Toxicity Of Carboplatin Research Articles

Detection of cytotoxic effects of carboplatin in human nasopharyngeal carcinoma epithelioid cell line CNE-1 by Raman spectroscopy combined with multivariate statistical analysis

Raman spectroscopy combined with multivariate analysis was used to examine the molecular mechanism of carboplatin toxicity in human nasopharyngeal carcinoma epithelioid cell line CNE-1. Multivariate analysis was performed through principal component analysis combined with linear discriminant analysis, through which a diagnostic algorithm that could discriminate between the control and treatment groups was generated. Compared with the control group (0 μmol/L, 0 hour), the 2 protein Raman peaks (1002 cm−1 and 1659 cm−1) and the 2 deoxyribonucleic acid Raman peaks (1303 cm−1 and 1338 cm−1) in the treatment group decreased with increasing carboplatin concentrations as well as with increasing treatment durations. Using principal component analysis combined with linear discriminant analysis, the discrimination accuracy, sensitivity, and specificity between the control group and the cell groups treated at 12 and 16 μmol/L carboplatin for 24 hours were all 100%, suggesting that 16 μmol/L is suitable as the therapeutic dosing. Using the same method, the discrimination accuracy, sensitivity, and specificity between the control group and the cell groups that were treated with 12 μmol/L carboplatin for 24 and 36 hours were all 100%, indicating that 24 hours could be suitable treatment duration. These results suggest that Raman spectroscopy combined with multivariate statistical analysis could be a useful tool for assessing carboplatin-induced cytotoxicity in human nasopharyngeal carcinoma cells.

Sarcopenia as a Predictive Factor for Carboplatin Toxicity in Patients with Advanced Non-Small Cell Lung Cancer

Sarcopenia in cancer patients often negatively impacts various outcomes. Carboplatin, a first-line chemotherapy for non-small cell lung cancer (NSCLC), is dosed based on body weight, which doesn’t account for sarcopenia. This study evaluated the association between sarcopenia and carboplatin-related toxicity in NSCLC patients. Patients with locally advanced or metastatic NSCLC treated with carboplatin were included. Toxicity events during the first two cycles of treatment were recorded. Sarcopenia was assessed using pretreatment computed tomography scans analyzed with Slice-O-Matic V4.2 software, defining sarcopenia as a skeletal muscle index (SMI) of <52.4 cm2/m2 for men and <38.5 cm2/m2 for women. Among 146 patients, 52% had sarcopenia. Hematological toxicity occurred in 71.2% of all patients and 77.6% of those with sarcopenia. The fat-free mass index (FFMI) was independently associated with hematological toxicity and dose-limiting toxicity (DLT), which was observed in 55.5% of patients. Sarcopenia significantly correlates with hematological toxicity and DLT during carboplatin treatment in NSCLC patients. Given its prevalence and noninvasive detection, further research is needed to understand its impact on treatment outcomes.

EP10.01-15 Sarcopenia as a Predictive Factor of Carboplatin Toxicity in Patients with Advanced Non-small Cell Lung Cancer

EP10.01-15 Sarcopenia as a Predictive Factor of Carboplatin Toxicity in Patients with Advanced Non-small Cell Lung Cancer

Efficacy and toxicity of carboplatin in the treatment of macroscopic mesenchymal neoplasia in dogs.

Palliative chemotherapy options for dogs with macroscopic non-osseous mesenchymal tumours are limited. The purpose of this study was to assess the response rate of these tumours to carboplatin chemotherapy. Medical records of 28 dogs treated with carboplatin for macroscopic mesenchymal neoplasia between 1990 and 2022 were retrospectively reviewed. Sixteen dogs with soft tissue sarcoma and 12 dogs with haemangiosarcoma were included. Responses observed included one complete response and three partial responses, for an overall response rate of 14.2% (4/28) and median time to progression of 42 days (range 21-259 days). Responses were only seen in patients with haemangiosarcoma, for a response rate of 33.3% (4/12) and median time to progression for responders of 103 days (range 39-252 days). Median time to progression for dogs with metastatic disease was similar to those with only local disease (distant median: 44 days; local median: 23 days, p = 0.56). Dogs with chemotherapy-naïve disease were compared to dogs having received previous chemotherapy treatment and had a median time to progression of 75 days and 40.5 days respectively (p = 0.13). Twenty-two dogs experienced 48 adverse events, with most being grade 1 or 2 (79%). Carboplatin was well tolerated, with variable macroscopic anti-tumour activity and short response duration. Carboplatin may be an acceptable rescue option for dogs with macroscopic haemangiosarcoma, especially those patients that cannot receive doxorubicin.

