Dose Of Cisplatin Research Articles

A comparative review of murine models of repeated low-dose cisplatin-induced chronic kidney disease.

This Review evaluates various mouse and rat models of chronic kidney disease (CKD) that result from repeated low-dose cisplatin (RLDC) treatment while also discussing ethical considerations on the topic. Cisplatin can cause nephrotoxicity, and high doses of cisplatin can cause acute kidney injury. The RLDC regimen has been used in the treatment of solid organ cancers and has shown efficacy in reducing the occurrence of acute kidney injury in patients. However, prolonged treatments may lead to CKD. Mouse and rat models that effectively replicate the pathological features of CKD are invaluable for studying the mechanisms of the disease and exploring potential therapeutic interventions. Whereas administration of a single higher dose in some RLDC models may lead to higher mortality rates, a single lower dose may not replicate the fibrotic characteristics of CKD. Here we gathered information on mouse and rat models of RLDC-induced CKD and analyzed the impact of different variables, such as animal age, cisplatin dosage and administration frequency, on success rates, mortality rate and weight loss. Among the different models, weekly intraperitoneal administration of 8 mg/kg or 9 mg/kg of cisplatin for a total of 4 weeks in 12-week-old male C57BL/6 mice showed the most similar clinical characteristics of CKD while adhering to ethical requirements. In this Review, we suggest the best timings for both drug intervention and observation based on the biological traits of the model. Furthermore, given the limited research available on RLDC-induced CKD rat models, it is urgent to focus on developing RLDC methods that can induce detailed characteristics of CKD in rats.

Effect of cisplatin/gold chitosan nanocomposite on oral squamous cell carcinoma and oral epithelial cells

BackgroundOral squamous cell carcinoma (OSCC) treatment represents a great challenge, since platinum-based therapeutic agents have deleterious effects on normal cells and tissues. Employing gold nanoparticles (AuNps) as carriers for cisplatin have proved effective in reducing cisplatin doses. Green synthesis of AuNps from eco-friendly agents like chitosan improves the AuNps’ biocompatibility and cytotoxicity. Thus, we synthesized a novel agent of cisplatin coupled to gold chitosan nanoparticles (Cis/AuCh nanocomposite) and examined its effect in addition to the effect of chitosan-reduced gold nanoparticles (AuCh Nps) on (HNO97) OSCC cell line and normal oral epithelial cells (OEC).ResultsUltraviolet–visible spectroscopic analysis, transmission electron microscope, X-ray diffraction, and Fourier transform infrared spectroscopy confirmed the successful synthesis of AuCh Nps and Cis/AuCh nanocomposite. The cytotoxicity assay showed that the IC50 doses of AuCh Nps and Cis/AuCh nanocomposite after 48 h were 12.5 μg/ml, and 6.2 μg/ml, respectively, on the HNO97 cell line. On the other hand, the IC50 doses were 40 μg/ml and 44.5 μg/ml on OEC, respectively. After treating both cell lines with the HNO97–IC50 doses, Cis/AuCh nanocomposite-treated HNO97 cell line revealed a significant rise in Caspase 3 immunohistochemical apoptotic index, besides a significant elevation in pro-apoptotic proteins and reduction in Bcl-2 compared to cisplatin. Conversely, opposite results were detected in AuCh Nps and Cis/AuCh nanocomposite-treated OEC. Flow cytometry results revealed S and G2/M shifts in HNO97 and OEC with more shift in the cisplatin-treated group than AuCh Nps and Cis/AuCh nanocomposite-treated groups in both cell lines. The expressions of the reactive oxygen species (ROS) markers; malondialdehyde and nitric oxide were the highest in Cis/AuCh nanocomposite-treated HNO97, while the reduced glutathione expression was the lowest. However, AuCh Nps and Cis/AuCh nanocomposite-treated groups did not display any significant changes in ROS markers expression from the untreated group in the OEC.ConclusionsAuCh NPs can be considered a good alternative way of cisplatin transportation for OSCC treatment. Cis/AuCh nanocomposite stimulates apoptosis, cell cycle arrest, and ROS production in oral cancer cells with less undesired effects on normal oral epithelial cells.

To Study Level of Gonadal Hormone in Cancer Patients Receiving Chemotherapy

Objectives: The objective of this study was to study the alteration in levels of testosterone, luteinising hormone (LH), follicle-stimulating hormone (FSH) and prolactin in male cancer patients’ post-chemotherapy who have been started on drugs causing grade III or more haematological toxicity requiring granulocyte colony-stimulating factor support. Materials and Methods: An open-labelled prospective single-centre study for the assessment of Gonadal dysfunction in male cancer patients on chemotherapy from August 2010 to October 2012. Results: Patients had a significant alteration in testosterone (23% n = 11), LH (52.08% n = 25), FSH (83.3% n = 40) and prolactin levels (22.92% n = 11) post-chemotherapy, which was statistically significant (P < 0.05). The high dose, as well as the low dose Cisplatin group, were associated with substantial gonadal dysfunction in testicular tumour patients. Hence, regimens using low-dose cisplatin at the cost of compromising the cure rate for the motive of preservation of fertility are not warranted. There was no statistically significant difference found in alteration in mean testosterone, mean LH or mean FSH Prolactin levels among cisplatin, cyclophosphamide or combined cisplatin and cyclophosphamide chemotherapy group, at least in the initial weeks of post-chemotherapy. Conclusion: There is a significant gonadal dysfunction in cancer patients receiving cytotoxic chemotherapy. Hence, increasing awareness to prevent, detect and treat expected long-term toxicities is crucial. Prechemotherapy cryopreservation of semen and assisted reproductive technologies are good options to describe the rate of involuntary infertility without affecting the survival of patients by decreasing doses of chemotherapy.

