNA topoisomerase II (Topo II) catalytic activity, protein phosphatases involved with cell-cycle control and histone phosphatases. The relative contribution of these mechanisms to the antitumor activity has not been elucidated, but Topo II inhibition seems to be the major mechanism of action at in vitro cytotoxic fostriecin levels. Tumor cell lines with decreased Topo II content showed similar or increased sensitivity to fostriecin, compared to the parent cell lines. The reduced-folate carrier is probably responsible for the cellular uptake of fostriecin. The possible clinical consequences of these in vitro observations are discussed.

Etoposide phosphate is a water-soluble prodrug of etoposide. It was expected that this prodrug could be used to overcome the solubility limitations and erratic bioavailability of oral etoposide. To investigate the possibility of prodrug conversion to etoposide within the gastrointestinal lumen, etoposide phosphate was dissolved in water and incubated with human gastric juice or human bile in vitro. Samples were collected during 150 min and analysed for etoposide concentration with high-performance liquid chromatography. Conversion of prodrug to etoposide during incubation with gastric juice was negligible. There was significant conversion during incubation with bile at pH 7-8. The percentage of prodrug converted to etoposide at pH 8 after 60 min was 78 +/- 18% (mean +/- S.D.) for a 0.1 mg ml(-1) prodrug solution and 36 +/- 26% for 0.5 mg ml(-1). At pH 7, after 60 min 22% of prodrug was converted to etoposide when incubated at 0.1 mg ml(-1) and 10% at 0.5 mg ml(-1). No conversion was found after inactivation of alkaline phosphate (AP) by overnight heating of bile at 65 degrees C or by the addition of disodium edetate to the bile. In conclusion, because of AP in bile, variable conversion of etoposide phosphate to etoposide can be expected within the intestinal lumen after oral administration. This could have important pharmacokinetic consequences.

Etoposide phosphate is a water-soluble prodrug of etoposide. The plasma pharmacokinetics of etoposide following oral administration of etoposide phosphate or oral etoposide were compared. Seventeen patients with solid tumours were enrolled to receive oral etoposide phosphate 125 mg m(-2) on days 1-5 every 3 weeks, with escalation to 175 mg m(-2) from course 3 when possible. Patients were randomized to receive oral etoposide phosphate or oral etoposide on day 1 of course 1 and the alternative compound on day 1 of course 2. Fifteen patients received two or more courses and were evaluable for pharmacokinetic comparisons. The median AUC(inf) (area under the concentration vs time curve from zero to infinity) of etoposide was 77.7 mg l(-1) h after etoposide phosphate (95% CI 61.3-100.5) and 62.0 mg l(-1) h after oral etoposide (95% CI 52.2-76.9). The difference in favour of etoposide phosphate was borderline significant: median 9.9 mg l(-1) h (95% CI 0.1-32.8 mg l(-1) h; P = 0.05). However, the inter-patient variability of etoposide AUC(inf) was not improved (coefficients of variation 42.3% and 48.4%). Etoposide phosphate was undetectable in plasma after oral administration. Toxicities of oral etoposide phosphate were not different from those known for etoposide. In conclusion, oral etoposide phosphate does not offer a clinically relevant benefit over oral etoposide.