Polynuclear Platinum Compounds

BBR3464

Figure 25.4 Anti-tumor trinuclear platinum(II) complex BBR3464

BBR3464

Figure 25.4 Anti-tumor trinuclear platinum(II) complex BBR3464

bifunctional DNA-binding agent with an overall 4+ charge. Phase I trials demonstrated a clear pattern of responses in cancers not normally treatable with cisplatin including responses in melanoma, pancreatic cancer and lung cancer. Objective responses in Phase II were verified in relapsed ovarian cancer and non-small-cell lung cancer. Pre-clinical studies indicated activity in p53-mutant tumors and a minimal induction of p53 following BBR3464 treatment. The interactions of anti-tumor polynuclear platinum compounds with target DNA (for reviews, see for instance Refs 11, 44) are distinct from the mono-nuclear-based cisplatin family and, indeed, unlike those of any DNA-damaging agent in clinical use. The ability of BBR3464 to induce DNA adducts such as long-range delocalized intra- and inter-strand cross-links45 which are not produced by conventional mononuclear platinum compounds suggests that BBR3464 may avoid, at least in part, the classical mechanism of cisplatin resistance related to DNA damage recognition and repair. The cross-links of BBR3464 distort the DNA conformation, but these distortions are not recognized by HMG-domain proteins.46,47 On the other hand, while intrastrand adducts of BBR3464 are readily removed from DNA by the NER system, the interstrand cross-links are not. It has been suggested46,47 that interstrand and not intrastrand cross-links of BBR3464 could persist for a sufficiently long time in cells, which would potentiate toxicity of the interstrand lesions toward tumors sensitive to this polynuclear platinum drug.

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