Cellular pharmacology of polynuclear platinum anti-cancer agents

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Abstract

Study of the cellular pharmacology of the dinuclear platinum complexes, BBR3005 ([{trans-PtCl(NH3)2}2H2N(CH2)6NH2]2+), BBR3171 ([{cis-PtCl(NH3)2}2H2N(CH2)6NH2]2+) and the trinuclear platinum complex, BBR3464 ([{trans-PtCl(NH3)2}2μ-{trans-Pt(NH3)2(H2N(CH2)6NH2)2}]4+) was undertaken in wild type and cisplatin-resistant L1210 murine leukemia cell lines. All complexes are potent cytotoxic agents against the wild type cell line. Only BBR3464 shows enhanced activity against the cisplatin-resistant cell line following a brief exposure. This enhanced activity is attributable, in part, to preserved accumulation, which contrasts with diminished accumulation of cisplatin and both dinuclear platinum complexes. The cisplatin-resistant cell line is relatively tolerant of DNA adducts induced by both cisplatin and BBR3464, but BBR3464 is much less affected. All complexes induce DNA interstrand cross-links. Di/trinuclear complex-induced interstrand cross-linking peaks early, suggesting rapid genomic access and interaction. Subsequent decay suggests susceptibility to DNA repair mechanisms. Peak and area-under-the-curve values for interstrand cross-linking among the complexes correlate poorly with cytotoxic effects, especially in the cisplatin-resistant cell line. This suggests that all interstrand cross-linking adducts are not equal in their cytotoxic effect, or other, non-interstrand cross-linking adducts are significant. BBR3464 has been selected for clinical development largely on the basis of results from in vivo activity and toxicity studies. These results show BBR3464 to have unique properties in the context of acquired cisplatin-resistance that enhance its candidacy as a potential anticancer agent.

Introduction

Cisplatin is an important cytotoxic anticancer agent with activity presumably mediated through interactions with DNA. It has been a disappointment that platinum complexes developed subsequent to cisplatin have not expanded appreciably upon its clinical role [1]. All platinum complexes studied clinically to date have a single platinum containing two potential binding sites (leaving groups) available to interact with DNA and other macromolecules. Our efforts in metal complex anticancer drug research have been guided by the premise that discovery of new agents complementary to cisplatin and other clinically established drugs, i.e., agents with novel biological properties, would require investigation of genuinely novel chemical structures [2]. Di/trinuclear complexes represent such a distinct class of platinum-based anticancer agents that contain two or more platinum centers linked by an alkanediamine chain [3], [4]. Polynuclear platinum complexes were conceptualized as agents capable of binding to DNA in manners not available to mononuclear platinum complexes with the expectation that novel modes of DNA binding might yield clinically useful biological activities [5].

The first representative of this class to enter clinical trials (June 1998) is the trinuclear [{trans-PtCl(NH3)2}2μ-{trans-Pt(NH3)2(H2N(CH2)6NH2)2}]4+ (BBR3464) (Fig. 1) [6]. Structure–activity relationships for this class developed over the years, and leading to the choice of BBR3464, have been summarized [7]. The most studied complexes are shown in Fig. 1. All complexes have shown promising anticancer activities in a variety of preclinical test systems but even so, properties differ amongst the three complexes. Thus, the presence of a 2+ charge localized to the internal platinum, which is not available for covalent interactions, dramatically enhances potency of BBR3464 over the ‘simple’ dinuclear compounds, a property also achieved by use of amplifying polyamines such as spermine and spermidine [8]. The geometric isomers BBR3005 ([{trans-PtCl(NH3)2}2H2N(CH2)6NH2]2+) and BBR3171 ([{cis-PtCl(NH3)2}2H2N(CH2)6NH2]2+) are both potent cytotoxic agents and active in vivo against a broad spectrum of murine and human xenograft tumors [3], [9]. Intriguingly, the 1,1/c,c isomer is less effective in overcoming cisplatin resistance than its 1,1/t,t congener [10]. The agent BBR3464 represents the first genuinely new platinum-based structure to enter the clinic in 30 years. Its preclinical anticancer profile has been summarized [11] and is highlighted by exceptional potency (therapeutic doses approximately one-tenth that of cisplatin), activity in a broad spectrum of solid human tumor xenograft models, consistently high activity in human tumors classified as mutant p53 and a novel pattern of DNA binding [6].

The limiting factors in determining in vivo anticancer activity for platinum drugs, or indeed any classes of DNA-modifying agents, are access to the genome through cellular accumulation and DNA binding and, secondly, the nature of the conformational and structural changes induced by the family of DNA lesions. The profile of DNA binding for BBR3005 and BBR3464 is similar and differs somewhat to BBR3171, especially with respect to the structure and quantitation of DNA–DNA interstrand cross-links [12]. To fully understand the relationship between structure and anticancer efficacy, cellular and molecular pharmacology must supplement DNA binding profiles, as determined from studies on plasmid DNA. Previously, the activity of BBR3464 in a resistant cell line with diminished cisplatin accumulation has been attributed to preserved cellular accumulation and DNA binding [13]. We sought to confirm and extend these findings with comparison of cytotoxicity, cellular accumulation, DNA binding, and interstrand cross-linking of BBR3464, BBR3005, BBR3171, and cisplatin in cell lines sensitive and resistant to cisplatin.

Section snippets

Platinum complexes

BBR3171 and BBR3005 were synthesized by general methods previously described [10]. BBR3464 was a gift from Novuspharma s.p.a., Monza. Cisplatin was purchased from Sigma.

L1210 cell lines

L1210/0 was maintained in McCoy’s 5a media supplemented with 5% horse serum. Cell doubling time was approximately 18 h. L1210/DDP, a line originally developed by Eastman and Illenye [14], was maintained in McCoy’s 5a media supplemented with 5% fetal calf serum. Cell doubling time was approximately 24 h. Experiments were done

Cytotoxicity

Following either continuous or brief (2 h) platinum complex exposure, growth inhibition was measured by cell counting after 72 h (L1210/0) or 96 h (L1210/DDP). Both IC50 and IC90 values are presented because the latter are used in subsequent experiments. Against L1210/0 with a continuous exposure assay, BBR3464, BBR3171, BBR3005, and cisplatin are similarly potent cytotoxic agents (Table 1). In a 2 h exposure assay, however, BBR3464 and BBR3171 show similar potency whereas cisplatin and BBR3005

Discussion

Previous studies have largely focused upon the DNA binding of di/trinuclear platinum complexes as revealed in studies in cell-free systems. As all the complexes studied here are potent cytotoxic agents that also show promising anticancer activity in diverse preclinical test systems including murine and human xenograft tumor models, it is also relevant to characterize the behavior of these complexes in cellular systems. These studies may yield further insight into their preclinical anticancer

Acknowledgements

N.F. thanks the NIH (RO1-CA78754) and American Cancer Society (RPG89-002-11-CDD) for grant support.

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