| Abstrakt: |
We examined the in vitro cytotoxicity, antitumour activity and preclinical pharmacokinetics of the novel sequence-selective, bifunctional alkylating agent DSB-120, a synthetic pyrrolo[1, 4][2, 1- c]benzodiazepine dimer. DSB-120 was shown to be a potent cytotoxic agent in vitro against a panel of human colon carcinomas [50% growth-inhibitory concentration (IC) 42±7.9 n M, mean±SE, n=7] and two rodent tumours (L1210 and ADJ/PC6). Antitumour activity was assessed in the bifunctional alkylating-agent-sensitive murine plasmacytoma ADJ/PC6 using a variety of administration protocols. The maximal antitumour eff- ects were observed following a single i.v. dose but the therapeutic index was only 2.6. DSB-120 was less effective when given i.p. either singly or by a daily+5 schedule. After a single i.v. dose at the maximum tolerated dose (MTD, 5 mg kg) the plasma elimination was biphasic, with a short distribution phase ( t 4 min) being followed by a longer elimination phase ( t 38 min). Peak plasma concentrations were 25 μg ml, the clearance was 1.3 ml g h and the AUC was 230 μg ml min. Concentrations of DSB-120 in ADJ/PC6 tumours were very low, showing a peak of 0.4 μg gat 5 min. The steady-state tumour/plasma ratio was about 5% and the AUC was only 2.5% of that occurring in the plasma. DSB-120 appeared to be unstable in vivo, with only 1% of an administered dose being recovered unchanged in 24-h urine samples. Plasma protein binding was extensive at 96.6%. In conclusion, the poor antitumour activity of DSB-120 may be a consequence of low tumour selectivity and drug uptake as a result of high protein binding and/or extensive drug metabolism in vivo. [ABSTRACT FROM AUTHOR] |
Full text from SpringerLink