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Expert Opinion on Drug Metabolism &... Oct 2013Picoplatin was developed as platinum coordination complex to overcome development of resistance, through conjugation to thioles, by the introduction of a methyl-pyridine... (Review)
Review
INTRODUCTION
Picoplatin was developed as platinum coordination complex to overcome development of resistance, through conjugation to thioles, by the introduction of a methyl-pyridine moiety into the cisplatin parent structure. Pharmacokinetic parameters of the drug, after intravenous and oral application, were studied in solid tumors and clinical Phase I - III trials performed, in particular in NSCLC and small cell lung cancer (SCLC). Results showed low clinical activity of picoplatin.
AREAS COVERED
This article presents an overview of the pharmacokinetic assessments of picoplatin in lung cancer. Specifically, the authors address the relationship between disposition and clinical activity of the drug.
EXPERT OPINION
Picoplatin failed to overcome resistance to platinum compounds in lung cancer to achieve significant improved survival of most patients. Even highest doses of the drug reaching 150 m/m² given intravenously every 3 weeks were not sufficient to achieve better response than existing chemotherapeutics and the oral bioavailability of a dose of 200 - 400 mg corresponded only to 80 mg/m² iv. Picoplatin therefore seem to be quite ineffective. Picoplatin is expected to overcome tumor resistance in cases which overexpress thiol-conjugating pathways; however, this was not proved in clinical trials. To conclude, this blocked platinum complex is not able to reverse cisplatin resistance to a significant extent in vivo and its mechanisms and kinetics and of DNA damage failed to produce significant clinical results compared to second-line standard therapy for lung cancer.
Topics: Administration, Oral; Animals; Biological Availability; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cisplatin; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Organoplatinum Compounds; Platinum Compounds; Randomized Controlled Trials as Topic
PubMed: 23829480
DOI: 10.1517/17425255.2013.815724 -
Nature Reviews. Cancer Aug 2007The accidental discovery of the anticancer properties of cisplatin and its clinical introduction in the 1970s represent a major landmark in the history of successful... (Review)
Review
The accidental discovery of the anticancer properties of cisplatin and its clinical introduction in the 1970s represent a major landmark in the history of successful anticancer drugs. Although carboplatin--a second-generation analogue that is safer but shows a similar spectrum of activity to cisplatin--was introduced in the 1980s, the pace of further improvements slowed for many years. However, in the past several years interest in platinum drugs has increased. Key developments include the elucidation of mechanisms of tumour resistance to these drugs, the introduction of new platinum-based agents (oxaliplatin, satraplatin and picoplatin), and clinical combination studies using platinum drugs with resistance modulators or new molecularly targeted drugs.
Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Neoplasms; Platinum Compounds
PubMed: 17625587
DOI: 10.1038/nrc2167 -
ACS Omega Nov 2022Thermosensitive liposomes (TSL) have been used for localized temperature-responsive release of chemotherapeutics into solid cancers, with a minimum of one invention...
Thermosensitive liposomes (TSL) have been used for localized temperature-responsive release of chemotherapeutics into solid cancers, with a minimum of one invention currently in clinical trials (phase III). In this study, TSL was designed using a lipid blend comprising 1,2-dipalmitoyl--glycero-3-phosphocholine (DPPC), 1,2-distearoyl--glycero-3-phosphocholine (DSPC), cholesterol, and 1,2-distearoyl--glycero-3-phosphoethanolamine--[maleimide(polyethylene glycol)-2000] (DSPE-PEG-2000) (molar ratio of 88:9:2.8:0.2). Either nedaplatin (ND) or -sulfonatocalix[4]arene-nedaplatin was encapsulated in the aqueous inner layer of TSL to form (ND-TSL) or -SC4-ND-TSL, respectively. The hydrophobic platinum-based drug picoplatin (P) was loaded into the external lipid bilayer of the TSL to develop P-TSL. The three nanosystems were studied in terms of size, PDI, surface charge, and on-shelf stability. Moreover, the entrapment efficiency (EE%) and release % at 37 and 40 °C were evaluated. In a 30 min in vitro release study, the maximum release of ND, -SC4-ND, and picoplatin at 40 °C reached 74, 79, and 75%, respectively, compared to approximately 10% at 37 °C. This demonstrated temperature-triggered drug release from the TSL in all three developed systems. The designed TSL exhibited significant in vitro anticancer activity at 40 °C when tested on human mammary gland/breast adenocarcinoma cells (MDA-MB-231). The cytotoxicity of ND-TSL, -SC4-ND-TSL, and P-TSL at 40 °C was approximately twice those observed at 37 °C. This study suggests that TSL is a promising nanoplatform for the temperature-triggered release of platinum-based drugs into cancer cells.