Outcome and toxicity of ifosfamide, carboplatin, and etoposide versus gemcitabine and vinorelbine regimen for pediatric patients with relapsed or refractory Hodgkin's lymphoma.

Pediatric classical Hodgkin lymphoma (CHL) is a curable disease; however, the optimal salvage regimen is unclear for relapsed/refractory (R/R) disease. This study aimed to compare response rates, toxicity, event-free survival (EFS), and overall survival (OS) of ifosfamide, carboplatin, and etoposide (ICE) with gemcitabine and vinorelbine (GV) regimen after first-line doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) in pediatric patients with R/R CHL. This is a retrospective cohort study of 132 pediatric patients with R/R CHL treated from July 2012 to December 2020 with ICE (n = 82) or GV (n = 50). The median age at relapse was 13.9 years, and 68.2% were men. Rates of complete response, partial response, and progressive disease before consolidation were 50.6%, 3.7%, and 45.7% for ICE and 28.5%, 0%, and 71.5% for GV (P = 0.011). By multivariate analysis, regimen (P = 0.002), time to relapse (P = 0.0001), and B-symptoms (P = 0.002) were independent factors to lower response rates. Hematological toxicity, electrolyte disturbance, hemorrhagic cystitis, infectious complications, and hospital admission for fever neutropenia were statistically significant higher for the ICE regimen. Treatment-related mortalities were 2.4% for ICE and 2% for GV (P = 0.86). The 3-year EFS was 39.3% ± 11.4% for ICE and 24.9% ± 12.5% for GV (P = 0.0001), while 3-year OS was 69.3% ± 10.6% and 74% ± 12.9% (P = 0.3), respectively. By multivariate analysis, regimen (P = 0.0001), time to relapse (P = 0.011), B-symptoms (P = 0.001), and leukocytosis (P = 0.007) were significant for EFS, while anemia (P = 0.008), and progressive disease on early response evaluation (P = 0.022) were significant for OS. The ICE regimen had a better overall response rate and EFS, but higher toxicity, than GV; however, OS and mortality were similar.

P-426 In vitro and in vivo toxicity of carboplatin and paclitaxel regimen on BRCA-mutated ovarian tissue fragments

