Data mining and analysis of oxaliplatin-related adverse events of nervous system / 中国药房

OBJECTIVE To provide reference for clinically safe drug use by mining oxaliplatin-related adverse drug events （ADE） of the nervous system. METHODS Oxaliplatin-related neurologic ADE data reported by the FDA adverse event reporting system （FAERS） between January 1st， 2004 and December 31st， 2022 were collected. The reporting odds ratio and proportional reporting ratio were used for data mining. The data were classified statistically by using systematic organ classification， high-level group term （HLGT） and preferred term （PT） in the MedDRA （version 26.0）. RESULTS A total of 7 266 cases of oxaliplatin- related ADE， which were classified as various neurological， were retrieved， and 100 PT were identified. Of these， fifty-seven PT were unspecified adverse reaction signals in the manual. Among these reports， males （46.85%） were more than females （42.98%）， the age of patients was 45-＜75 years （65.22%）， the number of reports was highest in Italy （16.32%）， and the severe type was hospitalization or prolonged hospitalization （38.16%）. The top 5 PT reports in the list of case number were peripheral neuropathy， paresthesia， neurotoxicity， loss of consciousness and dysarthria. The top 5 PT reports in the list of signal intensities were cold- induced paresthesia， neuromuscular rigidity， acute polyneuropathy， neuronal neuropathy， axonal and demyelinating polyneuropathy. A total of 13 HLGT were involved， with neurological diseases （not classified separately） having the highest number of signals （29）. CONCLUSIONS When using oxaliplatin in clinical practice， it is not only necessary to monitor the high incidence of acute and chronic peripheral neuropathy， but also to pay attention to the patient’s consciousness state and neurological symptoms. We should pay attention to the rare types of adverse reactions， such as guillain-barre syndrome， Lhermitte sign， posterior reversible encephalopathy syndrome， and hyperammoniacal encephalopathy， so as to ensure the safety of medication.

Attenuation and synergism of Hugan buzure recipe combined with oxaliplatin on hepatocellular carcinoma tumor bearing nude mice and its mechanism / 中国药房

OBJECTIVE To investigate the attenuation and synergism of Hugan buzure recipe （HBR） combined with oxaliplatin on hepatocellular carcinoma tumor bearing nude mice and its mechanism. METHODS Eight nude mice were selected from 40 nude mice as the blank group （normal saline）， and the remaining nude mice were inoculated with hepatoma cells Huh7 to establish the tumor-bearing model. The 32 modeled nude mice were randomly allocated to four groups： model group （normal saline， ig）， HBR group （0.69 g/kg， ig）， oxaliplatin group （10 mg/kg， ip）， and combination group （intraperitoneal injection of 0.69 g/kg HBR+intragastric administration of 10 mg/kg oxaliplatin）， with 8 mice in each group. Administer drug/normal saline once a day for 32 consecutive days； administer subcutaneous injection once every 7 days for a total of 5 times. During the experiment， the general condition of nude mice in each group was observed， and the tumor volume was measured every 4 days. On the 30th day of administration， the thermal stimulation paw withdrawal latency of nude mice in each group were detected. The tumor inhibition rate， spleen coefficient， the number of red blood cells， white blood cells and platelets in the whole blood of nude mice in each group， and the content of aspartate aminotransferase （AST） and creatinine in serum were detected after the end of administration. HE staining was used to observe the pathological changes in tumor tissues in nude mice in each group. The expression of microtubule-associated protein 1 light chain 3 （LC3），selective autophagy adaptor protein p62， B-cell lymphoma-2 （Bcl-2）， Bcl-2 associated X protein （Bax）， and Caspase-3 protein in tumor tissues. RESULT Compared with the model group， the tumor volume， tumor weight， white blood cells，red blood cells in the whole blood and spleen coefficients of nude mice in the oxaliplatin group were significantly decreased （P＜0.01）； the thermal stimulation paw withdrawal latency， AST and creatinine in serum were significantly increased （P＜0.05 or P＜0.01）. Compared with the oxaliplatin group， the tumor volume and tumor weight of nude mice in the combination group were significantly decreased （P＜0.01）； the white blood cells， red blood cells and platelets in the whole blood and spleen coefficients of nude mice were significantly increased （P＜0.05 or P＜0.01）； the thermal stimulation paw withdrawal latency， AST and creatinine in serum were significantly decreased （P＜0.01）； the expression levels of LC3， Bax and Caspase-3 proteins in tumor tissues of nude mice were significantly increased （P＜0.01）， and the expression levels of p62 and Bcl-2 proteins were significantly decreased （P＜0.01）. CONCLUSIONS HBR enhances the tumor inhibition rate of oxaliplatin by inducing apoptosis and autophagy， and can alleviate the peripheral neurotoxicity， hematological toxicity， hepatorenal toxicity， and immune organ toxicity caused by oxaliplatin in nude mice.

