DNA Interstrand Cross-links of the Novel Antitumor Trinuclear Platinum Complex BBR3464

Abstract

It is now well established that polynuclear platinum compounds in which two or three platinum coordination units are linked in a linear fashion compose an important new class of anticancer drugs [1,2]. The first clinical compound, currently denoted BBR3464 (see Fig. 1A), is a bifunctional trinuclear DNA-binding agent with an overall 4ϩ charge (3). The phase I trials (4, 5) demonstrated a clear pattern of responses in cancers not normally treatable with cisplatin (cis-diamminedichloroplatinum(II)) (see Fig. 1A), including responses in melanoma and pancreatic and lung cancer. Objective responses in phase II were verified in relapsed ovarian cancer and non-small cell lung cancer (6, 7). Pre-clinical studies indicated activity in p53 mutant tumors and a minimum induction of p53 following BBR3464 treatment. The interactions of antitumor polynuclear platinum compounds with target DNA (for reviews, see Refs. 1, 2, and 8) are distinct from those of the mononuclear based cisplatin family and, indeed, unlike those of any DNA-damaging agent in clinical use. Hence, it is important to understand these novel interactions to the greatest extent possible and how they affect DNA structure and function to exploit the full clinical potential of these new agents.Bifunctional binding of BBR3464 to double-stranded DNA preferentially involves guanine residues and is characterized by the rapid formation of long-range intra-and interstrand cross-links (CLs) 1 in which the platinated sites are separated by 1 or more bp (9). Quantitation of DNA interstrand crosslinking in natural and linear DNAs indicated ϳ20% of the DNA to be interstrand cross-linked. This value is significantly higher than that for cisplatin (10, 11); on the other hand, an intriguing aspect of BBR3464 is that long-range delocalized intrastrand adducts are equally or even more probable than interstrand CLs (9). As the [Pt,Pt] intrastrand CLs of BBR3464 are analogs of the major adducts of cisplatin, which forms ϳ90% bifunctional intrastrand adducts between neighboring purine residues on DNA, we examined first in our recent work (12) how the structures of the various types of the intrastrand CLs of BBR3464 affect conformational properties of DNA and how these adducts are recognized by the HMGB1 protein and removed from DNA during in vitro nucleotide excision repair (NER) reactions. These studies were performed because some structures altered by platinum adducts, such as stable directional bending and unwinding, attract various damaged DNAbinding proteins such as those containing HMG domains (13)(14)(15). The binding of these proteins has been postulated to mediate the antitumor properties of the platinum drugs (14,15). In addition, several reports have demonstrated that intrastrand CLs of cisplatin are removed from DNA during NER reactions and that NER is also a major mechanism contributing to cisplatin resistance (16 -18). Recent work has revealed that intrastrand CLs of BBR3464 create a local conformational distortion, but that none of these intrastrand adducts results in

Activation of Trans Geometry in Bifunctional Mononuclear Platinum Complexes by a Piperidine Ligand

“…The DNA bending toward the minor groove and unwinding due to one 1,3-intrastrand adduct of trans-(PtCl 2 (NH 3 )(pip)) has been found 30 Ϯ 2 and 8 Ϯ 2°, respectively (the direction of the bend was determined using the duplex (TGTGTϩ(A/T) 5 )(32) (Fig. 1B) in the same way as in our recent papers (21,32,33)). Moreover, the ligation of the 21-and 22-bp duplexes containing 1,3-intrastrand CL of trans-(PtCl 2 (NH 3 )(pip)) resulted in the formation of circles, suggesting that the 1,3-intrastrand CLs of this transplatin analogue increased the flexibility of the double helix (29,34).…”

“…1B that contained two guanine (G) residues in the top strand) were prepared as described (9,19,20). The interstrand cross-linked duplexes were also prepared and characterized in the same way as described previously (21,22).…”

Pt(II) and Ag(I) complexes with acesulfame: Crystal structure and a study of their antitumoral, antimicrobial and antiviral activities

“…Some strategies have been applied for the design of new drugs, such as the use of other types of ligands, in order to reduce side effects and increase the antitumoral effect of the drug. Much attention has also been focused on synthesis of new dinuclear or trinuclear species, like the compound [trans-PtCl(NH 3 ) 2 ) 2 (l-trans-Pt-(NH 3 ) 2 (NH 2 (CH 2 ) 6 -NH 2 ) 2 )](NO 3 ) 4 (BBR3464) which is in Phase II clinical trial and showed consistent activity against cisplatin-resistant human tumors [6,7].…”

Effect of the Metal Center on the Antitumor Activity of the Analogous Dinuclear Spermine Chelates (PdCl2)2(Spermine) and (PtCl2)2(Spermine)

“…The presence of the linkers allows for innovative mechanisms of DNA interaction, such as "long-distance" inter-and intrastrand crosslinks within the DNA helix [5], which probably contribute to the improved antitumor efficacy exhibited by some of these complexes, namely a clear pattern of responses in cancers not normally treatable with cisplatin [6,7]. In order to overcome cisplatin limitations, several other routes have been pursued, such as the synthesis of drugs based on palladium.…”