Hyaluronic acid modified metal-organic frameworks loading cisplatin achieve combined chemodynamic therapy and chemotherapy for lung cancer.

As one of the most commonly used chemotherapeutic agents in clinical practice, cisplatin is unable to selectively accumulate in tumor tissue due to its lack of targeting ability, leading to increased systemic toxicities. Additionally, the effectiveness of monotherapy is greatly limited. Therefore, the development of new cisplatin-based drug delivery systems is essential to improve the effectiveness of tumor treatment. In this study, an iron-based metal-organic framework (MOF) was synthesized to encapsulate cisplatin, and then coated with hyaluronic acid (HA) to create a MOF-based nanoplatform called MPt@HA NPs. This novel nanoplatform achieved the combination of chemodynamic therapy (CDT) with targeted chemotherapy for the treatment of lung cancer. The results showed that MPt@HA NPs have stronger cytotoxicity compared to conventional doses of cisplatin due to the generation of reactive oxygen species (ROS) through the Fenton reaction and DNA damage caused by cisplatin. Therefore, MPt@HA NPs effectively inhibit the tumor growth and prolong the median survival of tumor-bearing mice. Therefore, the MOF-based nanoplatform MPt@HA NPs may present a new option for multi-modal therapy of solid tumors.

Apoptosis induction and tumor growth suppression by hydroxyapatite nanoparticles–cisplatin combined treatment in Ehrlich solid carcinoma-bearing mice

BackgroundHydroxyapatite (HAP) resembles the components of biological hard tissue. Recent research has been interested in the biomedical application of HAP nanoparticles (HAP-NPs) in cancer treatment, HAP-NPs have high cytotoxic activity against cancerous cells, in addition, they are nontoxic to healthy normal cells, biocompatible, biodegradable, and have a high absorption rate within the tissue. Therefore, this study evaluated HAP-NPs' antitumoral activity in Ehrlich solid carcinoma (ESC)-bearing mice, in addition, we examined the anticancer efficacy of combined treatment of a common chemotherapeutic drug such as Cisplatin (CDDP) and HAP-NPs in ESC-bearing mice.MethodsForty female mice were inoculated with 200 µl of diluted ascites fluid containing approximately two million viable cancer cells in the mice's left thigh, after 14 days of inoculation, the mice were distributed into four groups: 10 mice in each. ESC group was administrated distilled water, the HAP-NPs group was treated orally with 100 mg/kg of hydroxyapatite nanoparticles, the CDDP group was administrated intraperitoneally with 5 mg/kg of Cisplatin, the HAP-NPs + CDDP group was treated with both doses of hydroxyapatite and cisplatin, the animal treatment was conducted for 20 days. Antitumor activity was assessed for two durations after 10 and 20 days. DNA damage assessment was performed using comet assay in ESC, in addition, we measured the expression of the following genes (P53, Bcl2, and Bax,) using quantitative real-time PCR, and the apoptotic-related proteins (P53 and Ki-67) using immunohistochemical analysis. A histopathological examination of ESC was performed.ResultsThe obtained data illustrated a promising anticancer activity of HAP-NPs, and the combined treatment of HAP-NPs and CDDP illustrated a higher anticancer efficacy. HAP-NPs, CDDP, and HAP-NPs + CDDP resulted in significant (P < 0.05) nucleic acid destruction, and significant (P < 0.05) overexpression of apoptotic-related genes (P53, Bax, and Bcl2) and proteins (Ki-67 and P53), causing the tumor bulk to be greatly reduced in HAP-NPs, CDDP, and HAP-NPs + CDDP (1100, 570, and 450 mm3), respectively, compared to ESC group was 2240 mm3.ConclusionHydroxyapatite nanoparticles can provoke DNA damage and regulate apoptosis, selectively eliminating tumor cells. The co-administration of HAP-NPs and CDDP resulted in a synergistic enhancement of cisplatin activity within the tumor tissue.