PubMed: 36440163
DOI: 10.1021/acsomega.2c04525 -
Cancer Chemotherapy and Pharmacology Jun 2011Picoplatin is a new generation platinum designed to overcome platinum resistance. The goal of this study was to assess picoplatin anti-tumor activity and measure various...
PURPOSE
Picoplatin is a new generation platinum designed to overcome platinum resistance. The goal of this study was to assess picoplatin anti-tumor activity and measure various cellular parameters in small-cell lung cancer (SCLC) cells resistant to cell killing by cisplatin and carboplatin.
METHODS
We developed several platinum-resistant SCLC cell lines to evaluate picoplatin activity and drug resistance mechanisms in vitro. Drug cytotoxicity was measured by MTS assay. Total cellular platinum accumulation was measured by inductively coupled plasma mass spectrometry (ICP-MS). Whole genome gene expression profiling was carried out by microarray analysis.
RESULTS
Picoplatin retained significant cytotoxic activity in platinum-resistant SCLC lines compared to cisplatin and carboplatin. Cellular picoplatin accumulation in platinum-resistant and parental cells was high relative to levels of cellular platinum found in the same cell lines after cisplatin or carboplatin treatment. Gene expression analyses revealed substantial differences in gene expression and highlighted specific annotation clusters in carboplatin-resistant cells. In addition, a similar gene expression pattern was observed in picoplatin-treated carboplatin-resistant and parental cells.
CONCLUSIONS
Our study demonstrates that picoplatin can overcome carboplatin and cisplatin resistance. The results suggest decreased platinum accumulation as a potential mechanism of platinum resistance in SCLC cells, provide candidate markers (e.g. several genes in the Hox, glutathione biosynthetic process, and MAGE families) that may serve as signatures for platinum resistance, support distinct effects of picoplatin on SCLC cells compared to other platinums, and provide a rationale to develop picoplatin for the treatment of recurrent SCLC following initial therapy with cisplatin or carboplatin.
Topics: Antineoplastic Agents; Carboplatin; Cell Line, Tumor; Cisplatin; Cluster Analysis; Drug Resistance, Neoplasm; Gene Expression Profiling; Genome, Human; Humans; Lung Neoplasms; Organoplatinum Compounds; Small Cell Lung Carcinoma
PubMed: 20809122
DOI: 10.1007/s00280-010-1435-5 -
Dalton Transactions (Cambridge, England... May 2024The reactivity of the anticancer drug picoplatin (-amminedichlorido(2-methylpyridine)platinum(II) complex) with the model proteins hen egg white lysozyme (HEWL) and...
The reactivity of the anticancer drug picoplatin (-amminedichlorido(2-methylpyridine)platinum(II) complex) with the model proteins hen egg white lysozyme (HEWL) and bovine pancreatic ribonuclease (RNase A) was investigated by electrospray ionisation mass spectrometry (ESI MS) and X-ray crystallography. The data were compared with those previously obtained for the adducts of these proteins with cisplatin, carboplatin and oxaliplatin under the same experimental conditions. ESI-MS data show binding of Pt to both proteins, with fragments retaining the 2-methylpyridine ligand and, possibly, a chloride ion. X-ray crystallography identifies different binding sites on the two proteins, highlighting a different behaviour of picoplatin in the absence or presence of dimethyl sulfoxide (DMSO). Metal-containing fragments bind to HEWL close to the side chains of His15, Asp18, Asp119 and both Lys1 and Glu7, whereas they bind to RNase A on the side chain of His12, Met29, His48, Asp53, Met79, His105 and His119. The data suggest that the presence of DMSO favours the loss of 2-methylpyridine and alters the ability of the Pt compound to bind to the two proteins. With both proteins, picoplatin appears to behave similarly to cisplatin and carboplatin when dissolved in DMSO, whereas it behaves more like oxaliplatin in the absence of the coordinating solvent. This study provides important insights into the pharmacological profile of picoplatin and supports the conclusion that coordinating solvents should not be used to evaluate the biological activities of Pt-based drugs.
