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

Abstract

Summary 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 cytotoxic agent and effective against cisplatin-resistant tumour cells. Anti-tumour efficacy studies were performed in a panel of human tumour xenografts refractory or poorly responsive to cisplatin. The novel platinum compound exhibited efficacy in all tested tumours and an impressive efficacy (including complete tumour regressions) was displayed in two lung carcinoma models, CaLu-3 and POCS. Surprisingly, BBR 3464 showed a superior activity against 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, SAOS, 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. Thus the pattern of cellular response was investigated in a panel of human tumour cells with a different p53 gene status. The results showed that the transfer of functional p53 resulted in a marked (tenfold) reduction of cellular chemosensitivity to the multinuclear platinum complex but in a moderate sensitization to cisplatin. In addition, in contrast to cisplatin, the triplatinum complex was very effective as an inducer of apoptosis in a lung carcinoma cell line carrying mutant p53. The peculiar pattern of anti-tumour activity of the triplatinum complex and its ability to induce p53-independent cell death may have relevant pharmacological implications, since p53, a critical protein involved in DNA repair and induction of apoptosis by conventional DNA-damaging agents, is defective in several human tumours. We suggest 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 platinum complexes, and compounds of this series could represent a new class of promising anti-tumour agents.

Growth suppression of established human osteosarcoma lung metastases in mice by aerosol gene therapy with PEI– p53 complexes

“…12,27 The noninvasive nature of inhalation therapy combined with the very low toxicity associated with the aerosol delivery of PEI formulations makes this therapeutic approach an excellent candidate for such combination therapy. Studies to determine the antitumor efficacy of aerosol PEI -p53 combined with the aerosol delivery of liposomal formulations of the chemotherapeutic agents paclitaxel and 9 -nitro -camptothecin, already shown to be effective against this model, 9 are currently underway.…”

Cytotoxic Activity of Metal Complexes of Biogenic Polyamines: Polynuclear Platinum(II) Chelates

“…The effect of the degree of flexibility of the compounds tested as anticancer drugs is clearly reflected in the results presently obtained for compound III (IC 50 value toward HeLa cells equal to 5 µM (Table 1)) when compared to the ones reported for the cationic trinuclear Pt(II) chelate BBR3464 (a bifunctional (1,0,1/ttt) type complex of formula [Pt(NH 3 ) 2 ] 3 -[H 2 N(CH 2 ) 6 NH 2 ] 2 Cl 2 ), which displays a higher (and equally irreversible) cytotoxic potency in similar types of cancer cells (e.g., 0.012 µM against the A2780 ovarian carcinoma line). 16,17,19,29,30 …”

“…The presence of more than one metal center in these Pt(II) multifunctional chelates is thus expected to lead to a higher efficacy and specificity regarding DNA binding (e.g., increased number of interstrand crosslinks, 28 possibly at more than one position). In addition, each type of polynuclear platinum structure (e.g., number and nature of the leaving groups and their geometry relative to the bridging amines) has been shown, in recent studies, to have its own particular cytotoxic characteristics (e.g., triplatinum BBR3464, currently in phase III of clinical trials 16,17,19,29,30 ). In fact, it is known that a simple chemical modification in the structure of a certain compound may alter its DNA binding properties and/or the relative amounts of interstrand crosslinks in double-stranded DNA, thus governing its antiproliferative and cytotoxic activity.…”

“…These compounds, which have been the subject of intense study for the past few years, [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] were found to be distinct from their mononuclear counterparts in terms of DNA binding features, yielding adducts containing "long-distance" intra-and interstrand cross-links not available to the conventional mononuclear platinum complexes. 9,23 Moreover, these polynuclear metal complexes have often been reported to overcome acquired cisplatin resistance [24][25][26][27] probably because of a distinct mechanism of DNA interaction that results in different types of drug-induced DNA lesions.…”

Apoptosis and growth arrest induced by platinum compounds in U2-OS cells reflect a specific DNA damage recognition associated with a different p53-mediated response

“…In particular, the introduction of a wild-type p53 gene in a p53-null tumor cell line (SAOS) increases the sensitivity to cisplatin, but reduces the cytotoxic effects of BBR 3464. 3 The tumor suppressor gene p53 is a multifunctional transcriptional regulator, which plays a critical role in coordinating cellular response to DNA damage. 4,5 The best known functions of p53 are regulation of cell cycle progression and induction of apoptosis.…”