Lebanese Cannabis sativa L. extract protects from cisplatin-induced nephrotoxicity in mice by inhibiting podocytes apoptosis

BackgroundCisplatin is an anti-cancer drug used to treat a plethora of solid tumors. However, it is associated with dose dependent nephrotoxicity limiting its use as anticancer agent.ObjectiveThe current study aimed to investigate the nephroprotective effect of native Lebanese Cannabis sativa in both in vitro and in vivo mice model of cisplatin-induced nephrotoxicity.MethodsPodocytes cell viability was assessed using MTS assay with cisplatin (30µM) in presence or absence of Cannabis oil extract (COE) at 0.5, 1 and 2µg/ml for 24h. Acute renal injury was established in adult female C57BL/6 mice with 20mg/kg, i.p. single dose cisplatin. Mice were divided into control group (vehicle), COE group, cisplatin group and cisplatin plus COE (2.5, 5 and 20mg/kg, i.p.). Animal body weight, serum creatinine, blood urea nitrogen (BUN), and proteinuria were measured.ResultsCell viability assay and western blot analysis revealed that COE prevented apoptosis induced by cisplatin in cultured immortalized rat podocytes. In addition, in vitro scratch assay demonstrated the ability of COE to promote and restore the migratory capacity of podocytes in cisplatin-treated cells.Interestingly, COE treatment improved urinary and serum parameters characterized by a significant decrease in serum creatinine, urea, and proteinuria at various COE doses. Western blot analysis showed that COE inhibited COX-2 protein induction as well as apoptosis marker production (Bax/Bcl2 ratio) in cisplatin-treated mice when compared to mice treated with cisplatin alone.ConclusionCollectively, the aforementioned findings indicate that COE could be a promising approach to protect against cisplatin-induced nephrotoxicity.

Optimization of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin therapy for Japanese patients with urothelial carcinoma.

Dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) regimen has been established as a systemic chemotherapy for patients with urothelial carcinoma. However, it is rarely used in Japan owing to the challenges associated with managing the related adverse events. This study aimed to optimize the dd-MVAC protocol for Japanese patients. Criteria were developed to adjust the doses of anticancer drugs used in dd-MVAC. In this regimen, the initial cycle of methotrexate and cisplatin was administered at 75% of the full dose. Patients who did not experience significant toxicities during the first cycle subsequently received the full dose starting from the second cycle. Additionally, the doses of methotrexate and cisplatin were adjusted according to the Cockcroft-Gault creatinine clearance. Based on these criteria, patients with urothelial carcinoma underwent dd-MVAC between August 2018 and May 2023, and all patients were scheduled to undergo six cycles. A total of 86 patients received dd-MVAC, with 36, 15, and 35 patients receiving it as neoadjuvant, adjuvant, and salvage chemotherapy, respectively. Fifty-nine patients (68.6%) completed the six scheduled cycles. Grade≥3 toxicities of Common Terminology Criteria for Adverse Events were observed in 76 (88.4%) patients; however, most were manageable. In the neoadjuvant cohort, the pathological complete response rate was 52.2% among patients with clinical N0 lower tract urothelial carcinoma. High levels of alkaline phosphatase at the initiation of treatment were correlated with failure to complete six cycles of dd-MVAC. Adjusting the dd-MVAC regimen based on renal function and significant adverse events may result in a high completion rate of scheduled treatments in Japanese patients with urothelial carcinoma.

Neoadjuvant Accelerated Methotrexate, Vinblastine, Doxorubicin, and Cisplatin Chemotherapy for Muscle-Invasive Urothelial Cancer: Large, Single-Center Analysis of Consecutive Patients' Data.

Background/Objectives: Bladder cancer is a significant clinical problem with approximately 500,000 new cases worldwide annually. In approximately 25% of cases, disease is diagnosed at a stage of invasion of the muscle layer of the bladder. The current standard approach in this disease is preoperative chemotherapy followed by radical cystectomy. Dose-dense MVAC (ddMVAC), a two-day chemotherapy regimen, is the reference treatment protocol in this setting. The presented study evaluated the effectiveness and safety of accelerated MVAC (aMVAC) chemotherapy-a one-day regimen given before the resection of the bladder due to muscle-invasive disease. Methods: A retrospective analysis included 119 consecutive patients diagnosed with urothelial muscle-invasive bladder cancer (MIBC) who underwent preoperative chemotherapy with the aMVAC regimen. The planned treatment included 4-6 cycles of preoperative chemotherapy. The analysis of the degree of histopathological response to treatment was based on the three-grade TRG (tumor regression grade) classification. Results: A complete pathological response (TRG1) was observed in 44 patients (36.7%), and a major pathologic response (<ypT2) was achieved in 58 patients (48.7%). A reduction in the cisplatin dose was associated with a statistically significant decrease in the chance of achieving complete pathologic responses (46.1% vs. 10%, RR for TRG1 = 0.69, p = 0.00118). Patients who received at least 4 cycles (compared to ≤3 cycles) of neoadjuvant chemotherapy had a significantly higher chance of achieving a pathological response (partial or complete) to treatment (78.1% vs. 52.2%, RR 0.68, p = 0.0374). Administration of at least five cycles of chemotherapy was associated (compared to four cycles) with a significantly higher likelihood of achieving a complete pathological response (63.2% vs. 33.8%, RR = 1.71, p = 0.0221). The vast majority of adverse events were in grades 1 and 2, according to CTCAE version 5.0. Only five patients experienced grade 3-4 toxicities. The most common adverse event was anemia, which occurred in 66.3% of patients. Conclusions: Our real-world data analysis confirms the activity, safety, and feasibility of the aMVAC regimen as neoadjuvant chemotherapy in patients with urothelial MIBC.