Topics: Muramidase; Ribonuclease, Pancreatic; Animals; Crystallography, X-Ray; Organoplatinum Compounds; Cattle; Protein Binding; Binding Sites; Models, Molecular; Chickens; Spectrometry, Mass, Electrospray Ionization; Dimethyl Sulfoxide; Carboplatin
PubMed: 38727007
DOI: 10.1039/d4dt00773e -
Journal of Photochemistry and... Sep 2016For the first time, the effects of picoplatin on the structure and esterase-like catalytic activity of human serum albumin (HSA) have been investigated by spectroscopic...
For the first time, the effects of picoplatin on the structure and esterase-like catalytic activity of human serum albumin (HSA) have been investigated by spectroscopic approaches and molecular modeling. The circular dichroism (CD) spectral examinations indicated that the binding of picoplatin with HSA induced a slight decrease of a-helix content of protein and unfolded the constituent polypeptides of the protein. The synchronous fluorescence and three-dimensional fluorescence spectral methods were used to estimate the effect of picoplatin on the micro-environmental changes of the Trp and Tyr residues of HSA, indicating that the micro-environment around the Tyr and Trp residue is partly disturbed by picoplatin. UV-vis absorption spectral result indicated the formation of the ground state complex between picoplatin with HSA. The ANS binding assay indicated the existence of competitive combination of picoplatin and ANS with HSA. The studies on the effects of picoplatin on the binding of HSA with bilirubin and heme showed that picoplatin binding caused a change of angle between two chromophores of bound bilirubin and the binding site of picoplatin does not locate in subdomain IB in HSA that bound with heme. The molecular modeling results showed that picoplatin binds to the connection between domain I and domain II by hydrophobic, hydrogen bonds, and van der Waals forces. In addition, HSA maintains most of its esterase activity in the presence of picoplatin. The investigations on how picoplatin interacts with HSA are important for the understanding of the anticancer mechanism and toxicity of platinum-based anticancer drug.
Topics: Bilirubin; Binding Sites; Circular Dichroism; Heme; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Molecular Docking Simulation; Organoplatinum Compounds; Protein Binding; Protein Structure, Tertiary; Serum Albumin; Spectrometry, Fluorescence; Spectrophotometry, Ultraviolet
PubMed: 27484966
DOI: 10.1016/j.jphotobiol.2016.07.031 -
Carbohydrate Research Sep 2014The inclusion complex of picoplatin with γ-cyclodextrin (γ-CD) was prepared and characterised by different analytical methods, including NMR, FTIR, TGA, phase...
The inclusion complex of picoplatin with γ-cyclodextrin (γ-CD) was prepared and characterised by different analytical methods, including NMR, FTIR, TGA, phase solubility as well as SEM. All of these approaches indicated that picoplatin was able to form an inclusion complex with γ-CD, and that the picoplatin/γ-CD inclusion compounds exhibited different spectroscopic features and properties from free picoplatin. The stoichiometry of the complex was 1:1; the pyridine group of picoplatin was deeply inserted into the cavity of γ-CD and the amine platinum group of picoplatin was near the narrower rim of γ-CD. The calculated apparent stability constant of the complex was 10,318M(-1). Moreover, the water solubility of picoplatin was significantly improved, according to phase-solubility studies. The complex maintained its anticancer activity, as shown by an in vitro cell-survival assay on A549 and MCF-7 cancer cell lines. All of these results showed that inclusion complexation may be a promising strategy to design a novel formulation of picoplatin as an anticancer therapy.
