Toxicity Of Platinum Research Articles

A novel exosome based therapeutic intervention against neuroendocrine prostate cancer

Neuroendocrine prostate cancer (NEPC) is a highly lethal variant of castration-resistant prostate cancer (CRPC) with poor survival rates. Current treatment options for NEPC are limited to highly toxic platinum drugs highlighting the urgent need for new therapies. This study aimed to develop a novel therapeutic approach using engineered exosomes against NEPC. Exosomes were modified to target CEACAM5, an NEPC surface antigen, by attaching CEACAM5 antibodies to HEK293T exosomes. These exosomes were loaded with drugs inhibiting EZH2 and the androgen receptor (AR) as recent research shows a persistent role of AR in NEPC wherein it plays a concerted role with EZH2 in driving neuronal gene programs. In vitro experiments with NEPC cell lines demonstrated that CEACAM5-targeted exosomes were specifically taken up by NEPC cells, leading to reduced cellular viability and decreased expression of neuronal markers. Further in vivo tests using a NEPC patient-derived xenograft model (LuCaP145.1) showed significant tumor regression in mice treated with engineered exosomes compared to control mice receiving IgG-labeled exosomes. These results suggest that CEACAM5-engineered exosomes hold promise as a targeted therapy for NEPC. Importantly, our exosome engineering strategy is versatile and can be adapted to target various surface antigens in prostate cancer and other diseases.

Molecular docking and spectroscopic study of bovine serum albumin interaction with new anticancer Pt complex with isopentyl dithiocarbamate ligand

Although cisplatin is useful in the treatment of cancer, it has a series of side effects that limit its use. Dithiocarbamates reduce the toxicity of platinum due to their structure and the presence of S, and N donating groups. In this article, the interaction of [Pt(bpy)(isopentyl.dtc)]NO3, where bpy is bipyridine and isopentyl.dtc is isopentyl-dithiocarbamate, with BSA, bovine serum albumin has been studied. The molecular binding method, including UV-Vis and fluorescence titration, was carried out in conditions including pH = 7.4 and temperatures of 27 and 37 °C. The negative values of enthalpy (ΔH°b) and entropy (ΔS°b) show that the driving forces of this interaction are hydrogen and van der Waals, and the negative value of the Gibbs free energy, ΔG°b indicates that the interaction proceeds spontaneously. The fluorescence results showed that the quenching mechanism is the static type and the Stern Volmer constant, KSV, was also obtained. The fluorescence titration method data displayed that the quenching mechanism is static. Binding constant (Kb), binding point (n), Hill coefficients, nH, Hill constant, KH, number of binding sites, g, BSA melting temperature, Tm, were also obtained. Finally, the molecular docking method result shows the binding constant, Ki and binding free energy for the platinum complex are −6.53 and 16.39 kcal mol−1, respectively, and also the proper position of binding on BSA can be considered the site I in the subdomain IIA.

Abstract 3064: Exosome-based therapeutic strategy for neuroendocrine prostate cancer

Abstract Background: Therapy-induced neuroendocrine prostate cancer (NEPC) is an aggressive variant of castration-resistant prostate cancer (CRPC) that is increasing in incidence with the widespread use of second generation of androgen receptor (AR)-pathway inhibitors (APIs) such as Enzalutamide (ENZ). NEPC arises from CRPC-Adenocarcinomas (CRPC-Adeno) via a reversible trans-differentiation process, referred to as neuroendocrine differentiation (NED) wherein prostate cancer cells (PCa) undergo a lineage switch. As a result of this lineage switching, PCa cells exhibit neuroendocrine (NE) features, characterized by expression of neuronal markers such as enolase 2 (ENO2), chromogranin A (CHGA) and synaptophysin (SYP). Due to lack of AR signaling, these PCa variants are impervious to anti-androgen therapy and constitute an aggressive variant of advanced CRPC with survival times < 1 year. Clinically, NEPC manifests as the presence of visceral metastatic disease including metastasis to liver, lung, central nervous system or bone despite low serum PSA levels. Current therapeutic options for NEPC are limited to highly toxic platinum drugs. The primary objective of our study is to evaluate novel, exosome-based therapies for NEPC. Methods: Exosomes were isolated from HEK-293T cells by ultracentrifugation. Isolated exosomes were characterized by Nanoparticle Tracking Analyses and electron microscopy. These exosomes were engineered to express biotinylated CEACAM-5 antibody on their cell surface. Exosomes were packaged with a combination of drugs (EZH2 inhibitor and AR inhibitor) by sonication. Engineered exosomes were tested in vitro using NEPC cell line NCI-H660 and in vivo using LuCaP 145.1 patient-derived xenograft model. Results: Engineered exosomes reduced the viability of NEPC cells. CEACAM5-labelled exosomes trafficked to tumor cells as CECAM5 is a surface protein expressed by NEPC cells. Conclusions: Engineered-exosome based therapy may provide a new avenue as a targeted therapy for NEPC. Citation Format: Amritha Sreekumar, Sharanjot Saini. Exosome-based therapeutic strategy for neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3064.