Evaluation of the impact of Momordica Charantia on the testis of cisplatin-treated albino rats: Biochemical, histopathological, and ultrastructural study.

Cisplatin is an antineoplastic drug that exhibits toxicity dependent on dosage and has adverse reproductive effects. Momordica charantia (Bitter melon) is a natural vegetable plant; its active ingredients possess antioxidant, apoptotic, antiproliferative, hypoglycemic, and other therapeutic properties. This study evaluates the effect of the administration of bitter melon extract, cisplatin, and cisplatin/bitter melon cotreatment on liver and kidney functions, serum and testicular oxidative status, testis histology, and sperm parameters. Adult male Wistar rats were randomly divided into four groups: Group I (Control) received normal saline, Group II received oral bitter melon extract (300 mg/kg), Group III received cisplatin (2.5 mg/kg), and Group IV received the same doses of cisplatin and bitter melon, for six successive weeks, daily. Our results showed that bitter melon extract stimulates antioxidant enzymes and has anti-lipid peroxidation properties through the significantly increased plasma levels of glutathione and significantly decreased testicular malondialdehyde. The cisplatin-treated group showed oxidative stress indicated by the significant decrease of catalase, glutathione, and superoxide dismutase levels and a significant increase in malondialdehyde levels in both serum and testis compared with the control group. In the cisplatin/bitter melon-cotreated group, there was a significant increase in superoxide dismutase and a significant decrease in malondialdehyde in both serum and testis compared with cisplatin-treated rats. The bitter melon alone or with cisplatin cotreatment resulted in reduced gonadosomatic index, sperm count, motility, and viability. These results were confirmed by histopathological examinations, apoptosis assay using flow cytometry, and immunohistochemical staining for proliferating cell nuclear antigen. In conclusion, the administration of bitter melon extract alone or in combination with cisplatin led to testicular structure disturbances and showed an anti-spermatogenic effect. These findings are likely due to a combination of inhibited cellular proliferation, increased cell death, minor decrease in testosterone levels, and localized oxidative stress that outweigh the antioxidant benefits of bitter melon extract.

Optimizing the cumulative cisplatin dose for concurrent chemoradiotherapy beneficiaries among elderly nasopharyngeal carcinoma patients: a real world study

This study aimed to find a safe and effective cumulative cisplatin dose (CCD) for concurrent chemoradiotherapy (CCRT) beneficiaries among elderly nasopharyngeal carcinoma (NPC) patients. A total of 765 elderly (≥ 60 years old) NPC patients treated with cisplatin-based CCRT and IMRT-alone from 2007 to 2018 were included in this study. RPA-generated risk stratification was used to identify CCRT beneficiaries. CCDs were divided into CCD = 0, 0 < CCD ≤ 80, 80 < CCD ≤ 160 and 160 < CCD ≤ 300 mg/m2 and their OS and nephrotoxicity compared. Pre-treatment plasma EBV DNA and clinical stage were incorporated into the RPA model to perform risk stratification. All patients were classified into either a high-risk group (n = 158, Stage IV), an intermediate-risk group (n = 193, EBV DNA > 2000 copy/mL & Stage I, II, III) or a low-risk group (n = 414, EBV DNA ≤ 2000 copy/mL & Stage I, II, III). The 5 year OS of CCRT vs. IMRT alone in the high-, intermediate- and low-risk groups after balancing covariate bias were 60.1 vs 46.6% (p = 0.02), 77.8 vs 64.6% (p = 0.03) and 86.2 vs 85.0% (p = 0.81), respectively. The 5 year OS of patients receiving CCD = 0, 0 < CCD ≤ 80, 80 < CCD ≤ 160 and 160 < CCD ≤ 300 mg/m2 after balancing covariate bias in the high-risk group were 45.2, 48.9, 73.4 and 58.3% (p = 0.029), in the intermediate-risk group they were 64.6, 65.2, 76.8 and 83.6% (p = 0.038), and in the low-risk group they were 85.0, 68.1, 84.8 and 94.0% (p = 0.029), respectively. In the low-risk group, the 5 year OS of Stage III patients receiving CCD = 0, 0 < CCD ≤ 80, 80 < CCD ≤ 160 and 160 < CCD ≤ 300 mg/m2 were 83.5, 76.9, 85.5 and 95.5% (p = 0.044), respectively. No Grade 3–4 nephrotoxicity occurred. Therefore, in our study, Stage I, II, & EBV DNA > 2000copy/ml and Stage III, IV elderly NPC patients may be CCRT beneficiaries. 80 < CCD ≤ 300 mg/m2 is recommended for the high-risk (Stage IV) group, and 160 < CCD ≤ 300 mg/m2 for the intermediate-risk (Stage I, II, III & EBV DNA > 2000copy/ml) and low-risk (Stage III & EBV DNA ≤ 2000 copy/ml) groups. No grade 3–4 nephrotoxicity occurred in any of the CCD groups.

Sub-toxic cisplatin concentrations induce extensive chromosomal, nuclear and nucleolar abnormalities associated with high malignancy before acquired resistance develops: Implications for clinical caution.

