Effect of Severe Renal Dysfunction on the Plasma Levels of DNA-Reactive Platinum after Oxaliplatin Administration.

Higher amounts of circulating ultrafilterable platinum (fPt) are found in patients with renal dysfunction receiving a constant dose of oxaliplatin. However, the increased systemic fPt levels do not increase oxaliplatin-induced toxicities. We hypothesized that renal dysfunction has minimal effect on the elimination rate of reactive fPt, and that the DNA-binding capacity is one of the properties of reactive Pt species. This study aimed to quantify DNA-reactive fPt in plasma and to evaluate the impact of severe renal dysfunction on its pharmacokinetics. The pharmacokinetics of oxaliplatin was assessed in rats with bilateral nephrectomy (BNx) and in a hemodialysis patient who received mFOLFOX7 therapy for advanced metastatic gastric cancer. The platinum concentrations were determined using inductively coupled plasma-mass spectrometry. The amount of DNA-reactive fPt in the plasma was evaluated by the reaction between plasma and calf thymus DNA. Compared to the sham group in rats, the BNx group had significantly higher plasma total fPt concentrations at 24 h after drug administration. However, there was no significant difference in the plasma levels of DNA-reactive fPt between the two groups. In a hemodialysis patient, the plasma levels of total fPt decreased to 35.9 and 7.3% at 2 and 14 d after treatment, respectively. The plasma level of DNA-reactive fPt also decreased to 1.9 and 0.6%, respectively, on these days. This study showed that severe renal dysfunction has a limited effect on the plasma levels of DNA-reactive fPt after oxaliplatin administration.

A chemiluminescence resonance energy transfer strategy and its application for detection of platinum ions and cisplatin.

A novel chemiluminescence resonance energy transfer (CRET) system was developed and combined with a structure-switching aptamer for the highly sensitive detection of platinum. Platinum was chosen as a model analyte to demonstrate the generality of the new CRET system. This aptameric platform consisted of a streptavidin labeled aptamer against platinum and a streptavidin-coated magnetic bead for the selective separation of platinum-bound aptamer. The platinum-aptamer probe contained several guanine (G) bases bound to the 3,4,5-trimethoxyphenyl-glyoxal (TMPG) donor group at the 5' end, a fluorescent acceptor (6-carboxy-2',4,7,7'-tetrachlorofluorescein, TET) at the 3' end, and a streptavidin aptamer sequence in which several base pairs were replaced by the G-G mismatch to induce the platinum-oligonucleotide coordination. The chemiluminescence (CL) generated by TMPG/G bases is transferred to the acceptor (TET). In the presence of platinum, the platinum-aptamer probe was folded such that the G bases at the 5' end and TET at the 3' were in close proximity. The complex was separated using streptavidin-coated magnetic beads by the addition of TMPG to form the TMPG/G bases complex. The ultraweak CL from the TMPG/G bases was strongly enhanced by TET. This novel CRET-based method can be easily performed with high limit of detection (50 ng·mL-1) and selectivity over other metal ions. This technique provides a novel method for simple, fast, and convenient point-of-care diagnostics for monitoring proteins and metal ions. Graphical abstract Schematic presentation of chemiluminescence resonance energy transfer (CRET) detection of platinum(II) by Pt-base pair coordination to the aptamer. TMPG: 3,4,5-trimethoxyphenyl-glyoxal, fluorophore TET: 6-carboxy-2',4,7,7'-tetrachlorofluorescein.

Long-term serum platinum changes and their association with cisplatin-related late effects in testicular cancer survivors.

BACKGROUND: The long-term toxicities after cisplatin-based chemotherapy (CBCT) reveal a remarkable inter-individual variation among testicular cancer survivors (TCSs). Therefore, we assessed long-term platinum (Pt) changes and their associations with CBCT-related late effects in TCSs. MATERIAL AND METHODS: In 77 TCSs treated with CBCT from 1984 to 1990, blood samples for analyses of Pt and a questionnaire including self-reported neuro- and ototoxicity (NTX) symptoms were collected during two follow-up surveys at median 12 (Survey I; SI) and 20 (Survey II; SII) years after treatment. Information about second cancers after SII was retrieved from the Norwegian Cancer Registry. RESULTS: A larger Pt decline from SI to SII was associated with a decreased risk of a second cancer diagnosis (HR 0.78, 95% CI 0.62-0.99 per 10 ng/L/year), and worsening of paresthesias in hands (OR 1.98, 95% CI 1.09-3.59 per 10 ng/L/year) and tinnitus (OR 1.51, 95% CI 1.01-2.27 per 10 ng/L/year). CONCLUSION: In summary, we found a significant association between a larger Pt decline and a reduced risk of second cancers and deterioration of paresthesias in hands and tinnitus.

