A novel charges trinuclear platinum complex effective against cisplatin-resistant tumours: hypersensitivity of p53-mutant human tumour xenografts

Multinuclear platinum compounds were rationally designed to bind to DNA in a different manner from that of cisplatin and its mononuclear analogues. A triplatinum compound of the series (BBR 3464) was selected for preclinical development, since, in spite of its charged nature, it was very potent as c ytotoxic agent and effective against cisplatin-resistant tumour cells. Anti -tumour efficacy studies were performed in a panel of human tumour xenograf ts refractory or poorly responsive to cisplatin. The novel platinum compoun d exhibited efficacy in all tested tumours and an impressive efficacy (incl uding complete tumour regressions) was displayed in two lung carcinoma mode ls, CaLu-3 and POCS. Surprisingly, BBR 3464 showed a superior activity agai nst p53-mutant tumours as compared to those carrying the wild-type gene;The involvement of p53 in tumour response was investigated in an osteosarcoma cell line, SAGS, which is null for p53 and is highly sensitive to BBR 3464, and in the same cells following introduction-of the wild-type p53 gene. Th us the pattern of cellular response was investigated in a panel of human tu mour cells with a different p53 gene status. The results showed that the tr ansfer of functional p53 resulted in a marked (tenfold) reduction of cellul ar chemosensitivity to the multinuclear platinum complex but ina moderate s ensitization to cisplatin. In addition, in contrast to cisplatin, the tripl atinum complex was very effective as an inducer of apoptosis in a lung carc inoma cell line carrying mutant p53. The peculiar pattern of anti-tumour ac tivity of the triplatinum complex and its ability to induce p53-independent cell death may have relevant pharmacological implications, since p53, a cr itical protein involved in DNA repair and induction of apoptosis by convent ional DMA-damaging agents, is defective in several human tumours. We sugges t that the peculiar DNA binding, properties of the triplatinum complex may contribute to the striking profile of anti-tumour efficacy. Taken together, the available information supports that anti-tumour activity of the novel compound is mediated by a mechanism-different from that of conventional pla tinum complexes, and compounds of this series could represent a new class o f promising anti-tumour agents.