Algal bioaccumulation and toxicity of platinum are increased in the presence of humic acids

Environmental context The growth in demand for platinum has led to an increase in the presence of this metal in the environment but little is known about its toxicity to aquatic organisms. The presence of organic matter should contribute to decreasing metal bioavailability but the opposite was found for platinum. How ubiquitous natural organic matter can alter the accumulation and effects of platinum group elements remains to be fully elucidated. Rationale There is a growing interest for platinum in ecotoxicology, mainly because of its use in automobile exhaust catalysts. When it reaches aquatic ecosystems, platinum can interact with ligands such as natural organic matter. According to the Biotic Ligand Model, the formation of such complexes should reduce metal bioavailability. As a consequence, toxicity should decrease in the presence of organic matter. Methodology This study focused on the uptake of platinum by two microalgae species (Chlorella fusca and Chlamydomonas reinhardtii) and its subsequent inhibitory effects on growth (96 h). Cells were exposed to platinum (5–300 µg L−1) at three concentrations (0, 10 and 20 mg C L−1) of standard Suwannee River humic acid (SRHA). Platinum bound to humic acid was determined experimentally using partial ultrafiltration to relate metal uptake and toxicity to speciation. Results Unexpectedly, results show that platinum toxicity, expressed as ultrafiltrable Pt (not bound to humic acid) and total Pt concentrations, is enhanced in the presence of humic acid for both algae. For C. fusca, the half maximal effective concentration (EC50) values decreased from 93 to 37 and 35 µg L−1 of ultrafiltrable Pt in the presence of 10 and 20 mg C L−1 SRHA and from 89 to 36 and 0.31 µg L−1 for C. reinhardtii. Discussion In contradiction with the Biotic Ligand Model, the results show that the presence of SRHA can significantly and importantly increase platinum uptake and toxicity as determined in two unicellular green algae, C. reinhardtii and C. fusca. The present work raises the issue of the impact of platinum on microalgae under realistic environmental conditions (ubiquitous presence of organic matter), primary producers being of great ecological importance.

Potential mechanisms of some selected heavy metals in the induction of inflammation and autoimmunity

Inflammation is a physiological event that protects tissues from infection and injury. Chronic inflammation causes immune cell over activation and sustained release of inflammatory cytokines and chemokines cause pathologic conditions including autoimmune diseases. Heavy metals exposure affects innate and adaptive immune systems through triggering inflammatory responses. It seems that extended inflammatory responses could accelerate heavy metal-induced autoimmunity. In the present review we discuss the exposure route and toxicity of Cadmium (Cd), Lead (Pb), Mercury (Hg), Vanadium (V) and Platinum (Pt) and their effects on inflammatory responses by innate and adaptive immune system and autoimmunity.

Near-Infrared Light-Triggered Polyprodrug/siRNA Loaded Upconversion Nanoparticles for Multi-Modality Imaging and Synergistic Cancer Therapy.

Stimuli-responsive nanosystems have been widely applied as effective modalities for drug/gene co-delivery in cancer treatment. However, precise spatiotemporal manipulations of drug/gene co-delivery, as well as multi-modality imaging-guided cancer therapy, still remain a daunting challenge. Here, multifunctional polyprodrug/siRNA loaded upconversion nanoparticles (UCNPs) are reported that combine computed tomography (CT), magnetic resonance (MR), and upconversion luminescence (UCL) tri-modality imaging and near-infrared (NIR) light-activated drug/gene on-demand delivery. The photoactivatable platinum(IV) (Pt(IV))-backbone polymers (PPt) and the siRNA targeting polo-like kinase 1 (Plk1) are loaded on the surface of polyethyleneimine (PEI)-coated UCNPs (PUCNP) to obtain the multifunctional polyprodrug/siRNA loaded UCNPs (PUCNP@Pt@siPlk1). The PUCNP@Pt@siPlk1 can be served as a "nanotransducer" to convert NIR light (980nm) into local ultraviolet (UV) to visible light for the cleavage of photosensitive PPt, resulting in the simultaneous on-demand release of high toxic platinum(II) (Pt(II)) and siPlk1. Meanwhile, the PUCNP@Pt@siPlk1 has CT, T1 -weighted MR, and UCL tri-modality imaging abilities. Based on these merits, PUCNP@Pt@siPlk1 displayed excellent synergistic therapeutic efficacy via image-guided and NIR light-activated platinum-based chemotherapy and RNA interfering in vitro and in vivo. Thus, this developed nanosystem with NIR light-controlled drug/gene delivery and multi-modality imaging abilities, will display great potential in combining chemotherapy and gene therapy.