Concentrations of Trace Elements in Hemodialysis Patients: A Prospective Cohort Study.

BACKGROUND: Low concentrations and excessive concentrations of trace elements have been commonly reported in hemodialysis patients, but available studies have several important limitations. STUDY DESIGN: Random sample of patients drawn from a prospective cohort. SETTING & PARTICIPANTS: 198 incident hemodialysis patients treated in 3 Canadian centers. MEASUREMENTS: We used mass spectrometry to measure plasma concentrations of the 25 elements at baseline, 6 months, 1 year, and 2 years following enrollment in the cohort. We focused on low concentrations of zinc, selenium, and manganese and excessive concentrations of lead, arsenic, and mercury; low and excessive concentrations of the other 19 trace elements were treated as exploratory analyses. Low and excessive concentrations were based on the 5th and 95th percentile plasma concentrations from healthy reference populations. RESULTS: At all 4 occasions, low zinc, selenium, and manganese concentrations were uncommon in study participants (≤5.1%, ≤1.8%, and ≤0.9% for zinc, selenium, and manganese, respectively) and a substantial proportion of participants had concentrations that exceeded the 95th percentile (≥65.2%, ≥74.2%, and ≥19.7%, respectively). Almost all participants had plasma lead concentrations above the 95th percentile at all time points. The proportion of participants with plasma arsenic concentrations exceeding the 95th percentile was relatively constant over time (9.1%-9.8%); the proportion with plasma mercury concentrations that exceeded the 95th percentile varied between 15.2% and 29.3%. Low arsenic, platinum, tungsten, and beryllium concentrations were common (>50%), as were excessive cobalt, manganese, zinc, vanadium, cadmium, selenium, barium, antimony, nickel, molybdenum, lead, and chromium concentrations. CONCLUSIONS: There was no evidence that low zinc, selenium, or manganese concentrations exist in most contemporary Canadian hemodialysis patients. Some patients have excessive plasma arsenic and mercury concentrations, and excessive lead concentrations were common. These findings require further investigation.

Long-term ototoxicity in women after cisplatin treatment for ovarian germ cell cancer.

OBJECTIVE: Evaluate long-term cisplatin-induced ototoxicity in women treated for malignant ovarian germ cell tumors (MOGCT). METHODS: Seventy-four women treated for MOGCT in Norway (1980-2009) were analyzed: 41 had received cisplatin-based chemotherapy (CBCT) ("Cases") and 33 had no CBCT ("Controls"). Median follow-up was 15years. Hearing was assessed by pure tone audiometry and by the SCIN questionnaire. Air conduction thresholds were reported as absolute hearing thresholds and age-adjusted thresholds. Absolute and age-adjusted hearing loss were defined as thresholds of >20dB at any frequency. Tinnitus was evaluated using the Tinnitus Handicap Inventory. Serum Platinum Concentration (SPC) was determined. RESULTS: Absolute hearing loss was identified in 21 Cases (51%) and 24 Controls (73%). After adjusting for age, only 9 Cases (22%) and 5 Controls (15%) remained. Age-adjusted hearing thresholds at 4, 6 and 8kHz were slightly but significantly higher in Cases compared to Controls. Subjective hearing loss was reported by 27% of Cases and 21% of Controls, who were significantly older. Elevated SPC values were detected up to 20years after CBCT, but SPC did not correlate significantly with age-adjusted hearing loss. The rate of tinnitus was similar in Cases and Controls. CONCLUSION: Long-term MOGCT survivors treated with CBCT have small but significant reductions in age-adjusted hearing thresholds at 4, 6 and 8kHz versus Controls. Approximately one in four women experienced subjective hearing loss. To avoid overestimation of clinically relevant cisplatin-induced ototoxicity, absolute hearing thresholds should be age-adjusted and compared to an age-matched control group.

Oxaliplatin Alters Expression of T1R2 Receptor and Sensitivity to Sweet Taste in Rats.