This study investigates the impact of sub-toxic cisplatin levels on nuclear and nucleolar abnormalities and chromosome instability in HeLa cells since our current knowledge of cisplatin effects on these parameters is based on studies with high concentrations of cisplatin. HeLa cells were exposed to gradually increasing sub-toxic doses of cisplatin (0.01 to 0.2 μg/ml). Cells treated with 0.1 and 0.2 μg/ml, termed HeLaC0.1 and HeLaC0.2, were not cisplatin-resistant, only exhibiting a slightly reduced viability, and were termed "cisplatin-sensitized cells." Giemsa and silver staining were used to detect nuclear and nucleolar abnormalities and chromosomal alterations. Notable abnormalities were observed in HeLaC0.1 and HeLaC0.2 cells after treatment with sub-toxic concentrations of cisplatin: nuclei showed abnormal shapes, blebs, micronuclei, fragmentation, pulverization, and multinucleation; nucleoli exhibited irregular shapes and increased numbers; anaphase cells showed more nucleolar organizing regions. Abnormal chromosome segregation, heightened aneuploidy (81-140 chromosomes), polyploidy, double minutes, dicentrics, chromatid exchanges, chromatid separations, pulverization, and chromosome markers were prominently noted. These abnormalities were intensified in cells pre-sensitized to 0.02 or 0.08 μg/ml cisplatin for seven days, then exposed to 0.03 or 0.1 μg/ml cisplatin for 24 hours, and finally cultured in cisplatin-free medium for 24 hours before chromosome analysis. HeLa cells subjected to increasing concentrations of sub-toxic cisplatin exhibited large-scale, multiple-type abnormalities in nuclei, nucleoli, chromosomes, and chromosomal numbers, indicating genetic/chromosomal instability associated with high malignancy, before the development of cisplatin resistance. These results suggest that low doses of cisplatin administration in the clinical setting may promote malignancy and caution should be used with this type of treatment.

Pharmacokinetics of cisplatin in the systemic versus hyperthermic intrathoracic or intraperitoneal chemotherapy

ObjectiveTo compare the pharmacokinetics and adverse effects of cisplatin administered via intravenous infusion for systemic chemotherapy (SC) versus injection into the perfusate during hyperthermic intrathoracic chemotherapy (HITHOC) or hyperthermic intraperitoneal chemotherapy (HIPEC).MethodsTotal 60 patients who received SC, HITHOC, or HIPEC in the Department of Oncology, Tangdu Hospital, were enrolled into this study. After administering same dose of cisplatin (40 mg) via either intravenous infusion (SC group) or injection into the perfusate during the HITHOC or HIPEC procedure, concentration of cisplatin in the plasma as well as in the hyperthermic perfusate at various time points was quantified by HPLC analysis. The area under the plasma or perfusate concentration–time curve over the last 24h dosing interval (AUC0–24h), mean residence time over the 24 h (MRT0–24h), terminal elimination half-life (t1/2z), time to peak concentration (Tmax), apparent clearance (Clz/F), and peak concentration (Cmax) in the perfusate and plasma were compared.ResultsIn the perfusate, the AUC0–24h (64.32 ± 27.12 µg/mL·h) and Cmax (21.62 ± 5.88 µg/mL) were significantly higher in the HITHOC group compared to that in the HIPEC group (31.68 ± 13.29 µg/mL·h and 16.96 ± 5.54 µg/mL, respectively, p ≤ 0.01). In contrast, MRT0–∞, t1/2z, and Clz/F were significantly lower in the HITHOC group compared to that in the HIPEC group (p < 0.01). In the plasma, average AUC0–24h and Cmax of the HITHOC group were 2.57 ± 0.55 µg/mL·h and 0.26 ± 0.08 µg/mL, respectively, which were significantly lower than that of systemic chemotherapy (SC) group (3.26 ± 0.56 µg/mL·h and 0.69 ± 0.14 µg/mL, respectively, p < 0.01), but no difference compared to that of HIPEC group (3.02 ± 0.52 µg/mL·h and 0.40 ± 0.15 µg/mL, respectively, p > 0.05). In contrast, MRT0-24h and Tmax in the plasma of HITHOC group were significantly longer compared to that of SC group (p < 0.05), but no significant difference compared to that of HIPEC group (p > 0.05). Absolute bioavailability of cisplatin in the thoracic (HITHOC group) and abdominal (HIPEC group) cavities was 20 and 10 times higher than that in the blood administered intravenously (SC group), respectively. There was no significant difference in the incidence of adverse events among the three groups (p < 0.05).ConclusionThe current study demonstrated that, in the perfusate, AUC0–24h and Cmax of cisplatin was significantly higher in the group of HITHOC compared to that of HIPEC, and that, in the plasma, AUC0–24h and Cmax of cisplatin was lower in the group of HITHOC compared to that of HIPEC or SC group. This study provided pharmacokinetic evidence to further support the concept that topical application of chemotherapeutic drug through minimally invasive HITHOC or HIPEC may enhance local exposure compared to systemic chemotherapy for the patients with malignant pleural effusion or ascites.