Topics: Antineoplastic Agents; Calorimetry, Differential Scanning; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Models, Molecular; Organoplatinum Compounds; Solubility; Spectroscopy, Fourier Transform Infrared; Thermodynamics; X-Ray Diffraction; gamma-Cyclodextrins
PubMed: 25119104
DOI: 10.1016/j.carres.2014.07.015 -
Expert Opinion on Investigational Drugs Jul 2007The three platinum-containing drugs that have been thus far approved by the FDA - cisplatin, carboplatin and oxaliplatin - have had a significant effect in the treatment... (Review)
Review
The three platinum-containing drugs that have been thus far approved by the FDA - cisplatin, carboplatin and oxaliplatin - have had a significant effect in the treatment of patients with some malignancies such as testicular, ovarian and colorectal cancer. However, much more remains to be achieved to widen the therapeutic use of this important class of drug, either via further analogue development or by judicious use of combining the existing drugs with new molecularly targeted agents. Two analogues arising from an academic (Institute of Cancer Research)/pharmaceutical (Johnson Matthey/AnorMed) collaboration - satraplatin (JM-216) and picoplatin (JM-/AMD-473) - have recently shown promising clinical activity; satraplatin (an orally available drug) in hormone-refractory prostate cancer and picoplatin in small-cell lung cancer. There have also been advances in delivery vehicles for platinum drugs (e.g., the diaminocyclohexane [DACH]-based AP-5346 and aroplatin/liposomal cis-bis-neodecanoato-trans-(R,R)-1,2-diaminocyclohexane platinum (II) [L-NDDP] are in early clinical development). Platinum-based drugs have also been successfully combined with molecularly targeted drugs (e.g., the recent approval of the vascular endothelial growth factor monoclonal antibody bevacizumab with carboplatin and paclitaxel in patients with NSCLC).
Topics: Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drugs, Investigational; Female; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Neoplasms; Organoplatinum Compounds; Platinum Compounds; Prostatic Neoplasms; Sensitivity and Specificity; Treatment Outcome
PubMed: 17594186
DOI: 10.1517/13543784.16.7.1009 -
Bioorganic & Medicinal Chemistry Letters Jun 2019Starting from the pioneering discovery of picoplatin and phenanthriplatin, many efforts were realized by different research groups in the synthesis of different... (Review)
Review
Starting from the pioneering discovery of picoplatin and phenanthriplatin, many efforts were realized by different research groups in the synthesis of different platinum(II) complexes, bearing a N-heterocycle moiety active as anticancer agents in different types of solid tumors. This review deals in particular with both the bifunctional and monofunctional platinum drugs, not only in dichloride platinum(II) complexes, but also in recent advances in modern platinum structures, i.e. cationic ones. Both the in vitro and in vivo studies of these anticancer agents are taken into account, with a special consideration for aggressive and orphan in treatment tumors.
Topics: Animals; Antineoplastic Agents; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Heterocyclic Compounds; Humans; Molecular Structure; Neoplasms; Organoplatinum Compounds; Structure-Activity Relationship
PubMed: 30935797
DOI: 10.1016/j.bmcl.2019.03.045 -
Molecular Cancer Therapeutics Apr 2010Picoplatin, a third-generation platinum agent, is efficacious against lung cancers that are otherwise resistant or become refractory during platinum treatment. This...
Picoplatin, a third-generation platinum agent, is efficacious against lung cancers that are otherwise resistant or become refractory during platinum treatment. This effort was aimed at the determination of the influence of organic cation transporters 1, 2, and 3 (OCT1, OCT2, and OCT3) and their genetic variants on cellular uptake of picoplatin and on the individual components of the ensuing cytotoxicity such as DNA adduct formation. The effect of OCT1 on picoplatin pharmacokinetics and antitumor efficacy was determined using OCT knockout mice and HEK293 xenografts stably expressing OCT1. The uptake and DNA adduct formation of picoplatin were found to be significantly enhanced by the expression of the OCTs. Expression of OCT1 and OCT2, but not OCT3, significantly enhanced picoplatin cytotoxicity, which was reduced in the presence of an OCT inhibitor. Common reduced functional variants of OCT1 and OCT2 led to reduction in uptake and DNA adduct formation of picoplatin in comparison with the reference OCT1 and OCT2. Pharmacokinetic parameters of picoplatin in Oct1(-/-) and Oct1(+/+) mice were not significantly different, suggesting that the transporters do not influence the disposition of the drug. In contrast, the volume of OCT1-expressing xenografts in mice was significantly reduced by picoplatin treatment, suggesting that OCT1 may enhance the antitumor efficacy of picoplatin. These studies provide a basis for follow-up clinical studies that would seek to examine the relationship between the anticancer efficacy of picoplatin and expression levels of OCTs and their genetic variants in tumors. Mol Cancer Ther; 9(4); 1058-69. (c)2010 AACR.
Topics: Animals; Cell Death; Cell Line, Tumor; Cimetidine; DNA Adducts; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mice; Organic Cation Transport Proteins; Platinum Compounds; Polymorphism, Single Nucleotide; Tissue Distribution; Xenograft Model Antitumor Assays
PubMed: 20371711
DOI: 10.1158/1535-7163.MCT-09-1084