As one of the adverse effects of oxaliplatin, a key agent in colon cancer chemotherapy, a taste disorder is a severe issue in a clinical situation because it decreases the quality of life of patients. However, there is little information on the mechanism underlying the oxaliplatin-induced taste disorder. Here, we examined the molecular and behavioral characteristics of the oxaliplatin-induced taste disorder in rats. Oxaliplatin (4-16 mg/kg) was administered to Sprague-Dawley (SD) rats intraperitoneally for 2 d. Expression levels of mRNA and protein of taste receptors in circumvallate papillae (CP) were measured by real-time quantitative polymerase chain reaction (PCR) and immunohistochemistry, respectively. Taste sensitivity was assessed by their behavioral change using a brief-access test. Morphological change of the taste buds in CP was evaluated by hematoxyline-eosin (HE) staining, and the number of taste cells in taste buds was counted by immunohistochemical analysis. Among taste receptors, the expression levels of mRNA and protein of T1R2, a sweet taste receptor subunit, were increased transiently in CP of oxaliplatin-administered rats on day 7. In a brief-access test, the lick ratio was decreased in oxaliplatin-administered rats on day 7 and the alteration was recovered to the control level on day 14. There was no detectable alteration in the morphology of taste buds, number of taste cells or plasma zinc level in oxaliplatin-administered rats. These results suggest that decreased sensitivity to sweet taste in oxaliplatin-administered rats is due, at least in part, to increased expression of T1R2, while these alterations are reversible.

[Identification and prognostic value of differentially expressed proteins of patients with platinum resistance epithelial ovarian cancer in serum].

OBJECTIVE: To identified differentially expressed proteins associated with platinum resistance in platinum resistance epithelial oarian cancer(EOC)patients in serum and investigate their clinical value. METHODS: A total of 106 patients withoverian tumor in affiliated tumor hospital of Guangxi Medical University from August 1998 to September 2013 were enrolled in this study, which include 52 cases od platinum-sensitive(PTS), 44 cases of platinum-resistant(PTR)and 10 cases of benign ovarian cyst(BOC). Thirty-three cases of normal women proceeded physical examination in our hospital in 2008 were chosen as control group(NC). Four groups of patients serum samples of 4 groups were collected and preserved.(1)Differentially express level of serum proteins of 10 cases of every group(PTS & PTR vs NC, PTS & PTR vs BOC, PTS vs PTR)were identified with isobaric tags for relative and absolute quantitative(iTRAQ)based quantitative proteomic approach and then was subjected to bioinformatics analysis.(2)Proteins that played a important role in multidrug resistance were validated by western blot(WB)and ELISA in 44 PTR patients, 52 PRS patients and 33 NC women.(3)Pearson correlation analysis was used to explain the relationship between proteins and clinical pathological parameters of PTR individuals. Kaplan-Meier method was supposed to explore serum biomarkers associated with clinical prognosis data. Receiver operating characteristic(ROC)curves were used to determine the diagnostic value of the markers. RESULTS: (1)Based on the result of bioinformatics analysis, 56 proteins, 39 proteins and 62 proteins were identified respectively among PTS & PTR vs NC, PTS & PTR vs BOC, PTS vs PTR. It showed that C6 and CNTN1 have a positive seletion effect among Asians and BCHE among Europeans through searching Haplotter database. CRP, FN1, S100A9, TF, ALB, VWF, APOC2, APOE, CD44, F2, GPX3 and ACTB proein were further verified related with platinum resistance by taking intersection analysis in the COREMINE database and TCGA.(2)The expression level of SERPINA1 protein in serum of PTR group, PTS group and NC groupwere 41.7±9.2, 32.8±6.6 and 14.2±3.6 respectively using WB assay, and(816±246),(686±205)and(756 ± 244)µg/µl respectively using ELISA; the expression level of ORM1 protein in PTR, PTS and NC serum were 37.9±7.0, 27.0±22.5 and 21.7±2.6 respectively using WB assay, and(221±35),(174±23)and(157±18)µg/µl respectively using ELISA; the expression level of FN1 protein in PTR, PTS and NC serum were 30.3±11.4, 18.2±5.2, 23.7±3.9 respectively by WB assay, and(71±13),(62±13),(69±13)ng/µl respectively by ELISA; the expression level of GPX3 protein in PTR, PTS and NC serum were 1.2±0.3, 2.2± 0.3, 1.6±0.3 respectively WB assay. The expression of each protein by using western blot method and ELISA method had the same trend as that using iTRAQ technology.(3)Pearson correlation analysis showed, the expression of SERPINA1, FN1 and ORM1 had a positive correlation with recurrence and death of PTR patients(P <0.01, P <0.05), but was negatively correlated with progress free survival of PTR patients(P <0.05). Kaplan-Meier analysis indicated that clinical stage, initial treatment outcomes, the express level of SERPINA1, FN1 and ORM1 were significantly related with progression-free survival(P <0.05), the initial treatment outcomes was related with overall survival(P=0.027). The overall predictive accuracy of each protein was reflected by the area under the ROC curve(AUC), FN1 ORM1 and SERPINA with ROC areas of 0.679, 0.910 and 0.666 respectively. The diagnosis value of ORM1 protein in ovarian cancer patients with platinum resistance performance is significantly higher than that of FN1 and SERPINA1 protein(P=0.000) CONCLUSIONS: The differentially express level of FN1, SERPINA1 and ORM1 between PTS and PTR play a essential role in measuring subtle changes in response to platinum-based chemotherapy and may be involved in biological processes of platinum resistance. ORM1 has higher diagnostic efficiency of platinum resistance in ovarian cancer patients. It may be a promising candidate biomarker for screening and diagnosis of ovarian cancer patients with platinum resistance.

