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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 -
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 -
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 -
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 -
Molecular Pharmacology Jun 2012Oxaliplatin, satraplatin, and picoplatin are cisplatin analogs that interact with DNA forming intrastrand and interstrand DNA cross-links (ICLs). Replicative bypass of...
Oxaliplatin, satraplatin, and picoplatin are cisplatin analogs that interact with DNA forming intrastrand and interstrand DNA cross-links (ICLs). Replicative bypass of cisplatin DNA adducts requires the cooperative actions of at least three translesion DNA synthesis (TLS) polymerases: Polη, REV1, and Polζ. Because oxaliplatin, satraplatin, and picoplatin contain bulkier chemical groups attached to the platinum core compared with cisplatin, we hypothesized that these chemical additions may impede replicative bypass by TLS polymerases and reduce tolerance to platinum-containing adducts. We examined multiple responses of cancer cells to oxaliplatin, satraplatin, or picoplatin treatment under conditions where expression of a TLS polymerase was limited. Our studies revealed that, although Polη contributes to the tolerance of cisplatin adducts, it plays a lesser role in promoting replication through oxaliplatin, satraplatin, and picoplatin adducts. REV1 and Polζ were necessary for tolerance to all four platinum analogs and prevention of hyperactivation of the DNA damage response after treatment. In addition, REV1 and Polζ were important for the resolution of DNA double-stranded breaks created during replication-associated repair of platinum-containing ICLs. Consistent with ICLs being the predominant cytotoxic lesion, depletion of REV1 or Polζ rendered two different model cell systems extremely sensitive to all four drugs, whereas Polη depletion had little effect. Together, our data suggest that REV1 and Polζ are critical for promoting resistance to all four clinically relevant platinum-based drugs by promoting both translesion DNA synthesis and DNA repair.
Topics: Antineoplastic Agents; Base Sequence; Blotting, Western; Cell Line, Tumor; DNA Adducts; DNA Damage; DNA Repair; DNA-Binding Proteins; DNA-Directed DNA Polymerase; Drug Resistance, Neoplasm; Flow Cytometry; Fluorescent Antibody Technique; Humans; Nuclear Proteins; Nucleotidyltransferases; Organoplatinum Compounds; RNA, Small Interfering
PubMed: 22387291
DOI: 10.1124/mol.111.076828 -
Oncology Reviews Mar 2012Combination chemotherapy is the current strategy of choice for treatment of small cell lung cancer (SCLC). Platinum containing combination regimens are superior to... (Review)
Review
Combination chemotherapy is the current strategy of choice for treatment of small cell lung cancer (SCLC). Platinum containing combination regimens are superior to non-platinum regimens in limited stage-SCLC and possibly also in extensive stage-SCLC as first and second-line treatments. The addition of ifosfamide to platinum containing regimens may improve the outcome but at the price of increased toxicity. Suboptimal doses of chemotherapy result in inferior survival. Early intensified, accelerated and high-dose chemotherapy gave conflicting results and is not considered a standard option outside of clinical trials. A number of newer agents have provided promising results when used in combination regimens, for example, gemcitabine, irinotecan and topotecan. However, more studies are required to appropriately evaluate them. There is a definitive role for radiotherapy in LD-SCLC. However, timing and schedule are subject to further research. Novel approaches are currently being investigated in the hope of improving outcome.
PubMed: 25992206
DOI: 10.4081/oncol.2012.e4 -
Journal of Thoracic Disease Oct 2013Although chemotherapeutic advances have recently been heralded in lung adenocarcinomas, such success with small-cell lung cancer (SCLC) has been ominously absent.... (Review)
Review
Although chemotherapeutic advances have recently been heralded in lung adenocarcinomas, such success with small-cell lung cancer (SCLC) has been ominously absent. Indeed, the dismal outlook of this disease is exemplified by the failure of any significant advances in first line therapy since the introduction of the current standard platinum-etoposide doublet over 30 years ago. Moreover, such sluggish progress is compounded by the dearth of FDA-approved agents for patients with relapsed disease. However, over the past decade, novel formulations of drug classes commonly used in SCLC (e.g. topoisomerase inhibitors, anthracyclines, alkylating and platinum agents) are emerging as potential alternatives that could effectively add to the armamentarium of agents currently at our disposal. This review is introduced with an overview on the historical development of chemotherapeutic regimens used in this disease and followed by the recent encouraging advances witnessed in clinical trials with drugs such as amrubicin and belotecan which are forging new horizons for future treatment algorithms.