Abstract Study question Does carboplatin and paclitaxel regimen have a toxic cumulative impact on the ovarian reserve of young breast cancer patients with germline Breast Cancer (BRCA) mutation? Summary answer Based on follicle classification and survival through apoptosis and DNA repair mechanism recruitment analyses, gonadotoxic but no cumulative effect was observed in BRCA-mutated ovarian tissue. What is known already Ovarian function recovery and fertility issues remain major concerns for young patients diagnosed with cancer. Breast cancer is the first cancer diagnosed among women under 40 years and around 10% of them are BRCA germline mutation carriers. Beside their predisposition to breast and ovarian cancers, BRCA carriers might be more sensitive to chemotherapy-induced gonadotoxicity due to the role of BRCA in DNA repair mechanism. Current therapies for BRCA-mutated breast cancer patients often include carboplatin and paclitaxel, drugs that are both considered as moderately gonadotoxic. However, the effect of combined therapy in BRCA-mutated ovarian tissue is unknown. Study design, size, duration Ovarian tissue cryopreserved for fertility preservation before chemotherapy and donated for research by breast cancer patients with or without BRCA1/2 mutation (&amp;lt; 35 years at diagnosis) were used in this study. Two models were investigated: 3 days in vitro culture with carboplatin (10 µg/mL) and/or paclitaxel (1 µM) and ovarian tissue xenograft into mice followed by 3 weeks injections of carboplatin (50mg/kg/week) and paclitaxel (10mg/kg every 3 days). Control conditions were performed for each model. Participants/materials, setting, methods Ovarian tissue from 3 BRCA-mutated and 3 non-mutated patients were thawed and exposed in vitro and in vivo to chemotherapy. Follicle density (number of follicles/mm²) as well as ratios of quiescent/activated and healthy/atretic follicles were evaluated following haematoxylin-eosin staining. Apoptosis and DNA repair mechanisms were analysed using TUNEL/GDF9 co-staining and phosphorylated H2A histone family member X (γH2AX)/ZP-3 co-staining, respectively. Genes expression level will be evaluated on isolated follicles to assess the activation process. Main results and the role of chance First, the impact of in vitro culture and in vivo xenotransplantation was evaluated by follicle counting and classification. A decrease of follicular density (5 to 95% irrespective of patient, model, nor condition) and an increase of activated and atretic follicles was observed after both in vitro and in vivo experiments in all conditions. However, a slight increase of quiescent follicle pool was observed in the in vitro control condition, with no difference between mutated and non-mutated fragments. Then, immunofluorescence staining was performed to evaluate follicle damage. For quantification, 30 to 150 follicles per patient were counted within each condition and classified as positive if at least one cell was stained. Apoptosis was assessed with TUNEL/GDF9 co-staining. In both models, the ratio of positive follicles was higher in fragments treated with chemotherapy (40-60%) compared to control conditions (15-20%). Recruitment of DNA repair complex was analysed using γH2AX/ZP3 co-staining. In both models, an increase in positive follicles ratio was observed in treated fragments (15-40%) compared to control conditions (5-10%). Interestingly, the positive follicles ratio was lower in BRCA-mutated (15-18%) than in non-mutated fragments (25-40%) after 3-days in vitro culture, irrespective of the treatment used. Limitations, reasons for caution Reasons of caution include the high inter-variations between patients as well as intra-variations in one patient regarding follicular density within ovarian tissue. Moreover, BRCA-mutated patients included (27.67 ± 2.08) are younger than control ones (33.67 ± 1.53). Ongoing experiments with additional patients should support the results already obtained. Wider implications of the findings Carboplatin and paclitaxel combined exposure in vitro or in vivo does not seem to have a cumulative deleterious impact on ovarian reserve. Ovarian tissue with BRCA-mutation did not appear to be more sensitive to chemotherapy exposure. Further investigations focusing on DNA repair mechanisms will be performed in both models. Trial registration number Not applicable

The impact of clinical equations on carboplatin dosing: A systematic review to determine appropriate dosing of carboplatin in adult cancer patients.

e15005 Background: The Calvert formula is used to estimate the carboplatin dose needed to achieve the desired Area Under the Curve (AUC) despite little consensus on which estimated Glomerular Filtration Rate (eGFR) equation best reflects renal clearance. Cockcroft-Gault (CG) is often used when calculating estimated Creatinine Clearance (CrCl) for the Calvert formula. Equations like Modification of Diet in Renal Disease or CKD-EPI (based on serum creatinine (SrCr) or cystatin C), take into account parameters such as race, gender, weight. We compared several publications to determine the most effective dosing strategy for carboplatin. Methods: Utilizing PubMed, 19 articles were found with the keywords “carboplatin, dosing, eGFR, measure GFR, creatinine clearance, muscle mass.” Our inclusion criteria consisted of being published within the last 10 years, included carboplatin dosing, and evaluated either measured GFR, measured CrCl, carboplatin clearance or toxicities caused by carboplatin. Studies not meeting these parameters were excluded. Of the 19 articles, 11 articles were identified regarding the accuracy of eGFR and its effects on carboplatin dosing and/or dose limiting toxicities. An extensive literature review of each article was used to find a consensus among the clinical equations used in carboplatin dosing. Results: There remains no consensus on the most accurate eGFR equation. Eight studies evaluated accuracy of varying equations in estimating GFR, creatinine clearance or carboplatin clearance. Two studies created new equations (one measuring GFR and the other measuring CrCl) and compared them to current equations for accuracy. Ultimately, only two studies were in agreement that CKD-EPI was the most viable option when GFR uses SrCr. Based on four studies, CG is an inadequate measurement of eGFR. CG ranked low due to a high mean percent error when compared to measured GFR, indicating a larger discrepancy between measured GFR and the estimated value of CG, as compared to other equations. Three of the studies evaluated for a correlation in skeletal muscle mass and hematological toxicities, indicating that changes in muscle mass could correlate with hematological toxicities. One small study developed a new equation based on muscle mass and SrCr and showed positive results for accuracy when compared to measure CrCl. Conclusions: Although a definitive equation to estimate renal clearance could not be established, equations like CG have limited accuracy due to race, weight, age, and gender. The single study that utilized muscle mass demonstrated the most promise and presents a better option for patients, particularly when muscle mass changes over time. Other studies illustrated that muscle mass is significantly correlated with carboplatin toxicity and should be considered for future studies to determine the safest method for dosing carboplatin.

