Cancer chemotherapy and pharmacology
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Cancer Chemother. Pharmacol. · Jan 1996
Preclinical pharmacology and antitumour activity of the novel sequence-selective DNA minor-groove cross-linking agent DSB-120.
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 (IC50) 42 +/- 7.9 nM, 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. ⋯ 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.