IN-VITRO SCHEDULE-DEPENDENCY OF MYELOTOXICITY AND CYTOTOXICITY OF ECTEINASCIDIN 743 (ET-743)

Background. Ecteinascidin (ET-743) is a marine derived compound with a n interesting preclinical profile currently completing phase I clinica l trials. The present study was undertaken to compare the toxicity of different schedules of ET-743 against human hemopoietic progenitors an d tumour cell lines. Materials and methods. Human hemopoietic progenit ors and solid tumour cell lines were incubated with ET-743 for one hou r, 24 hours and one hour daily for five consecutive days to define by comparison an 'in vitro therapeutic index'. Additional experiments wer e set up to assess whether incubation for 24 hours or five days could change either the sensitivity of cells or the activity of ET-743. Resu lts. Prolonged or repeated exposures were more toxic than a single one hour exposure (P < 0.001), but due to the higher sensitivity to prolo nged exposure of several tumor cell lines: prolonged treatment yielded a more favorable in vitro therapeutic index. After incubation for 24 hours, ET-743 showed a significantly (P < 0.01) lower inhibiting capac ity. Incubation before treatment rendered progenitors more resistant, but incubation after treatment increased their sensitivity, so that ov erall the toxicity of ET-743 on hemopoietic cells appears to be close to AUC dependency. Conclusions. Despite the possible effect of some ex perimental artefacts, prolonged exposure could represent the best sche dule of administration of ET-743.