BBR-3464

Table 1. Comparison at Maximum Tolerated Dose of BBR 3464 (0.2-0.4 mg/kg) and Cisplatin (3-6 mg/kg) after i.v. Repeated Treatment on Human Solid Tumors...

Fig. 2. Schematic limiting binding modes for a di- or trinuclear bifunctional DNA-binding compound. The l,l/f,f geometry forms both types of adduct the 1,1 tc,c (n = 4, 6) forms only interstrand cross-links. Long-range intrastrand cross-links can, however, occur for a species such as BBR 3464.

An important point to note is that, in our detailed examination, the profile of antitumor activity of a simple dinuclear compound such as 1,1//,/ (n = 6) is generally similar to that of BBR 3464 (activity in cisplatin-resistant cell lines, enhanced activity in solid tumors classified as mutant p53 [3]) -what differs is the potency, producing the remarkable profile in Table 1. In the absence of major differences in aqueous chemistry the dramatically enhanced antitumor activity of BBR 3464 may be ascribed to this enhanced DNA affinity. 

This review summarized our systematic studies on dinuclear platinum compounds leading to identification of a novel clinical agent BBR 3464. The profile of antitumor activity is shared by the general structure with po-... 

It is desirable to show how new platinum structures may differ in signalling pathways from those of cisplatin and oxaliplatin. An important example is the role of pS3, the tumor suppresor g te, in modulation of cytotoxicity of platinum drugs. BBR 3464 di lays high activity in human tumor cell lines characterized by both wild type and mutant pS3 gene (21). In contrast, on average, cells with mutant pS3 are more resistant to the effea of cisplatin (25). It has been hypothesized that sensitivity or resistance of tumor cells to cisplatin might be also associated widi the processes involving pS3 (26,27). Transfer of functional pS3 into p53-null SAOS osteosarcoma cells actually reduced cellular sensitivity... 

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