Long-term exposure to circulating platinum is associated with late effects of treatment in testicular cancer survivors.

BACKGROUND: The success of cisplatin-based (Platinol, Bristol-Myers Squibb Company, New York, NY, USA) chemotherapy for testicular cancer comes at the price of long-term and late effects related to healthy tissue damage. We assessed and modelled serum platinum (Pt) decay after chemotherapy and determined relationships between long-term circulating Pt levels and known late effects. PATIENTS AND METHODS: In 99 testicular cancer survivors, treated with cisplatin-based chemotherapy, serum and 24-h urine samples were collected during follow-up (1-13 years after treatment). To build a population pharmacokinetic model, measured Pt data were simultaneously analysed, together with cisplatin dose, age, weight and height using the NONMEM software. Based on this model, area under the curve between 1 and 3 years after treatment (Pt AUC1-3 years) was calculated for each patient. Predicted long-term Pt exposure was related to renal function and to late effects of treatment assessed median 9 (3-15) years after chemotherapy. RESULTS: Decay of Pt was best described by a two-compartment model. Mean terminal T1/2 was 3.7 (range 2.5-5.2) years. Pt AUC1-3 years correlated with cumulative cisplatin dose, and creatinine clearance before and 1 year after treatment. Patients with paraesthesia had higher Pt AUC1-3 years (30.9 versus 27.0 µg/l month) compared with those without paraesthesia (P = 0.021). Patients with hypogonadism, elevated LDL-cholesterol levels or hypertension also had higher Pt AUC1-3 years. CONCLUSIONS: Renal function before and after cisplatin treatment is an important determinant of long-term Pt exposure. Known long-term effects of testicular cancer treatment, such as paraesthesia, hypogonadism, hypercholesterolaemia and hypertension, are associated with long-term circulating Pt exposure.

A shotgun approach for the identification of platinum-protein complexes.

A shotgun approach including peptide-based OFFGEL-isoelectric focusing (IEF) fractionation has been developed with the aim of improving the identification of platinum-binding proteins in biological samples. The method is based on a filter-aided sample preparation (FASP) tryptic digestion under denaturing and reducing conditions of cisplatin-, oxaliplatin-, and carboplatin-protein complexes, followed by OFFGEL-IEF separation of the peptides. Any risk of platinum loss is minimized throughout the procedure due to the removal of the reagents used after each stage of the FASP method and the absence of thiol-based reagents in the focusing buffer employed in the IEF separation. The platinum-peptide complexes stability after the FASP digestion and the IEF separation was confirmed by size exclusion chromatography-inductively coupled plasma-mass spectrometry (SEC-ICP-MS). The suitability of peptide-based OFFGEL-IEF fractionation for reducing the sample complexity for further nano-liquid chromatography-electrospray ionization-tandem mass spectrometry (nLC-ESI-MS/MS) analysis has been demonstrated, allowing the detection of platinum-containing peptides, with significantly lower abundance and ionization efficiency than unmodified peptides. nLC-MS/MS analysis of selected OFFGEL-IEF fractions from tryptic digests with different complexity degrees: standard human serum albumin (HSA), a mixture of five proteins (albumin, transferrin, carbonic anhydrase, myoglobin, and cytochrome-c) and human blood serum allowed the identification of several platinum-peptides from cisplatin-HSA. Cisplatin-binding sites in HSA were elucidated from the MS/MS spectra and assessed considering the protein three-dimensional structure. Most of the potential superficial binding sites available on HSA were identified for all the samples, including a biologically relevant cisplatin-cross-link of two protein domains, demonstrating the capabilities of the methodology.