Effect of TOP2A and ERCC1 gene polymorphisms on the efficacy and toxicity of cisplatin and etoposide-based chemotherapy in small cell lung cancer patients.

IntroductionThe main treatment regimen for small cell lung cancer (SCLC) involves platinum-based chemotherapy (cisplatin or carboplatin) and etoposide. Single nucleotide polymorphisms (SNPs) in TOP2A and ERCC1 genes were tested as prognostic and predictive factors in non-small cell lung cancer (NSCLC). There are limited data about the clinical relevance of these genetic alterations in SCLC. We undertook this retrospective study to determine the influence of SNPs in TOP2A (rs34300454; rs13695; rs11540720) and ERCC1 (rs11615; rs3212986) genes on the efficiency and toxicity of chemotherapy with platinum and etoposide in SCLC Caucasian patients.Material and methodsThe studied group included 103 Caucasian SCLC patients (65 male, 38 female, median age 65 ±7.5 years). Detailed clinical-demographical data were collected and response to treatment was monitored. DNA was isolated from peripheral blood leukocytes using QIAamp DNA Mini Kit. Single nucleotide polymorphisms were analyzed using TaqMan hydrolyzing probes in real-time PCR technique on an Eco Illumina device.ResultsPatients with C/C genotype in rs13695 of the TOP2A gene had significantly lower risk of neutropenia during chemotherapy than C/T heterozygous patients (p = 0.02, χ² = 5.51, OR = 2.676, 95% CI: 1.165–6.143). Patients harbouring homozygous C/C genotype in rs3212986 of the ERCC1 gene had significantly higher risk of anaemia during chemotherapy, than heterozygous C/A patients (p = 0.045, χ² = 4.01, OR = 0.417, 95% CI: 0.175–0.991). Furthermore, heterozygous G/A genotype in rs11615 of the ERCC1 gene was associated with significant shortening of OS (9 vs. 12 months) compared to homozygous A/A genotype (p = 0.01, χ² = 6.31, HR = 1.657, 95% CI: 1.0710–2.5633).ConclusionsSNPs in ERCC1 and TOP2 genes may be associated with the toxicities and survival of SCLC patients treated with cisplatin and etoposide.

Interaction of Half Oxa-/Half cis-Platin Complex with Human Superoxide Dismutase and Induced Reduction of Neurotoxicity.

The formation of amorphous protein aggregates containing human superoxide dismutase (hSOD1) is thought to be involved in amyotrophic lateral sclerosis onset. cis-Platin inhibits the oligomerization of apo hSOD1, but its toxicity precludes any possible use in therapy. Herein, we propose a less toxic platinum complex, namely oxa/cis-platin, as hSOD1 antiaggregation lead compound. Oxa/cis-platin is able to interact with hSOD1 in the disulfide oxidized apo form by binding cysteine 111 (Cys111). The mild neurotoxic phenomena induced in vitro and in vivo by oxa/cis-platin can be successfully reverted by using lypoyl derivatives, which do not interfere with the antiaggregation properties of the platin derivative.