PubMed: 24163749
DOI: 10.3978/j.issn.2072-1439.2013.07.43 -
Dalton Transactions (Cambridge, England... Jan 2015Conjugates of a Pt(IV) derivative of picoplatin with monomeric (Pt-c(RGDfK), 5) and tetrameric (Pt-RAFT-{c(RGDfK)}4, 6) RGD-containing peptides were synthesized with the...
Conjugates of a Pt(IV) derivative of picoplatin with monomeric (Pt-c(RGDfK), 5) and tetrameric (Pt-RAFT-{c(RGDfK)}4, 6) RGD-containing peptides were synthesized with the aim of exploiting their selectivity and high affinity for αVβ3 and αVβ5 integrins for targeted delivery of this anticancer metallodrug to tumor cells overexpressing these receptors. Solid- and solution-phase approaches in combination with click chemistry were used for the preparation of the conjugates, which were characterized by high resolution ESI MS and NMR. αVβ3 and αVβ5 integrin expression was evaluated in a broad panel of human cancer and non-malignant cells. SK-MEL-28 melanoma cells were selected based on the high expression levels of both integrins, while CAPAN-1 pancreatic cancer cells and 1BR3G fibroblasts were selected as the negative control. Internalization experiments revealed a good correlation between integrin expression and the cellular uptake of the corresponding fluorescein-labeled peptides and that the internalization capacity of the tetrameric RGD-containing peptide was considerably higher than that of the monomeric one. Cytotoxic experiments indicated that the antitumor activity of picoplatin in melanoma cells was increased by 2.6-fold when its Pt(IV) derivative was conjugated to c(RGDfK) (IC50 = 12.8 ± 2.1 μM) and by 20-fold when conjugated to RAFT-{c(RGDfK)}4 (IC50 = 1.7 ± 0.6 μM). In contrast, the cytotoxicity of the conjugates was inhibited in control cells lacking αVβ3 and αVβ5 integrin expression. Finally, cellular uptake studies by ICP-MS confirmed a good correlation between the levels of expression of integrins, intracellular platinum accumulation and antitumor activity. Indeed, accumulation and cytotoxicity were much higher in SK-MEL-28 cells than in CAPAN-1, being particularly higher in the case of the tetrameric conjugate. The overall results highlight that the great ability of RAFT-{c(RGDfK)}4 to bind to and to be internalized by integrins overexpressed in SK-MEL-28 cells results in higher accumulation of the Pt(IV) complex, leading to a high antitumor activity. These studies provide new insights into the potential of targeting αVβ3 and αVβ5 integrins with Pt(IV) anticancer pro-drugs conjugated to tumor-targeting devices based on RGD-containing peptides, particularly on how multivalency can improve both the selectivity and potency of such metallodrugs by increasing cellular accumulation in tumor tissues.
Topics: Antineoplastic Agents; Cell Line; Cell Line, Tumor; Drug Delivery Systems; Humans; Integrin alphaVbeta3; Neoplasms; Oligopeptides; Organoplatinum Compounds; Prodrugs; Receptors, Vitronectin
PubMed: 25369773
DOI: 10.1039/c4dt02710h -
Clinical Pharmacology : Advances and... 2010Dichloroacetate (DCA) inhibits pyruvate dehydrogenase kinase (PDK), and thus promotes glucose oxidation over glycolysis and induces apoptotic death of tumor cells. The...
PURPOSE
Dichloroacetate (DCA) inhibits pyruvate dehydrogenase kinase (PDK), and thus promotes glucose oxidation over glycolysis and induces apoptotic death of tumor cells. The present study investigated the potential of DCA to increase the antitumor effects of platinum- based compounds against a panel of permanent cell lines, including small cell lung cancer (SCLC), ovarian cancer, and Ewing's sarcoma in vitro.
