A Better Platinum-Based Anticancer Drug Yet to Come?

Abstract

In attempts to overcome the drawbacks of cisplatin - severe toxicity, drug resistance and poor oral bioavailability - the development of platinum-based drugs has progressed from carboplatin and oxaliplatin to the newest generation of drugs, such as satraplatin, picoplatin and the multinuclear platinum complex BBR3464 (triplatin). Despite encouraging preclinical in vitro and in vivo results, outcomes of clinical trials of these coordination complexes remained below expectations. Biased rationale underlying the drug design along with in vitro and in vivo preclinical tests with inadequate predictive power seem to have eventually resulted in the selection of drug candidates of limited clinical activity. The nature of the active species generated in vivo, uptake, efflux, intracellular trafficking and detailed mechanisms involved in chemoresistance of platinum drugs in vivo are topics that need further investigation to provide clues for the rational formulation of new drugs. Insufficient diffusion in tumor tissues is likely to constitute an important limiting step in the treatment of solid tumors with platinum compounds. Preclinical assays with improved predictive power for the clinical outcome of the compounds should be based on more representative tumor models, such as resistant primary cancer cell lines, spheroids and orthotopic xenograft models, respectively. Finally, use of new pharmaceutical formulations and bifunctional complexes, as well as their selection by decisive preclinical tests, are expected to result in the generation of platinum-based anticancer drugs with the potential to achieve clinical activity even in multidrug-resistant tumors.

Platinum-Based Drugs and DNA Interactions Studied by Single-Molecule and Bulk Measurements

“…Currently, the development of new platinum-containing compounds is an active area of research (9)(10)(11). In addition to monofunctional Pt complexes, multinuclear Pt(II) agents have been developed.…”

“…Compared with BBR3005, BBR3464 forms interstrand cross-links at a lower frequency (~20% of the total DNA adducts) but with significantly faster reaction kinetics (3). Although these features represent promising antitumor properties against both CIS-sensitive and CIS-resistant tumors, the efficiency of BBR3464 during preclinical studies has been disappointing (10).…”

Unsymmetric Mono- and Dinuclear Platinum(IV) Complexes Featuring an Ethylene Glycol Moiety: Synthesis, Characterization, and Biological Activity

“…[4][5][6][7][8] As a consequence, different approaches have emerged to improve the cytotoxic profile of anticancer platinum compounds, including sterically hindered platinum agents, trans configured platinum compounds, multinuclear platinum(II), and platinum(IV) complexes. [9][10][11][12][13] The platinum(IV) complexes seem to have the ability to overcome the drawbacks of platinum(II) drugs because of their (i) reduced systemic toxicity, as they act as prodrugs, (ii) possible oral application, and (iii) high kinetic inertness. However, only four platinum(IV) complexes ( Figure 1) entered clinical trials so far and none of them have been currently approved as an anticancer drug.…”

Combination of palladium nanoparticles and tubastatin-A potentiates apoptosis in human breast cancer cells: a novel therapeutic approach for cancer

“…Among many cancer chemotherapeutic strategies, platinum-based drugs, nitrogen mustards, and drugs like temozolomide are the most frequently used. 6 However, because DNA alkylating agents produce toxic side effects, the platinum-based drugs, such as cisplatin, are used instead for the treatment of many types of cancers.…”