Toxicity and feasibility of vincristine, etoposide, and carboplatin alternating with vincristine, doxorubicin, and cyclophosphamide in children with advanced retinoblastoma in Guatemala.

Retinoblastoma is highly curable, with event-free survival (EFS) of greater than 95% in high-income countries. However, in lower middle-income countries, outcomes of EFS are 30%-60% due to delayed diagnosis and lack of resources resulting in extra-ocular disease. We report the toxicity profile and outcomes of intensified therapy for advanced retinoblastoma: vincristine, etoposide, carboplatin (VEC) alternating with vincristine, doxorubicin, and cyclophosphamide (VDoCx) in Guatemala. Compared to VEC alone, similar rates of neutropenia, anemia, and thrombocytopenia were seen, with no toxic deaths. Although survival was not a primary objective, a modest survival benefit supports further investigation of VEC+VDoCx for advanced retinoblastoma.

Cannabis-derived products antagonize platinum drugs by altered cellular transport

Cannabinoids, a class of compounds derived from Cannabis sativa L., have recently become more widely accessible for public consumption in the form of diverse cannabis products, in parallel with weakening the measures that so far restricted their availability. The US Food and Drug Administration has approved several cannabis-derived drugs for management of various diseases as well as chemotherapy-induced nausea and vomiting. Besides the attenuation of adverse effects of chemotherapy, numerous reports about cannabinoid-mediated anticancer effects further motivate cancer patients to support their therapy with such products. Here we present a set of preclinical data with human cell culture models, suggesting that cannabidiol and cannabis extracts may effectively counteract the anticancer effects of the clinically widely used standard-of-care platinum-based drugs. We show that even low concentrations of cannabinoids reduced the toxicity of cisplatin, oxaliplatin, and carboplatin, an effect which was accompanied by decreased platinum adduct formation and a set of commonly used molecular markers. Mechanistically, our results excluded the possibility that the observed enhanced survival of cancer cells was mediated transcriptionally. Instead, trace metal analyses strongly indicate an inhibitory impact of cannabinoids on intracellular platinum accumulation, thereby implicating changes in cellular transport and/or retention of these drugs as the likely cause of the observed biological effects. Our study raises the possibility that the desirable effect of counteracting adverse effects of chemotherapy might, at least for some cannabinoids, reflect impaired cellular availability, and consequently attenuation of the anticancer effects of platinum drugs. Data availabilityAll data supporting the conclusions are available in the article and supplementary files. Raw data are available upon request from the corresponding author.

Efficacy and toxicity of carboplatin and gemcitabine administered on day 1 and day 8 (day1&8) versus day 1-only for platinum-sensitive recurrent epithelial ovarian cancer

ObjectiveTo compare response rate, progression-free survival, overall survival, and toxicity of carboplatin and gemcitabine administered on day 1 and day 8 (day1&8) versus a modified day 1-only regimen in recurrent...

Addition of intravitreal carboplatin with melphalan for management of vitreous seeding in retinoblastoma.

