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The synthesis of a series of platinum complexes of trans coordination geometry [centered around the general formula, trans-ammine(amine)dichlorodihydroxoplatinum(IV) plus corresponding tetrachloroplatinum(IV) or Pt(II) counterparts] is described as part of a drug discovery program to identify more effective platinum-based anticancer drugs, particularly targeted toward the circumvention of resistance to cisplatin. Complexes have been evaluated for antitumor activity using in vitro and in vivo tumor models. In vitro against a panel of cisplatin-sensitive and -resistant human tumor cell lines (predominantly ovarian), many of the trans platinum complexes studied (e.g., 1, R = cyclohexyl) exhibited comparable potency to cisplatin and also overcame acquired cisplatin resistance, where resistance was due mainly to either reduced drug uptake or enhanced platinum-DNA adduct removal. Moreover, 14 trans complexes showed significant in vivo antitumor activity against the subcutaneous murine ADJ/PC6 plasmacytoma model; all were platinum(IV) complexes, 13/14 possessing axial hydroxo ligands the other possessing axial ethylcarbamato ligands. Where tested, all of their respective platinum(II) or tetrachloroplatinum(IV) counterparts were inactive. Notably, three dihydroxoPt(IV) complexes (18, 29, 34) (R = c-hexyl, c-heptyl, and 1-adamantyl) retained some efficacy against a cisplatin-resistant variant of the ADJ/PC6. Compounds 18 (trans-[PtCl2(OH)2NH3-(RNH2)]) R = c-C6H11, 22, R = Me3C, 27, R = n-C6H13, 28, R = PhCH2, and 36 (trans-[PtBr2(OH)2NH3(c-C6H11NH2)]) also produced evidence of antitumor activity (> 5 days growth delay) against subcutaneously grown advanced stage human ovarian carcinoma xenografts. These data demonstrate that a series of trans-ammine(amine)dichlorodihydroxoplatinum(IV) complexes are active in vivo against both murine and human subcutaneous tumor models and represent potential leads to a new generation of platinum-based anticancer drug.

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. The maximal antitumour effects 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 x 5 schedule. After a single i.v. dose at the maximum tolerated dose (MTD, 5 mgkg-1) the plasma elimination was biphasic, with a short distribution phase (t1/2 alpha 4 min) being followed by a longer elimination phase (t1/2 beta 38 min). Peak plasma concentrations were 25 micrograms ml-1, the clearance was 1.3 ml g-1 h-1 and the AUC0-infinity was 230 micrograms ml-1 min. Concentrations of DSB-120 in ADJ/PC6 tumours were very low, showing a peak of 0.4 micrograms g-1 at 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.

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