The status of platinum anticancer drugs in the clinic and in clinical trials

Wheate, Nial J.; Walker, Shonagh; Craig, Gemma E.; Oun, Rabbab

doi:10.1039/c0dt00292e

Cited by 1,441 publications

(1,223 citation statements)

References 172 publications

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“…1 A) forms the foundation of the numerous platinum-based compounds that have been reported thus far (1). CIS has been referred to as the penicillin of cancer because of its efficacy and versatility in the treatment of several solid tumors (2). The main cellular target of this drug is DNA.…”

Section: Introductionmentioning

confidence: 99%

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

Salerno

Beretta

Zanchetta

et al. 2016

Biophysical Journal

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Platinum-containing molecules are widely used as anticancer drugs. These molecules exert cytotoxic effects by binding to DNA through various mechanisms. The binding between DNA and platinum-based drugs hinders the opening of DNA, and therefore, DNA duplication and transcription are severely hampered. Overall, impeding the above-mentioned important DNA mechanisms results in irreversible DNA damage and the induction of apoptosis. Several molecules, including multinuclear platinum compounds, belong to the family of platinum drugs, and there is a body of research devoted to developing more efficient and less toxic versions of these compounds. In this study, we combined different biophysical methods, including single-molecule assays (magnetic tweezers) and bulk experiments (ultraviolet absorption for thermal denaturation) to analyze the differential stability of double-stranded DNA in complex with either cisplatin or multinuclear platinum agents. Specifically, we analyzed how the binding of BBR3005 and BBR3464, two representative multinuclear platinum-based compounds, to DNA affects its stability as compared with cisplatin binding. Our results suggest that single-molecule approaches can provide insights into the drug-DNA interactions that underlie drug potency and provide information that is complementary to that generated from bulk analysis; thus, single-molecule approaches have the potential to facilitate the selection and design of optimized drug compounds. In particular, relevant differences in DNA stability at the single-molecule level are demonstrated by analyzing nanomechanically induced DNA denaturation. On the basis of the comparison between the single-molecule and bulk analyses, we suggest that transplatinated drugs are able to locally destabilize small portions of the DNA chain, whereas other regions are stabilized.

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Section: Introductionmentioning

confidence: 99%

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

Salerno

Beretta

Zanchetta

et al. 2016

Biophysical Journal

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“…This molecule (Figure 1 a) is one of the major drugs in cancer chemotherapy,3 successfully applied for the treatment of different cancers 4. Unfortunately, it presents a number of dose‐limiting side effects (e.g., nephrotoxicity, neurotoxicity, ototoxicity, and myelosuppression), hence some tumors develop resistance to the treatment.…”

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confidence: 99%

Correct Modeling of Cisplatin: a Paradigmatic Case

2017

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Quantum chemistry is a useful tool in modern approaches to drug and material design, but only when the adopted model reflects a correct physical picture. Paradigmatic is the case of cis‐diaminodichloroplatinum(II), cis‐[Pt(NH3)2Cl2], for which the correct simulation of the structural and vibrational properties measured experimentally still remains an open question. By using this molecule as a proof of concept, it is shown that state‐of‐the‐art quantum chemical calculations and a simple model, capturing the basic physical flavors, a cis‐[Pt(NH3)2Cl2] dimer, can provide the accuracy required for interpretative purposes. The present outcomes have fundamental implications for benchmark studies aiming at assessing the accuracy of a given computational protocol.

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“…The first examples of Pt complexes of the well known anti-epilepsy drug and HDAC inhibitor, valproic acid, trans-[Pt(VPA −1H ) 2 T ra n s p la ti n tr a n s -[ P tC l2 (p y )2 ] tr a n s -[ P t( V P A )2 (p y )2 ] tr a n s -[ P tC l2 (N H 3 )( p y )] tr a n s -[ P t( V P Fold increase in revertant colonies relative to control Fig. 6.…”

Section: Resultsmentioning

confidence: 99%

“…Currently nearly 50% of all anti-cancer therapies are platinum (Pt)-based [1,2]. Surprisingly only three Pt-based drugs have been approved for worldwide clinical use, namely cisplatin, carboplatin and oxaliplatin ( Fig.…”

Section: Introductionmentioning

confidence: 99%