To evaluate the efficacy and toxicity of intravitreal carboplatin plus melphalan for the treatment of vitreous seeds in eyes with retinoblastoma (RB). This retrospective series at a tertiary referral center included 22 consecutive RB patients who had received intravitreal carboplatin (16μg per 0.05ml) combined with melphalan (30μg in 0.03ml) [IVi (Ca-Me)] for treatment of vitreous seeds. Tumor control and drug toxicities were recorded. There were 22 eyes of 22 patients, divided into primary group (n = 13) without history of previous intravitreal chemotherapy (IViC) and refractory group (n = 9) with history of previous IViC using melphalan and/or topotecan. The demographics and clinical findings of the primary and refractory groups did not differ significantly. The 6-month follow-up revealed complete vitreous seed control (77% vs. 89%, p = 0.47). Vitreous seed recurrence was detected in 1 eye of each group at 6months. During the next 18-month follow-up period, no recurrence of seed was observed. The response to IVi (Ca-Me) was not significantly influenced by previous IViC (p = 0.70), primary systemic or intra-arterial chemotherapy (p = 0.45), or the type of regression (p = 0.35). The most common tumor treatment complications were retinal detachment (RD) (n = 2), early hypotony (n = 2) and late hypotony (n = 4, unrelated), cataract (n = 2), and severe pigment dispersion (n = 1). Enucleation was performed in 8 eyes, for total RD (n = 1), phthisis bulbi (n = 5), and extensive solid tumor recurrence (n = 2). There was no case of orbital invasion, systemic metastasis, or death. Based on this interventional case series for primary and refractory vitreous RB seeds, carboplatin plus melphalan therapy may be effective with few toxic side effects.

Efficacy and toxicity of carboplatin and gemcitabine dosed on day 1/day 8 versus day 1 alone for platinum-sensitive recurrent epithelial ovarian cancer.

5541 Background: Carboplatin, gemcitabine +/- bevacizumab is a preferred regimen for recurrent, platinum-sensitive ovarian cancer (PSOC). A phase III trial established that the regimen of carboplatin on Day 1 (D1) and gemcitabine on D1 and Day 8 (D8) was associated with acceptable toxicity and improved progression free survival (PFS) compared to carboplatin alone. Treatment with gemcitabine on D8 incurs more exposure to cytotoxic therapy and increased burden on patients and the healthcare system, especially during the COVID-19 pandemic. However, it is unknown whether D1/D8 gemcitabine imparts an improvement in efficacy compared to D1 alone. Our objective was to compare efficacy and toxicity of carboplatin and gemcitabine D1/D8 (CG-D1/8) with a modified D1 regimen (CG-D1). Methods: A retrospective single-institution cohort study was performed in women with recurrent PSOC treated with carboplatin, gemcitabine +/- bevacizumab from 2009-2020. Data was analyzed by intention to treat comparing women who received CG-D1/8 vs CG-D1. Data was also analyzed by 3 groups: CG-D1/8 vs CG-D1/8 but dropped D8 vs CG-D1. The primary endpoint was response rate (RR), defined as complete or partial response at 6 cycles or maximum cycles if &lt;6. Secondary outcomes included PFS, overall survival (OS), toxicity, Neulasta use and dose reduction. Results: Of 200 patients, 26% completed CG-D1/D8, 21.5% started CG-D1/D8 but dropped D8, and 52.5% received CG-D1. There were no significant differences in age, race, or ECOG between cohorts. Among CG-D1/D8, 45.3% dropped D8 primarily due to neutropenia (51.2%) or thrombocytopenia (30.2%). The RR at 6 cycles was 68.7% for CG-D1/8 completed, 70.7% for CG-D1/8 dropped D8, and 69.3% for CG-D1 (p=0.97). The median PFS was 13.1, 12.1 and 12.4 months for CG-D1/8 completed, CG-D1/8 dropped D8, and CG-D1, respectively (p=0.29). Similarly, median OS was 28.2, 33.5 and 34.3 months for the above groups respectively (p=0.42). While there was no difference in concurrent bevacizumab use for CG-D1/8 and CG-D1 (34.7% vs 29.5%, p=0.43), among the CG-D1/8 patients, a significantly higher proportion of patients who dropped D8 received bevacizumab (51.2% vs 21.2%, p=0.006). Table 1 lists secondary outcomes. Conclusions: There was no significant difference in RR, PFS or OS among women with PSOC receiving CG-D1/8 vs CG-D1, regardless of whether D8 was dropped. CG-D1/8 was associated with significantly greater hematologic toxicity. These findings suggest a modified D1 regimen may be a suitable alternative to standard CG-D1/8 treatment and warrant prospective validation. [Table: see text]

A Redox-active Mn Porphyrin, MnTnBuOE-2-PyP5+, Synergizes with Carboplatin in Treatment of Chemoresistant Ovarian Cell Line.