Urine Periostin Level and Renal Function in Malignancy Patients Treated with High-Dose Cisplatine

Cisplatin has been used extensively as a cancer treatment. Nephrotoxicity, which is assessed by blood urea levels, blood creatinine, and estimated glomerular filtration rate (eGFR), is caused by cisplatin metabolites that build up in the kidneys. Because of these indicators' numerous flaws, optimal biological markers are required. One of the key mediators of inflammatory processes, such as kidney fibrosis and inflammation, is periostin. In cancer patients undergoing high-dose cisplatin therapy, the purpose of this study is to ascertain how urine periostin changes and how it relates to kidney function. This cross-sectional study was carried out at the National Center General Hospital of Cipto Mangunkusumo's medical hematology-oncology outer clinic and medical hematology-oncology ward on the eighth floor starting in November 2019 and ending when the minimum sample was obtained through consecutive sampling. Data was analyzed by IBM SPSS Statistics for Windows version 23.0 based on the research objective. Of the 37 responders, 70.3% were men, 29.7% were between the ages of 41 and 50, 78.4% were married, 59.5% had completed high school, 37.8% were employed, 59.5% had NPC, and 64.9% had a Karnofsky score of 80. Between before and one week following chemotherapy II, the respondents' blood creatinine and urea levels rose. The eGFR value has also decreased. Periostin levels, on the other hand, tended to rise one week following treatment III after declining during chemotherapy I and II (p value&gt;0.05). Urine periostin levels and other kidney function indicators did not significantly correlate (p&gt;0.05), according to the correlation test, and several domains had negative directions. The correlation coefficient values were modest (r = 0.017-0.254). There is a changing of urine periostin level of malignant patients receiving high dose cisplatin therapy which increase after the third chemotherapy. No significant correlation was found between periostin levels and kidney function in malignant patients with high-dose cisplatin therapy.

β-Arbutin and cisplatin: A combined approach to modulating apoptosis, cell viability, and migration in bladder cancer cells

One of the preferred treatments for bladder cancer, one of the most common cancers worldwide, is cisplatin-based chemotherapy. Since most tumor cells show cisplatin resistance, it is very important to discover new agents without adverse side effects. β-arbutin, a hydroquinone-β-D-glucopyranoside, has biological properties such as antioxidant, antimicrobial, anti-inflammatory, and anticancer, and is a phytochemical widely used as a skin whitener. In this study, β-arbutin was purified from the animal feed plant Onobrychis buhseana Boiss. (sainfoin). The study aimed to investigate the combined effects of cisplatin, a clinically used chemotherapeutic agent, and β-arbutin on HT-1376 bladder cancer cells for apoptosis, cell viability, and migration. In the study, after HT-1376 bladder cancer cells were cultured, optimum β-arbutin and cisplatin doses were determined on HT-1376 cells using the WST-1 test. To determine the apoptotic and migratory effects, flow cytometry and wound healing assays were performed. In HT-1376 cells, β-Arbutin led to greater apoptotoic and migratory effects when used alone and combined with Cisplatin (p < 0.0001 for apoptotic and migratory effects treated with β-Arbutin alone, p < 0.0001 for apoptotic and migratory effects when combined with Cisplatin). As a result, it can be suggested that β-arbutin may be a good drug candidate for treating bladder cancer.

Targeting autophagy in HCC treatment: exploiting the CD147 internalization pathway

Background/AimsChemotherapy resistance in liver cancer is a major clinical issue, with CD147 playing a vital role in this process. However, the specific mechanisms underlying these processes remain largely unknown. This study investigates how CD147 internalization leads to cytoprotective autophagy, contributing to chemotherapy resistance in hepatocellular carcinoma (HCC).MethodsUtilizing bioinformatics methods for KEGG pathways enrichment and screening key molecules associated with chemotherapy resistance through analyses of GEO and TCGA databases. An overexpression/knockdown system was used to study how CD147 internalization leads to autophagy in vitro and in vivo. The process was observed using microscopes, and molecular interactions and autophagy flux were analyzed. Analyzing the internalization of CD147 intracellular domains and the interaction with G3BP1 in clinical chemotherapy recurrence HCC tissues by immunohistochemistry, tissue immunofluorescence, and mass spectrometry. A tumor xenograft mice model was used to study cytoprotective autophagy induced by CD147 and test the effectiveness of combining cisplatin with an autophagy inhibitor in nude mice models.ResultsIn our study, we identified the tumor-associated membrane protein CD147, which implicated in chemoresistance lysosome pathways, by evaluating its protein degree value and betweenness centrality using Cytoscape. Our findings revealed that CD147 undergoes internalization and interacts with G3BP1 following treatment with cisplatin and methyl-β-cyclodextrin, forming a complex that is transported to lysosomes via Rab7A. Notably, higher doses of cisplatin enhanced CD147-mediated lysosomal transport while concurrently inhibiting SG assembly. The CD147-G3BP1 complex additionally inhibits mTOR activity, promoting autophagy and augmenting chemoresistance in hepatoma cells. In vivo studies investigations and analyses of clinical samples revealed that elevated internalization of CD147 is associated with chemotherapy recurrence in liver cancer and the maintenance of stem cells. Mice experiments found that the combined administration of cisplatin and hydroxychloroquine enhanced the efficacy of treatment.ConclusionsThis study reveals that CD147 internalization and CD147-G3BP1 complex translocation to lysosomes induce cytoprotective autophagy, reducing chemotherapy sensitivity by suppressing mTOR activity. It is also shown that chemotherapy drugs combined with autophagy inhibitors can improve the therapeutic effect of cancer, providing new insights into potential targeted therapeutic approaches in treating HCC.