Metallomics in drug development: characterization of a liposomal cisplatin drug formulation in human plasma by CE-ICP-MS.

A capillary electrophoresis inductively coupled plasma mass spectrometry method for separation of free cisplatin from liposome-encapsulated cisplatin and protein-bound cisplatin was developed. A liposomal formulation of cisplatin based on PEGylated liposomes was used as model drug formulation. The effect of human plasma matrix on the analysis of liposome-encapsulated cisplatin and intact cisplatin was studied. The presence of 1 % of dextran and 4 mM of sodium dodecyl sulfate in HEPES buffer was demonstrated to be effective in improving the separation of liposomes and cisplatin bound to proteins in plasma. A detection limit of 41 ng/mL of platinum and a precision of 2.1 % (for 10 µg/mL of cisplatin standard) were obtained. Simultaneous measurements of phosphorous and platinum allows the simultaneous monitoring of the liposomes, liposome-encapsulated cisplatin, free cisplatin and cisplatin bound to plasma constituents in plasma samples. It was demonstrated that this approach is suitable for studies of the stability of liposome formulations as leakage of active drug from the liposomes and subsequent binding to biomolecules in plasma can be monitored. This methodology has not been reported before and will improve characterization of liposomal drugs during drug development and in studies on kinetics.

Phase I clinical trial of the novel platin complex dicycloplatin: clinical and pharmacokinetic results.

UNLABELLED: TRANSLATIONAL RELEVANCE: Dicycloplatin (DCP) is a novel super molecule composed of carboplatin (CBP) and 1,1-cyclobutane dicarboxylate (CBDCA) joined by a strong hydrogen bond. The solubility and stability of platinum complexes have a direct bearing on their activity, toxicity and pharmacokinetics. Preclinical studies have shown that DCP overcomes the problem of CBP instability in aqueous solution and maintains anticancer effects. Clinical evaluation in a Phase I dose-escalation study in patients with tumors showed that DCP was tolerated at doses ranging from 100 to 550 mg/m(2) and had potential efficacy in Chinese cancer patients. DCP showed favourable bioavailability and stability in vivo, and the recommended Phase II dosage for DCP-containing chemotherapy is 450 mg/m(2). DCP is currently being investigated as a monotherapy in several cancer types, such as prostatic carcinoma, and in combination with paclitaxel in a Phase II non-lung cancer study. PURPOSE: Dicycloplatin (DCP) is a novel supramolecule composed of carboplatin (CBP) and 1,1-cyclobutane dicarboxylate (CBDCA) joined by a strong hydrogen bond. DCP is stable in aqueous solution unlike CBP alone. The purpose of this study was to assess the maximally tolerated dose, safety, and pharmacokinetics of DCP in Chinese cancer patients. EXPERIMENTAL DESIGN: 29 patients were included in this study. DCP was administered by intravenous infusion over 1 hour once every 21 days. The dose of DCP was escalated from 50 mg/m(2) to 650 mg/m(2) using a modified Fibonacci scheme. Pharmacokinetic analysis was performed in 26 patients to determine the total and ultrafiltered platinum concentrations in plasma. RESULTS: 29 and 20 patients were evaluated for toxicities and response, respectively. The primary adverse effects were nausea/vomiting (58.6%), thrombocytopenia (24.1%), neutropenia (17.2%), anemia (20.7%), fatigue (10.3%), anorexia (10.3%), liver enzyme elevation (10.3%) and alopecia (3.5%). There was no significant toxicity with doses up to 350 mg/m(2). At higher doses, a variety of dose-limiting toxicities (DLTs) were observed, including Grade 3/4 anemia, Grade 3/4 thrombocytopenia, and Grade 3/4 emesis under antiemetic treatment. The maximum tolerated dose of DCP was 550 mg/m(2). Two partial responses occurred in patients with non-cell lung cancer who had received cisplatin- or carboplatin-based chemotherapy. Plasma decay of total and free platinum concentrations was best fitted by using a twocompartment analysis. The terminal plasma half-life of total platinum after DCP administration ranged from 41.86 to 77.20 hours without significant dose dependency. However, the terminal plasma half-life of free platinum concentrations ranged from 42.34 to 61.07 hours. CONCLUSIONS: DCP displayed a favorable safety profile at doses between 50 mg/m(2) and 550 mg/m(2), and first efficacy signals were observed. DLTs were thrombocytopenia, anemia and emesis. The recommended starting dose for a subsequent Phase II study is 450 mg/m(2) once every 3 weeks.