We have employed a redox-active MnP (MnTnBuOE-2-PyP5+, Mn(III) meso-tetrakis (N-n-butoxyethylpyridinium-2-yl) porphyrin) frequently identified as superoxide dismutase mimic or BMX-001, to explore the redox status of normal ovarian cell in relation to two ovarian cancer cell lines: OV90 human serous ovarian cancer cell and chemotherapy-resistant OV90 cell (OVCD). We identified that OVCD cells are under oxidative stress due to high hydrogen peroxide (H2O2) levels and low glutathione peroxidase and thioredoxin 1. Furthermore, OVCD cells have increased glycolysis activity and mitochondrial respiration when compared to immortalized ovarian cells (hTER7) and parental cancer cells (OV90). Our goal was to study how ovarian cell growth depends upon the redox state of the cell; hence, we used MnP (BMX-001), a redox-active MnSOD mimetic, as a molecular tool to alter ovarian cancer redox state. Interestingly, OVCD cells preferentially uptake MnP relative to OV90 cells which led to increased inhibition of cell growth, glycolytic activity, OXPHOS, and ATP, in OVCD cells. These effects were further increased when MnP was combined with carboplatin. The effects were discussed with regard to the elevation in H2O2 levels, increased oxidative stress, and reduced Nrf2 levels and its downstream targets when cells were exposed to either MnP or MnP/carboplatin. It is significant to emphasize that MnP protects normal ovarian cell line, hTER7, against carboplatin toxicity. Our data demonstrate that the addition of MnP-based redox-active drugs may be used (via increasing excessively the oxidative stress of serous ovarian cancer cells) to improve cancer patients' chemotherapy outcomes, which develop resistance to platinum-based drugs.

A review of the therapeutic properties of dithiocarbamates

The persistence of infectious diseases that continue to plague the world, as well as the formation of harmful substances within the human body, such as free radicals and reactive oxygen species (ROS) have sparked new research. Thus, the need for innovative approaches for developing new or modification of existing therapeutic agents. The design of biologically important metal complexes of dithiocarbamates (DTCs) has been made possible by recent advancements in innovative research. Dithiocarbamates are reduced thiuram disulfides with excellent complexing capabilities and have various applications. They are potent and work in tandem with the core metal ions of coordinating compounds to produce synergistic effects. Dithiocarbamates have many uses, including as antidotes for metal poisoning, cisplatin or carboplatin toxicity, and clinical trials for cancer, Lyme disease, human immunodeficiency virus and antibiotics. They exert anti-oxidant effect in cells. The understanding of the mechanisms of action of this therapeutic agent is important in drug repurposing. This review highlights the protective and therapeutic properties of dithiocarbamate compounds in biological systems.

Ovarian toxicity of carboplatin and paclitaxel in mouse carriers of mutation in BRIP1 tumor suppressor gene

More than 10% of women diagnosed with breast cancer during reproductive age carry hereditary germline pathogenic variants in high-penetrance BRCA genes or in others genes involved in DNA repair mechanisms such as PALB2, BRIP or ATM. Anticancer treatments may have an additional negative impact on the ovarian reserve and subsequently on the fertility of young patients carrying such mutations. Recently, the combination of carboplatin and paclitaxel is being recommended to these BRCA-mutated patients as neoadjuvant therapy. However, the impact on the ovary is unknown. Here, we investigated their effect of on the ovarian reserve using mice carriers of BRCA1-interacting protein C-terminal helicase-1 (BRIP1) mutation that plays an important role in BRCA1-dependent DNA repair. Results revealed that the administration of carboplatin or paclitaxel did not affect the ovarian reserve although increased DNA double-strand breaks were observed with carboplatin alone. Co-administration of carboplatin and paclitaxel resulted in a significant reduction of the ovarian reserve leading to a lower IVF performance, and an activation of the PI3K-Pten pathway, irrespective of the genetic background. This study suggests that co-administration of carboplatin and paclitaxel induces cumulative ovarian damage and infertility but a heterozygote genetic predisposition for DNA damage related to BRCA1 gene function does not increase this risk.