Phase I clinical trial testing the dose escalation and expansion of Pressurized IntraThoracic Hyperthermic Aerosol Cisplatin administration (PITHAC) for the management of pleural carcinosis.

Pleural carcinosis originates from various cancers. Its management consists in systemic therapies combined to dyspnea relief procedures. Prior studies have tested hyperthermic intrathoracic chemotherapy to treat pleural carcinosis with interesting patient survival results. However, these approaches were limited by local toxicity. Pre-clinical data have shown that hyperthermia combined to local pleural chemotherapy increased the immune response against tumors. Recently, pressurized intraperitoneal aerosol chemotherapies (PIPAC) showed improved cytostatic penetration in abdominal carcinosis with a 10-fold-lower chemotherapy dose and minimal side-effects. This approach was also tested in limited numbers of patients with pleural carcinosis but never combined with hyperthermia. Pressurized IntraThoracic Hyperthermic Aerosol Cisplatin (PITHAC) is an open-label dose-escalation phase I trial. Patients with pleural carcinosis, eligible for the surgical management of their pleural effusion can be enrolled. Cisplatin (7.5-12-5-35-70 mg/m2) heated at 39±1 °C is delivered into the thoracic cavity before the surgical effusion management. Initially, the study consists in a dose escalation of the four different cisplatin doses. The primary endpoint is the maximal tolerated dose of cisplatin administered by PITHAC. The secondary and translational endpoints are adverse events and the immune response directed against cancer following PITHAC. There is then an expansion phase at the recommended cisplatin dose on an additional 15 patients with identical outcomes. Pressurized intrathoracic delivery of chemotherapy under hyperthermic conditions was never tested so far. We plan to determine the safety of such an approach in patients managed for pleural carcinosis. If proven safe, PITHAC could be combined with systemic immunotherapies for the management of cancer. ClinicalTrials.gov Identifier: NCT06281860.

Predicting cisplatin tolerability in older adults with head and neck cancer - Insights for improved chemoradiation outcomes.

Cumulative cisplatin doses of ≥ 200 mg/m2 improve survival in adults with head-and-neck squamous cell carcinoma (HNSCC) undergoing chemoradiation, but many older adults with HNSCC cannot receive this prognostically relevant dose due to toxicities. This study aims to develop predictive models to assess the likelihood of older adults with HNSCC receiving ≥ 200 mg/m2 cisplatin during chemoradiation. 366 patients from the SENIOR database, an international cohort of adults ≥ 65 years with HNSCC, received definitive chemoradiation with single-agent cisplatin and were analyzed. A Generalized Linear Model (GLM), Support Vector Machine (SVM), and Random Forest Model (RFM) were trained and compared for their performance in predicting a cumulative cisplatin dose of ≥ 200 mg/m2. 195 (53 %) patients achieved a cumulative cisplatin dose of ≥ 200 mg/m2. In the GLM, laryngeal carcinoma (β = 1.37, p = 0.01), tumoral p16 positivity (β = 0.69, p = 0.04), higher hemoglobin levels (β = 0.26, p = 0.002), elevated C-reactive protein (CRP) concentration (β = 0.02, p = 0.003), and increased estimated glomerular filtration rate (eGFR) (β = 0.02, p = 0.008) were associated with a higher probability of reaching ≥ 200 mg/m2 cisplatin. Hemoglobin, CRP, eGFR, and p16 status constituted the most important features in the SVM and RFM. AUC values for the GLM, SVM, and RFM were 0.70 (95 % CI, 0.67-0.73), 0.71 (95 % CI, 0.68-0.73), and 0.73 (95 % CI, 0.71-0.75), respectively. We developed predictive models to support clinicians in identifying older adults with HNSCC capable of tolerating ≥ 200 mg/m2 cumulative cisplatin during chemoradiation. Once validated, these models could improve personalized treatments and enhance shared decision-making in older adults with HNSCC.