METHODS
DCA at a concentration of 10 mM was combined with cisplatin, carboplatin, satraplatin, the satraplatin metabolite JM118, oxaliplatin, oxoplatin, and picoplatin, and the cytotoxic activity was evaluated in proliferation tests employing a panel of different cell lines. Additionally, cells were pretreated with DCA and then exposed to the platinum drugs and etoposide, or incubated with cisplatin or etoposide followed by application of DCA, respectively.
RESULTS
DCA 10 mM significantly increased the cytotoxicity of the platinum-based drugs carboplatin, satraplatin, JM118, and oxoplatin, but not cisplatin, picoplatin, and oxaliplatin in vitro. Preincubation of cell lines with DCA 10 mM for three days reduced the antiproliferative activity of platinum-based agents in sequential application, but exposure of cells pretreated with cisplatin or etoposide to DCA resulted in minor sensitization. The inhibitory effect of DCA showed no correlation with sensitization to the platinum compounds.
CONCLUSION
DCA alone in a concentration that shows low antiproliferative activity is capable of increasing the cytotoxicity of selected platinum compounds upon coincubation, and such combinations may be interesting for clinical application in tumors like SCLC, Ewing's sarcoma, and ovarian cancer refractory to cisplatin chemotherapy as standard care. The mechanism of this synergistic effect of DCA in combination with specific platinum species remains to be investigated.
PubMed: 22291503
DOI: 10.2147/CPAA.S11795 -
Annals of Oncology : Official Journal... Jul 2004AMD473 (previously ZD0473) is a new-generation platinum compound with activity against a wide range of human tumour cell lines and xenografts, including carboplatin- and... (Clinical Trial)
Clinical Trial
A phase I study of AMD473 and docetaxel given once every 3 weeks in patients with advanced refractory cancer: a National Cancer Institute of Canada-Clinical Trials Group trial, IND 131.
BACKGROUND
AMD473 (previously ZD0473) is a new-generation platinum compound with activity against a wide range of human tumour cell lines and xenografts, including carboplatin- and cisplatin-resistant lines. To assess its potential combined with a taxane, a phase I study of AMD473 and docetaxel in advanced cancer was initiated by the National Cancer Institute of Canada-Clinical Trials Group.
PATIENTS AND METHODS
Patients with advanced cancer, measurable disease, performance status Eastern Cooperative Oncology Group 0-2, no major organ dysfunction, and one or no previous taxane regimen received escalating doses of AMD473 and docetaxel every 3 weeks, with a starting dose of AMD473 80 mg/m(2) and docetaxel 60 mg/m(2).
RESULTS
Thirty-three patients enrolled on four dose levels were evaluable for toxicity and 25 patients were evaluable for response. The maximum tolerated dose was dose level 4 (AMD473 120 mg/m(2) and docetaxel 75 mg/m(2)), with grade 4 neutropenia in both minimally and heavily pretreated patients causing dose-limiting toxicity. As well at dose level 4, one patient had grade 3 vomiting despite premedication. Dose level three was expanded for both groups of patients and was defined as the recommended phase II dose at AMD473 100 mg/m(2) and docetaxel 75 mg/m(2). Non-hematologic toxicities included fatigue, diarrhoea and other mild toxicities. There was one partial response in a patient with prostate cancer and stable disease in 15 patients. No apparent pharmacokinetic interaction was noted.
CONCLUSION
AMD473 and docetaxel can be combined with a recommended phase II dose level of 100 mg/m(2) and 75 mg/m(2), respectively, given intravenously every 3 weeks. The combination has activity and should be explored in responsive tumour types.
Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cohort Studies; Diarrhea; Docetaxel; Female; Head and Neck Neoplasms; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Neoplasms, Squamous Cell; Neutropenia; Organoplatinum Compounds; Prostatic Neoplasms; Taxoids; Treatment Outcome
PubMed: 15205207
DOI: 10.1093/annonc/mdh278