Phase II study of gemcitabine, carboplatin and veliparib in multiple relapsed/refractory germ cell tumors (GCTs).

e17009 Background: GCTs represent a model for the cure of cancer. Nonetheless, a small proportion of patients develop disease recurrence. PARP is overexpressed in GCTs compared to normal testis and PARP overexpression is early event in GCTs development. Gemcitabine and carboplatin showed activity in refractory GCTs. This study aimed to determine the efficacy and toxicity of gemcitabine, carboplatin and PARP inhibitor, veliparib, in patients with multiple relapsed/refractory GCTs. Methods: Fifteen patients with multiple relapsed/refractory GCTs were enrolled in the phase II study from October 2016 to October 2020. All patients were pretreated with at least 2 cisplatin-based therapies (median 2, range 2 – 4); 3 tumors (20.0%) were absolutely refractory to cisplatin and 5 patients (33.3%) had visceral non-pulmonary metastases. Gemcitabine was administered at a dose 800mg/m2 day 1 and 8 every 3 weeks; carboplatin AUC = 4, day 1, every 3 weeks and veliparib 250mg bid day continuously. The primary end point was 12-months progression-free survival (PFS), if &lt; 8 patients experienced 12-months PFS, the treatment will be considered ineffective. Results: Median age was 31 years (range: 22 – 48 months). Median number of treatment cycles was 4 (range 2 – 8). During a median follow-up period of 9.2 months (range: 1.9 – 23.8), all (100%) patients experienced disease progression and 14 patients (93.3%) died. Twelve-months PFS was achieved in 1 (6.7%) patient. Median PFS was 3.1 months, 95%CI (2.2 – 3.9) and median OS was 10.5 months, 95% CI (8.9 – 11.1). Partial remission was observed in 4 (26.7%) and disease stabilization in 5 (33.3%) of patients. Favorable response (complete or partial remission with negative serum tumor markers) experienced 3 (20%) patients. Treatment was well tolerated, however, 12 (80%) of patients experienced grade 3/4 neutropenia, 9 (60%) anemia, 14 (93.3%) thrombocytopenia and 2 (13.3%) febrile neutropenia. Conclusions: This study failed to achieve its primary end point and our data suggest limited efficacy of gemcitabine, carboplatin and veliparib in multiple relapsed/refractory germ cell tumors. Clinical trial information: NCT02860819.

Comparisons of segment-specific toxicity of platinum-based agents and cadmium using S1, S2, and S3 cells derived from mouse kidney proximal tubules

Renal toxicants such as cisplatin and cadmium cause segment-specific damages in kidney proximal tubules. Recently, we established an in vitro experimental system for evaluating segment-specific toxicity and transport of chemicals using immortalized S1, S2, and S3 cells derived from the S1, S2, and S3 regions of mouse kidney proximal tubules. In the present study, we examined the toxicity and accumulation of cisplatin, carboplatin, oxaliplatin, and cadmium in S1, S2, and S3 cells. We found that not only cisplatin but also carboplatin and oxaliplatin exhibited higher lethal toxicity in S3 cells than in S1 and S2 cells. At sublethal doses, cisplatin showed delayed induction of Kim-1 and clusterin on days 3 and 6, which may reflect the latent renal toxicity of cisplatin in vivo. The high sensitivities of S3 cells to the platinum-based agents were not due to the high accumulation of Pt in S3 cells. Exposure to cadmium resulted in similar toxicity among these cells, suggesting that S3 cells were not sensitive to any renal toxicants. Thus, the utilization of S1, S2, and S3 cells may provide a useful tool for the in vitro evaluation of the proximal tubule segment-specific toxicity of chemicals.