Platinum(IV) complex-based two-in-one polyprodrug for a combinatorial chemo-photodynamic therapy

A combinatorial therapy that utilizes two or more therapeutic modalities is more effective in overcoming the limitations than each individual method used alone. Despite great advances have been achieved, the combination of chemotherapy and photodynamic therapy (PDT) still cannot satisfy the clinic requirements as the antitumor efficacy could be severely affected by tumor-associated hypoxia. Herein, for the first time, we reported a platinum(IV) complex-based polyprodrug that can in situ generate the highly toxic platinum(II) species as chemotherapeutics and simultaneously induce a high level of reactive oxygen species (ROS) in a PDT-like process without the use of photosensitizer and consumption of oxygen. By in situ polymerizing the platinum(IV) complex-based prodrug monomer (PPM) and 2-methacryloyloxy ethyl phosphorylcholine (MPC), nanosized hydrogel-like polyprodrug could be synthesized. Upon being exposed to light, Pt(IV) moieties in this photoactivable polyprodrug were reduced to generate Pt(II) species. At the meantime, a high level of ROS was generated without the presence of endogenous oxygen, which was confirmed by electron spin resonance (ESR) and fluorescence probes. With the unique nanosized architecture and photoresponsive feature, the as-synthesized polyprodrug exhibited the advantages of sustained drug release, long-term circulation, preferable tumor accumulation, and reversing drug resistance by downregulating the expression of multidrug resistance-associated protein 1 (MRP1) in the anticancer treatment.

ATP7B rs9535826 is associated with gastrointestinal toxicity of platinum-based chemotherapy in nonsmall cell lung cancer patients

Platinum-based chemotherapy is considered as the first-line treatment for nonsmall cell lung cancer (NSCLC) patients. However, platinum resistance and toxicity are major obstacles to its clinical applications. The two P-type ATPases ATP7A and ATP7B have been identified to play an essential role in the transport of platinum. Their genetic polymorphisms may affect the treatment outcome and toxicity of platinum. In this study, we aimed to investigate the association of ATP7A and ATP7B genetic polymorphisms with clinical outcome and toxicity of platinum-based chemotherapy in NSCLC patients. Four hundred and twenty-seven NSCLC patients were enrolled. All patients have accepted platinum-based chemotherapy for at least two cycles. ATP7A (rs2227291 and rs6622665) and ATP7B (rs1061472 and rs9535826) polymorphisms were genotyped by allele-specific matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. Chemotherapeutic response, overall survival time, and hematological and gastrointestinal toxicity were recorded and their associations with genetic factors were evaluated. ATP7A rs2227291 and rs6622665 deviated from Hardy-Weinberg equilibrium. Therefore, the two single-nucleotide polymorphisms were not taken into consideration. For ATP7B polymorphism, ATP7B rs9535826 was associated with gastrointestinal toxicity, and the GG genotype showed lower gastrointestinal toxicity (odds ratio = 0.30; 95% confidence interval = 0.10-0.90; P = 0.031). The genotypes of ATP7B gene may be novel and significant biomarkers for predicting the gastrointestinal toxicity of platinum-based chemotherapy in NSCLC patients.

Dicarboxylato platinum(ii) complexes containing dimethyl sulfoxide and triazolopyrimidine as potential anticancer agents: synthesis, structural and biological studies in solution

N,O,S-donors platinum(ii) complexes were synthesized and well characterized. We demonstrate that modification of coordination sphere by insertion of dmso molecule and bulky triazolopyrimidine ligand is good direction for the design effective less toxic platinum(ii) complexes.

Institutional retrospective analysis of definitive chemo-radiotherapeutic treatment (QRT) in locally advanced cervical cancer.

e17016 Background: Retrospective analysis of toxicity and treatment impact of gemcitabine and platinum plus radiotherapy in patients with locally advanced cervix cancer. Methods: Descriptive, retrospective and observational study of patients with locally advanced cervix cancer (EIla/IVa).The analysis included toxicity Grade III/V and it impact in treatment. Results: We analyze 56 pts, median age: 46.5, median follow up: 24 months. Patients and tumoral characteristics are described in the table below. Regarding platinum group, 2pts required dose reductions of chemotherapy, 2pts suspended a cycle due to toxicity and 4pts needed RT split. 100% pts completed chemo radiotherapy concurrent treatment. Regarding platinum+gemcitabine group: 11pts required CT dose reductions, 14pts suspended a cycle due to toxicity and 5 didn´t complete CT due to toxicity; 6 had a RT split and 18 completed RT. Grade 3-4 toxicity was more frequent in the platinum+gemcitabine group (38.9% vs 73.7%, p=0.01) In platinum group, 14 pts presented disease recurrence. In the platinum + gem group 3pts had a recurrence. Median disease free interval (DFI) was not reached in both groups, but in the univariate analysis statistical significance was achieve, favouring the combine treatment (Log rank test, p=0.03). 2 year global survival rate was 82.1% in platinum group and 91.7% in platinum+gemcitabine groups. Conclusions: This report shows that the scheme of concurrent combine chemotherapy offers higher toxicity, requiring treatment discontinuation in some patients. Nevertheless, in a univariate analysis the platinum+gemcitabine group showed better results, even in a population with more advance disease with greater risk of relapse, understanding that the retrospective evaluation may miss confounders. A correct institutional manage of toxicities may allow the use of intense treatment to obtain potential benefits. [Table: see text]