Phase I and pharmacokinetic study of pemetrexed plus cisplatin in chemonaive patients with locally advanced or metastatic malignant pleural mesothelioma or non-small cell lung cancer.

PURPOSE: Pemetrexed is approved as monotherapy and in combination with cisplatin. The established combination dose was identified before the addition of folic acid and vitamin B(12) to the treatment regimen. We evaluated the toxicity and pharmacokinetics (PK) of higher pemetrexed doses with cisplatin and vitamin supplementation. EXPERIMENTAL DESIGN: Patients with malignant pleural mesothelioma or non-small cell lung cancer received pemetrexed doses from 500 to 900 mg/m(2) + 75 mg/m(2) cisplatin once every 21 days. Folic acid and vitamin B(12) were administered per label recommendations. RESULTS: Twenty-one patients received a combined total of 84 cycles. The maximum tolerated dose was 900 mg/m(2) pemetrexed + 75 mg/m(2) cisplatin. Dose-limiting toxicities at this dose included grade 3 anemia, bronchopneumonia, and neutropenia, and 1 death from sepsis secondary to grade 4 febrile neutropenia, considered possibly related to study drugs. The recommended dose was 800 mg/m(2) pemetrexed + 75 mg/m(2) cisplatin. Pemetrexed PK were consistent across doses; pemetrexed did not seem to affect total or free platinum PK. CONCLUSIONS: Pemetrexed with vitamin supplementation was safe and well tolerated at higher doses than the currently established 500 mg/m(2) + 75 mg/m(2) cisplatin. Based on this study, the recommended dose would be 800 mg/m(2) pemetrexed + 75 mg/m(2) cisplatin. However, recent studies showed a lack of improved efficacy for 900 or 1,000 mg/m(2) single-agent pemetrexed versus 500 mg/m(2) and a lack of PK/pharmacodynamic exposure-response relationship for the pemetrexed/cisplatin combination across pemetrexed exposures corresponding to this dose range. Based on currently available evidence, we recommend retaining the established dose.

Initial analysis of relationship between plasma platinum concentration and hematological adverse reaction associated with weekly chemotherapy using nedaplatin in combination with radiotherapy for cervical carcinoma.

PURPOSE: Established therapeutic guidelines for cervical carcinoma recommend concurrent chemo- and radiotherapy as standard treatment for locally advanced cervical carcinoma. Nedaplatin (CDGP) is a platinum agent developed in Japan that is less nephrotoxic than cisplatin (CDDP), but with equivalent antitumor potency. In the standard dosage regimen for cervical carcinoma, CDGP is administered once every four weeks (monthly regimen). We investigated the efficacy and safety of a new dosage regimen, in which CDGP was administered once weekly for five weeks (weekly regimen). METHODS: We measured plasma platinum concentration of patients after administration of CDGP, and analyzed the relationship between plasma platinum concentration and hematological adverse reactions such as thrombocytopenia and leucopenia. RESULTS: The relative rates of change in platelet and white blood cell counts tended to increase as the plasma concentration of platinum increased. Furthermore, the rate of change in platelet counts in relation to the area under the curve was greater for the monthly regimen as compared to weekly. On the other hand, the relative rates of change in WBC were nearly the same between the regimens. CONCLUSIONS: These findings indicate that when using chemotherapy with CDGP for a patient with a cervical carcinoma, a weekly regimen might reduce the severity of thrombocytopenia, while still exhibiting the same therapeutic efficacy as the monthly regimen.

Blood-triggered generation of platinum nanoparticle functions as an anti-cancer agent.