Protective effect of chrysin, a flavonoid, on the genotoxic activity of carboplatin in mice

Carboplatin is amongst the most commonly used anticancer drugs for the management of several human malignancies. However, it has displayed genotoxic properties against normal cells. Evaluation of natural products for their protective effects against chemotherapeutic drug induced toxicity has been growing in recent years. A naturally occurring flavonoid, chrysin, has strong antioxidant abilities and protects against DNA impairment. This study used multiple assays to evaluate the levels of damage to DNA in normal cells and to examine any possible protective role of chrysin against such damage. Male BALB/c mice were administered chrysin orally in two doses of 20 and 40 mg/kg for 10 consecutive days and then a single injection of carboplatin [90 mg/kg body weight (b.w.)] was administered intraperitoneally to induce carboplatin toxicity. 24 h after the carboplatin injection, mice were sacrificed. DNA damage was evaluated using several genotoxicity tests (8-Hydroxydeoxy-guanosine marker, comet assay, micronucleus test, and chromosomal aberration assay) to identify diverse types of damage to the DNA. The results suggest that pretreatment with chrysin significantly decreased the level of DNA damage caused by carboplatin probably due to its potent antioxidant traits. Therefore, chrysin can be considered to be developed as a chemoprotective agent against chemotherapy associated side-effects.

Serum concentration and safety of intravenous drip versus subcutaneous administration of carboplatin in dogs

Carboplatin is used to treat certain cancers in dogs and cats and is routinely administered via intravenous drip (IVD). Subcutaneous (SC) administration has also been described. However, the toxicity, serum concentrations, and area under blood concentration-time curves (AUCs) of SC carboplatin are unknown. This study aimed to compare serum carboplatin concentrations in dogs after SC and IVD and to monitor any adverse events. In this crossover study, five dogs received SC or IV carboplatin (300 mg/m2). After a minimum of 3 weeks, each dog received the other treatment. No gross skin toxicity or abnormal clinical signs were observed in any of the dogs. Blood test abnormalities were detected in most dogs. Decreased neutrophil and platelet counts, and increased C-reactive protein (CRP) levels were found. There was no significant difference in the neutropenia, thrombocytopenia, and CRP scores between the groups. Systemic toxicities of SC carboplatin were comparable to those of IVD carboplatin. The time to maximum carboplatin concentration after SC was longer than that after IVD (P<0.001). SC carboplatin remained in the serum longer than IVD carboplatin (P=0.008). The AUC of SC was less than that of IVD (P=0.002). The AUC and time taken to reach the maximum concentration of SC carboplatin were lower than those of IVD carboplatin. This study suggests that SC carboplatin may be an efficacious option for the treatment of tumors in dogs, particularly where IVD administration is challenging.

Carboplatin delivery system based on poly(ethylene glycol) methyl ether–cholesterol modified soy lecithin liposomes

Liposomes are well studied and proved to have enormous potential for carboplatin delivery in cancer treatment. However, to achieve an ideal liposome system with less leakage and controlled release for an effective delivery of carboplatin (CPT) to tumor sites is still in progress. In this study, poly(ethylene glycol) methyl ether-cholesterol (mPEG-Chol) was prepared and used as a component, together with soy lecithin and cholesterol, to synthesize liposomes through thin film hydration method. The particle size distribution of obtained system of mPEG-Chol modified soy lecithin liposomes (mPEG-Chol-SLP) was then reduced by sonication, followed by extrusion. The properties of these nanoparticles including particle size, polydispersity index, zeta potential, and morphology were assessed by dynamic light scattering (DLS), zeta potential measurement, and transmission electron microscopy (TEM). Using dialysis method as the in vitro tests, the drug loading and releasing efficiency were calculated with pre-determined formulas. The cytotoxicity in the human breast cancer cell line (MCF-7) was evaluated through the cell proliferation assay WST-1. The results showed that CPT-loaded mPEG-Chol-SLP was spherical in shape with the average particle diameter and polydispersity index of 173.10 nm and 0.174, respectively. Moreover, the system was negatively charged, relatively colloidal stable, 70.49% for drug loading efficiency, and slowly released up to 48 h. In addition, the cytotoxicity data showed that mPEG-Chol-SLP was biocompatible nanocarrier and successfully reduced the toxicity of CPT. These results demonstrated that the obtained CPT-loaded mPEG-Chol-SLP reached one step closer to an ideal nanocarrier for CPT delivery.