Toxicity of platinum, palladium and rhodium to Daphnia magna in single and binary metal exposure experiments

Mainly due to automobile traffic, but also due to other sources, the platinum group elements (PGE) platinum (Pt), palladium (Pd) and rhodium (Rh) are introduced into aquatic biotopes where they accumulate in sediments of lakes and rivers. However, the toxicity of these noble metals to aquatic organisms is not well understood and especially toxicity studies under standardized condition are lacking. Thus, the toxicity of Pt, Pd and Rh to Daphnia magna was tested in single metal exposure experiments according to OECD guideline 202. Immobility and lethality was recorded after 24 h and 48 h of exposure and EC50 and LC50, respectively, were determined. As the nominal exposure concentration of Pd differed significantly from the quantified concentration, the control of the real exposure concentration by chemical analysis is mandatory, especially for Pd.The toxicity decreased in the order Pd > Pt ≫ Rh with e.g. LC50(48 h) values of 14 μg/L for Pd, 157 μg/L for Pt and 56,800 μg/L for Rh. The exposure period had a clear effect on the toxicity of Pt, Pd and Rh. For Pt and Rh the endpoint immobility was more sensitive than the endpoint lethality whereas Pd toxicity was similar for both endpoints. The Hill slopes, which are a measure for the steepness of the concentration-response curves, showed no significant discrepancies between the different metals.The binary metal exposure to Pt and Pd revealed a more-than-additive, i.e. a synergistic toxicity using the toxic unit approach. The present study is a start to understand the toxicity of interacting PGE. The modes of action behind the synergistic effect are unclear.

P1.01-049 Predictors of High Grade Toxicity of Chemotherapy among Malignant Pleural Mesothelioma Patients

Malignant pleural mesothelioma is an aggressive thoracic malignancy associated with exposure to asbestos, and its incidence is anticipated to increase during the first half of this century. Chemotherapy is the mainstay of treatment, yet sufficiently robust evidence to substantiate the current standard of care has emerged only in the past 5 years. A retrospective cohort study of 100 MPM patients referred to NCI, Cairo University in 3 years. Detailed data, Pearson's Chi (×2) square and Logistic regression model were used for statistical analysis. We found a statistical significant relation between age (0.005), male gender (0.002), endemic area residence (0.001), industrial workers (0.018), duration of exposure (0.04), smokers (0.009), Simian virus (0.019), P53 (0.001), RbP (0.001), PS (0.0.16) and development of high grade toxicity of platinum based chemotherapy. Median age = 46 years, only 17% of cases developed high grade toxicity complications of platinum based chemotherapy. Males were 59% of cases. PS, residence, smoking, occupation, history of asbestos exposure, family history, simian virus, P53, Rbp, dyspnea, chest pain, cough, expectoration, hemoptysis, weight loss, fatigue, metastatic symptoms, chronic lung infection, Tuberculous pleuritic, effusion, pleural thickening, Tracheal shift, TNM staging, surgical operations, pathological staging, radiotherapy, cause of death and chemotherapy toxicity are assessed in our patients. Many factors predict high grade chemotherapy toxicity. So, search for target therapy and immunotherapy instead of chemotherapy in this selected group can improve both quality of life and response rate.

AB049. PS02.13: Platinum based chemotherapy in locally advanced non-metastatic thymic carcinoma

Background: Thymic carcinoma is a rare malignant tumor. At present, cisplatin based doublet or triplet antitumor drugs are used in neo-adjuvant setting for advanced thymic carcinomas. However, no optimal chemotherapeutic regimen is well established and recent small case studies with carboplatin and paclitaxel doublet demonstrates the similar efficacy with less toxicity. We retrospectively evaluated effectiveness and toxicity of platinum based doublet chemotherapy for patients with advanced thymic carcinoma.