Since the discovery of metal nanoparticles (NPs) in the 1960s, unknown toxicity, cost and the ethical hurdles of research in humans have hindered the translation of these NPs to clinical use. In this work, we demonstrate that Pt NPs with protein coronas are generated in vivo in human blood when a patient is treated with cisplatin. These self-assembled Pt NPs form rapidly, accumulate in tumors, and remain in the body for an extended period of time. Additionally, the Pt NPs are safe for use in humans and can act as anti-cancer agents to inhibit chemotherapy-resistant tumor growth by consuming intracellular glutathione and activating apoptosis. The tumor inhibitory activity is greatly amplified when the Pt NPs are loaded in vitro with the chemotherapeutic drug, daunorubicin, and the formulation is effective even in daunorubicin-resistant models. These in vivo-generated metal NPs represent a biocompatible drug delivery platform for chemotherapy resistant tumor treatment.

Proteomic analysis of the bio-corona formed on the surface of (Au, Ag, Pt)-nanoparticles in human serum.

Adsorption of biomolecules onto nanoparticles surface in biological samples led to the formation of a bio-corona, it could modified the "identity" of nanoparticles, contributing to the determination of their toxicity and biocompatibility. Gel electrophoresis in combination with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was employed to qualitatively analyze and identify the human serum proteins adsorbed on the surface of three different nanomaterials stabilized with citrate: 10.02 ± 0.91 nm gold nanoparticles (AuNPs), 9.73 ± 1.70 nm silver nanoparticles (AgNPs) and, 2.40 ± 0.30 nm platinum nanoparticles (PtNPs). An exhaustive analysis and classification of all identified proteins related with their function were also developed.

Long-term platinum retention after treatment with cisplatin and oxaliplatin.

BACKGROUND: The aim of this study was to evaluate long-term platinum retention in patients treated with cisplatin and oxaliplatin. METHODS: 45 patients, treated 8-75 months before participating in this study, were included. Platinum levels in plasma and plasma ultrafiltrate (pUF) were determined. In addition, the reactivity of platinum species in pUF was evaluated. Relationships between platinum retention and possible determinants were evaluated. RESULTS: Platinum plasma concentrations ranged between 142-2.99 x 10(3) ng/L. Up to 24% of plasma platinum was recovered in pUF. No platinum-DNA adducts in peripheral blood mononuclear cells (PBMCs) could be detected. Ex vivo incubation of DNA with pUF of patients revealed that up to 10% of the reactivity of platinum species was retained. Protein binding proceeded during sample storage. Sodium thiosulfate (STS) appeared to release platinum from the plasma proteins. Platinum levels were related to time, dose, STS co-administration, and glomerular filtration rates (GFR). CONCLUSION: Our data suggest that plasma platinum levels are related to time, age, dose, GFR, and STS use. Platinum in plasma, probably, represent platinum eliminated from regenerating tissue. Platinum species in pUF were partly present in a reactive form. The effects of the reactivity on long-term consequences of Pt-containing chemotherapy, however, remains to be established.

Development and validation of an inductively coupled plasma mass spectrometry method with optimized microwave-assisted sample digestion for the determination of platinum at ultratrace levels in plasma and ultrafiltrate plasma.

A highly sensitive inductively coupled plasma mass spectrometry (ICP-MS) method with microwave-assisted sample digestion for the determination of total platinum in rat whole and ultrafiltrate plasma was developed and validated. A first step of this study concerned the optimization of the mineralization procedure, in order to obtain good extraction recovery (higher than 90%) and repeatability (less than 6%) and the absence of matrix effect. ICP-MS analysis was then performed using the "hot plasma/protective ion extraction" mode, achieving high sensitivity and very high signal/noise ratio. Iridium was added as internal standard. The method was then submitted to validation, performed according to the FDA Bioanalytical Validation Methods guidelines and to the Eurachem guide. Validation was carried out in terms of limit of detection (LOD), limit of quantitation (LOQ), linearity, precision, accuracy and stability. An instrumental LOQ of 1.9ngL(-1), corresponding to a concentration of 955ngL(-1) in matrix under the adopted conditions, was obtained, allowing the quantitative analysis of Pt ultratraces. Instrumental linearity was verified in the range 1.9-14,000ngL(-1), corresponding to a concentration range from 955ngL(-1) to 6825microgL(-1) in matrix. Accuracy was evaluated by analyzing control samples for both matrices at different concentration levels; a good agreement (<15%) was obtained. Sample stability was tested by analyzing control samples maintained for 4h at room temperature or submitted to three freezing-thawing cycles. Finally, the developed method was applied to the analysis of plasma and ultrafiltrate plasma of rats treated with oxaliplatin-base drug, thus demonstrating its reliability in pharmacokinetic studies.