Magnesium Imbalance before and during Concomitant Chemoradiation in Cervical Cancer Patients: A Prospective Interventional Study

Introduction: Cervical cancer is a major health concern, especially in developing countries. It is the second most common cancer among women in India, largely due to limited access to advanced screening and Human Papilloma Virus (HPV) vaccination. Despite significant advancements in cervical cancer prevention and treatment, the disease remains a major health burden, particularly in low-resource settings. Magnesium (Mg), an essential mineral involved in immune function, inflammation and Deoxyribonucleic Acid (DNA) repair, has been linked to various cancers, including colorectal and breast cancers, but its role in cervical carcinoma is underexplored. Aim: To investigate the association between magnesium levels and cervical carcinoma and to explore the association of hypomagnesemia with concomitant chemotherapy using cisplatin during chemoradiation. Materials and Methods: This was a hospital-based prospective interventional study, in which a total of 322 subjects were included in the study, of which 161 were healthy controls and 161 were diagnosed cases of cervical carcinoma. The magnesium levels were estimated before and after treatment using the Xylidyl blue complexing method on an autoanalyser. The data were compared between the two groups using appropriate statistical analysis with Statistical Package for the Social Sciences (SPSS) software version 20.0. Results: The mean magnesium levels were 2.08±0.24 mg/ dL in controls and 1.56±1.02 mg/dL in cancer patients (p-value&lt;0.001). Mean serum levels decreased in cancer patients postchemoradiation to 0.74±0.39 mg/dL. During concomitant chemoradiation with cisplatin, hypomagnesemia was observed as grade I in 62 (38.5%), grade II in 25 (15.5%), grade III in 12 (7.5%) and grade IV in 36 (22.4%). A significant correlation was found between hypomagnesemia and hyponatremia, hypokalemia and cumulative cisplatin dose toxicity. Conclusion: The study demonstrated a high prevalence of hypomagnesemia in cervical cancer patients, especially those undergoing cisplatin-based chemotherapy, with levels declining further during treatment. Routine magnesium monitoring and proactive management are essential to prevent complications and improve outcomes.

Development of a robust predictive model for neutropenia after esophageal cancer chemotherapy using GLMMLasso.

Neutropenia can easily progress to febrile neutropenia and is a risk factor for life-threatening infections. Predicting and preventing severe neutropenia can help avoid such infections. This study aimed to develop an optimal model using advanced statistical methods to predict neutropenia after 5-fluorouracil/cisplatin chemotherapy for esophageal cancer and to create a nomogram for clinical application. Patients who received 5-fluorouracil/cisplatin chemotherapy at Chiba University Hospital, Japan, between January 2011 and March 2021 were included. Clinical parameters were measured before the first, second, and third chemotherapy cycles and were randomly divided by patient into a training cohort (60%) and test cohort (40%). The predictive performance of Logistic, Stepwise, Lasso, and GLMMLasso models was evaluated by the area under the receiver-operating characteristic curve (AUC). A nomogram based on GLMMLasso was developed, and the accuracy of probabilistic predictions was evaluated by the Brier score. The AUC for the first cycle of chemotherapy was 0.781 for GLMMLasso, 0.751 for Lasso, 0.697 for Stepwise, and 0.669 for Logistic. The respective AUCs for GLMMLasso in the second and third cycles were 0.704 and 0.900. The variables selected by GLMMLasso were cisplatin dose, 5-fluorouracil dose, use of leucovorin, sex, cholinesterase, and platelets. A nomogram predicting neutropenia was created based on each regression coefficient. The Brier score for the nomogram was 0.139. We have developed a predictive model with high performance using GLMMLasso. Our nomogram can represent risk visually and may facilitate the assessment of the probability of chemotherapy-induced severe neutropenia in clinical practice.

Malleatin A and B: New Premyrsine-Type Diterpenes from &lt;i&gt;Euphorbia malleata&lt;/i&gt; with Cytotoxic Effects Against A2780 Wild and A2780 R-CIS Ovarian Cancer Cell Lines in Mono or Combination Treatment with Cisplatin

Background: This study focused on macrocyclic diterpenes derived from Euphorbia, particularly myrsinanes, and their potential in cytotoxic and combination treatments for resistant cancer cells. We examine premyrsinanes isolated from Euphorbia malleata and explore their cytotoxic properties. Methods: Euphorbia malleata was collected from Taragh-Roud, Natanz, Iran. The semi-polar chloroform/acetone extract was chromatographed and fractionated using a large silica column. Fractions containing diterpene resonances were selected based on 1H-NMR spectra and were further subjected to smaller silica or Sephadex columns, followed by a recycling HPLC system. The isolated compounds were identified through 1D and 2D-NMR experiments and mass spectrometry. The cytotoxicity of the isolated compounds was assessed using the MTT assay against A2780 wild and A2780 cisplatin-resistant (R-CIS) cells, both in mono and combination treatments with cisplatin. Results: Using a Waters 616 HPLC pump and a YMC prep silica column, we successfully isolated two new premyrsinane diterpenes (Malleatin A and Malleatin B) alongside two known compounds (beta-sitosterol and loliolide). Malleatin A exhibited cytotoxicity against A2780 wild and A2780 R-CIS cells, with an IC50 range of 50 - 65 μM in the MTT assay. While cisplatin demonstrated significant cytotoxic effects on the A2780 wild cell line, it was ineffective against the A2780 R-CIS cells due to their resistance. However, the combination therapy of Malleatin A and cisplatin exhibited a synergistic effect, significantly increasing the mortality rate of the resistant cells compared to monotherapy. The Combination Index (CI) of 0.58 indicates effective synergy, and the Dose Reduction Index (DRI) of 3.65 suggests a favorable reduction in the dosage of cisplatin needed, potentially reducing its associated side effects.