PUB083 Neo-Adjuvant Platinum Based Chemotherapy in Locally Advanced Thymic Carcinoma

Thymic carcinoma is a rare malignant tumor. At present, cisplatin based doublet or triplet antitumor drugs are used in neo-adjuvant setting for advanced thymic carcinomas. However, no optimal chemotherapeutic regimen is well established and recent small case studies with carboplatin and paclitaxel doublet demonstrates the similar efficacy with less toxicity. We retrospectively evaluated effectiveness and toxicity of platinum based doublet chemotherapy for patients with advanced thymic carcinoma. Between 2001 and 2011, we retrospectively identified 21 patients from hospital information system with pathologically confirmed advanced thymic carcinoma, who were treated with platinum based doublet chemotherapy followed by surgical resection. The most commonly used regimen being carboplatin plus docetaxel in 65% of the patients. Other regimens included cisplatin plus gemcitabine, carboplatin plus gemcitabine and cisplatin plus doxorubicin plus cyclophosphamide. The clinical response rate was achieved in 61.5 % of the patients. The disease control rate was achieved in 92% of the patients. The median progression-free survival was 7.9 months (95% CI 1.3–10.0) and median overall survival was 33.8 months (95% CI 8.3–45.9). The toxicity profiles of platinum doublets demonstrated grade 3-4 hematological and non-hematological toxicities in 18% and 24% of the patients respectively. No febrile neutropenia and toxic death was recorded. We concluded that platinum doublet chemotherapy is active and tolerable for advanced thymic carcinoma in the front-line setting with regard to efficacy, toxicity, and usage in clinical setting.

Cisplatin in the modern era: The backbone of first-line chemotherapy for non-small cell lung cancer.

The treatment of advanced non-small cell lung cancer (NSCLC) may be changing, but the cisplatin-based doublet remains the foundation of treatment for the majority of patients with advanced NSCLC. In this respect, changes in practice to various aspects of cisplatin use, such as administration schedules and the choice of methods and frequency of monitoring for toxicities, have contributed to an incremental improvement in patient management and experience. Chemoresistance, however, limits the clinical utility of this drug in patients with advanced NSCLC. Better understanding of the molecular mechanisms of cisplatin resistance, identification of predictive markers and the development of newer, more effective and less toxic platinum agents is required. In addition to maximising potential benefits from advances in molecular biology and associated therapeutics, modification of existing cisplatin-based treatments can still lead to improvements in patient outcomes and experiences.

The relationship between polymorphisms of genes regulating DNA repair or cell division and the toxicity of platinum and vinorelbine chemotherapy in advanced NSCLC patients.

Platinum-based chemotherapy and 3rd generation drugs is still the main treatment option for advanced non-small cell lung cancer (NSCLC) patients without activating EGFR mutations or ALK rearrangements. However, the side effects associated with cytostatics are well known. Changes in the genes (e.g. single nucleotide polymorphisms, SNPs) encoding proteins regulating DNA repair or cell division could potentially influence on both the susceptibility of cancer cells to chemotherapy, and the occurrence of toxicities. In presented study, the relationship between the fourteen SNPs in nine DNA repair and cell division regulating genes: ERCC1, XPD, XPA, XPC, XRCC1, XPG, RRM1, BRCA1, STMN1 and the toxicity of first-line chemotherapy in NSCLC patients were investigated. SNPs were determined by SNaPshot PCR® in DNA isolated from peripheral blood of 55 NSCLC patients treated with platinum compound and vinorelbine. The toxicity of therapy was evaluated according to the Common Toxicity Criteria (CTC) Version 4.03. The odds ratio (OR) of severe haematological toxicity was significantly lower in carriers of the T allele of XRCC1 gene (1196A > G, OR = 0.22, 95 % CI: 0.06-0.82, p = 0.018) and higher in the carriers of the T allele (2704C > A) of XPC gene (OR: 7.50, 95 % CI: 0.89-63.17, p = 0.036) compared to the remaining patients. Risk of severe hepatotoxicity was significantly lower in carriers of the C allele of STMN1 (-2166T > C, OR = 0.09, 95 % CI: 0.01-1.12, p = 0.025) than in patients with T allele of this gene. In carriers of G allele (2251A > C, OR: 0.24, 95 % CI: 0.07-0.81, p = 0.017) and T (934G > A, OR: 0.26, 95 % CI: 0.07-0.90, p = 0.029) of XPD gene, risk of severe nephrotoxicity was significantly lower than in other patients. Selected SNPs of genes encoding DNA repair enzymes and cell division regulation proteins could be useful biomarkers for prediction of platinum and vinorelbine-based chemotherapy toxicity in patients with advanced NSCLC.