[Changes in peripheral neuropathy and platinum concentrations in patients undergoing surgery following modified FOLFOX6 therapy].

BACKGROUND: Gornet et al.(2002) reported that patients who received chemotherapy containing oxaliplatin for metastatic colorectal cancer experienced exacerbation of neurotoxicity after surgical resection and suggested that the possible mechanism behind exacerbation of neurotoxicity was perioperative transfer of accumulated platinum from the red blood cells into the plasma. However, no further reports about this issue have been published. PATIENTS AND METHODS: We investigated changes of neurotoxicity after resection in three patients who received modified FOLFOX6 therapy prior to surgery. In addition, changes of the total plasma, ultrafiltrate, and erythrocyte platinum levels were determined by inductively coupled plasma mass spectrometry. RESULTS: Exacerbation of neurotoxicity was not seen in any of the patients postoperatively. The platinum concentrations of all samples did not change significantly from before surgery to 4, 24, and 48 hours postoperatively. CONCLUSION: Further assessment of patients is needed to draw a definite conclusion, but our preliminary data suggest that the risk of neurotoxicity exacerbation due to perioperative changes of the platinum pool is low.

Platinum, palladium, rhodium, molybdenum and strontium in blood of urban women in nine countries.

BACKGROUND: There is little reliable information on human exposure to the metals platinum (Pt), palladium (Pd) and rhodium (Rh), despite their use in enormous quantities in catalytic converters for automobile exhaust systems. OBJECTIVES: To evaluate blood concentrations of Pt (B-Pt), Pd (B-Pd) and Rh (B-Rh) in women from six European and three non-European countries, and to identify potentially influential factors. In addition, molybdenum (Mo) and strontium (Sr) were analysed. METHODS: Blood from 248 women aged 47-61 was analysed by high resolution inductively coupled plasma mass spectrometry under strict quality control. RESULTS: The medians were: B-Pt 0.8 (range <0.6-5.2), B-Pd <5 (<5-9.3), B-Rh <0.4 (<0.4-3.6)ng/L and B-Mo 2.0 (0.2-16) and B-Sr 16.6 (3.5-49) µg/L. Two women with highly elevated B-Pt (242 and 60ng/L), previously cancer treated with cis-platinum, were not included in the data analysis. All elements varied geographically (2-3 times) (B-Pd P=0.05; all other elements P<0.001); variations within each area were generally 5-10 times. Traffic was not associated with increased concentrations. CONCLUSIONS: General population blood concentrations of Pt, Pd and Rh are within or below the single digit ng/L range, much lower than in most previous reports. This is probably due to improved analytical performance, allowing for more reliable information at ultra-trace levels. In general, Mo and Sr agreed with previously reported concentrations. All elements showed geographical and inter-individual variations, but no convincing relationships with self-reported traffic intensity were found. Pt from the antineoplastic drug cis-platinum is retained in the body for years.

Supramolecular polymeric chemotherapy based on cucurbit[7]uril-PEG copolymer.

We develop a strategy of supramolecular polymeric chemotherapy based on a new kind of water-soluble polymer that bears cucurbit[7]uril (CB[7]) in the main-chain. To this end, we synthesized a bis-alkynyl functionalized CB[7] and polymerized it with α,ω-diazide-PEG through click reaction to form the desired CB[7] based main-chain polymer (poly-CB[7]). Anticancer drug, oxaliplatin, could be encapsulated into the cavity of poly-CB[7] to form a supramolecular polymeric complex, which displayed low cytotoxicity to normal cells. In addition, the cytotoxicity of the oxaliplatin was recovered when the complex met cancer cells that could overexpress spermine, e.g. colorectal cancer cell, through competitive replacement of oxaliplatin from CB[7] cavity by spermine. Interestingly, the cytotoxicity of the supramolecular polymeric complex to cancer cells is higher than oxaliplatin itself. The enhanced cytotoxicity should result from a combined effect by combining the release of oxaliplatin from the supramolecular polymeric complex and decrease of spermine in the micro-environment of the cancer cells, as spermine is needed for cell growth and proliferation. One more advantage of the supramolecular polymeric complex is its long circulation performance in vivo compared with the supramolecular complex between oxaliplatin and CB[7]. Therefore, this line of research may open new horizons for supramolecular polymeric chemotherapy.