Abstract 5402: Tissue accumulation and toxicity of platinum released from a novel chitosan hybrid gel for intraperitoneal drug delivery

Abstract Attempted surgical removal of advanced stage peritoneal cancers is mostly insufficient and often fails in areas affected by disseminated disease. But the successful elimination of peritoneal surface spread is known to have a significant impact on patient survival. However, standard therapies such as surgical cytoreduction and systemic chemotherapy combined with radiation have only shown limited-efficacy, accessibility, and nonspecific toxicity as well as frequent development of multidrug resistance (MDR). To overcome those limitations, we previously reported about the development of a mucoadhesive, chitosan-hybrid gel (CS(BCDDP)) embedded with cisplatin (CDDP) containing alginate beads for intraperitoneal administration (# 1948, AACR 2012). Here we report additional results illustrating CDDP release from CS(BCDDP) at different pH in vitro, CDDP accumulation to genomic DNA (gDNA) isolated from tissues as well as toxicity data in vivo. To determine the amount of CDDP released from CS (BCDDP) in vitro, B50μgCDDP, CDDP-chitosan (CS50μgCDDP) and CS (B50μgCDDP) pellets (8 mm ø, 1.5 mm thickness) were prepared and placed into a 6 well plate containing 2 ml/well PBS (pH 6, 7, 7.4 and 8). Multiple samples were collected during the 24 h incubation (37°C, 100rpm) period. The majority (75%) of CDDP was successfully released from CS(BCDDP) within the first 2 h at pH 7.4 showing the rate of drug release to be inversely correlated with pH yielding a more rapid release under acidic pH conditions. To assess CDDP accumulation to gDNA, inductively coupled plasma mass spectrometry (ICP-MS) was performed with tissue samples obtained from the left peritoneal sidewall of female nu/nu mice 24 hours after treatment with CS50μgCDDP, CS(B50μgCDDP), intravenously (i.v.) CDDP(IV50μgCDDP) and intraperitoneal (i.p) CDDP (IP50μgCDDP), respectively. The results demonstrated a greater than three-time enhancement of CDDP-accumulation to the gDNA from CS(B50μgCDDP) when compared to CS50μgCDDP and IV50μgCDDP administration. In addition, CS(B50μgCDDP) showed similar levels of CDDP adduction compared to direct IP50μgCDDP administration. Moreover, assessment of CDDP accumulation in kidneys and blood 24 h following treatment with either IP50μgCDDP or CS(B50μgCDDP), demonstrated significantly decreased kidney toxicity from CS(B50μgCDDP) when compared to IP50μgCDDP. Our results, therefore strongly suggest that administration of this hybrid gel directly to mucosal surfaces such as the peritoneal cavity is feasible making it an advantageous, safe and non-toxic intraperitoneal drug delivery system for the treatment of disseminated peritoneal cancers such as advanced or recurrent ovarian cancer. Currently ongoing experiments are evaluating the efficacy and safety of our hybrid gel/CDDP in an orthotopic peritoneal cancer animal model. Citation Format: Sungpil Cho, Yongen Sun, Elke A. Jarboe, Andrew P. Soisson, Mark K. Dodson, David K. Gaffney, C.Mattew Peterson, Margit M. Janat-Amsbury. Tissue accumulation and toxicity of platinum released from a novel chitosan hybrid gel for intraperitoneal drug delivery. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5402. doi:10.1158/1538-7445.AM2014-5402

Potent Anticancer Activity and Possible Low Toxicity of Platinum(II) Complexes with Functionalized 1,1‐Cyclobutanedicarboxylate as a Leaving Ligand

Two platinum(II) complexes, DN603 and DN604, were designed and prepared by using 3-oxocyclobutane-1,1-dicarboxylate as a ligand. The compounds were prepared according to the concept that incorporation of a functionalized moiety in the leaving ligand that did not affect its coordination bonding to the metal atom would play a key role in the anticancer activity of the resulting platinum complex. The newly prepared compounds were found to show potent in vitro anticancer activity comparable to cisplatin and oxaliplatin; especially DN604, which exhibited low acute toxicity similar to carboplatin, and presented acceptable solubility and stability in water. Chemical and biological results indicated that the functionalized moiety, uncoordinated, led to potent anticancer activity and low apparent toxicity of the platinum complexes by affecting the kinetic properties of the compounds.