Research advances in hepatic sinusoidal obstruction syndrome / 临床肝胆病杂志

Hepatic sinusoidal obstruction syndrome （HSOS）， also known as hepatic veno-occlusive disease， is hepatic vascular disease of hepatic sinusoidal obstruction and hepatic venular occlusion and fibrosis due to various causes. This article systematically elaborates on the research advances in HSOS from the aspects of understanding and naming， etiology and pathogenesis， clinical manifestation， diagnosis and differential diagnosis， prevention， and treatment. HSOS can occur in patients receiving bone marrow hematopoietic stem cell transplantation， radiotherapy/chemotherapy， and medication containing pyrrolidine alkaloids， and the common clinical manifestations of HSOS include abdominal distension， distending pain in the liver area， ascites， jaundice， and hepatomegaly. The diagnostic criteria for HSOS vary with etiology， and it needs to be differentiated from other diseases such as drug-induced liver diseases and hepatic venous outflow tract obstruction. Defibrotide and low-molecular-weight heparin have a therapeutic effect on HSOS associated with hematopoietic stem cells and pyrrolidine alkaloids， respectively， and there are currently no effective drugs for HSOS caused by oxaliplatin chemotherapy.

Mechanism of EGFR inhibitor AG1478 combined with oxaliplatin in inhibiting PI3K/AKT pathway and promoting autophagy in HI 975 cells / 中国药理学通报

Aim To explore the effect of oxaliplatin combined with epidermal growth factor receptor tyrosine kinase inhibitor AG1478 on autophagy in non-small cell lung cancer H1975 cells. Methods H1975 cells were cultured in vitro using gradient concentrations of AG1478 (0, 5, 10, 15, 20, 25, 30, 35, 40 jjimol • IT

Effects of gene polymorphism on efficacy and toxic effect of chemotherapy regimen containing oxaliplatin treatment in stage Ⅲ and Ⅳ colorectal cancer / 中国药房

OBJECTIVE To investigate the effects of GSTP1， XRCC1， ABCB1， MTHFR gene polymorphisms on efficacy and toxic effect of chemotherapy regimen containing oxaliplatin in patients with stage Ⅲ and Ⅳ colorectal cancer patients. METHODS Clinical data of 76 patients with stage Ⅲ and Ⅳ colorectal cancer who received chemotherapy regimen containing oxaliplatin （XELOX，FOLFOX） were collected from the Second Affiliated Hospital of Soochow University from September 2018 to March 2020. The correlation of genotypes with progression-free survival （PFS） and toxic effect was analyzed by using univariate and multivariate COX regression model. RESULTS Carriers of the ABCB1 3435T＞C locus C allele （TC/CC） had a significantly higher risk of progression compared to TT genotype patients [HR＝2.39， 95%CI （1.05，5.50）， P＝0.038]. The risk of progression in patients at stage Ⅳ was significantly higher than those at stage Ⅲ [HR＝8.11， 95%CI（3.39，19.40）， P＜0.001]. Chemotherapy regimen， Karnofsky performance status score and tumor site had no significant effect on disease progression （P＞0.05）. Mutations in gene loci were not correlated with adverse reactions （P＞0.05）. CONCLUSIONS Patients carrying ABCB1 TC/CC and receiving chemotherapy regimen containing oxaliplatin have a higher risk of disease progression， which may be associated with longer PFS in patients （TT genotype） with stage Ⅳ colorectal cancer receiving the chemotherapy， while GSTP1， XRCC1， and MTHFR gene polymorphisms have no significant impact.

Research progress on oxaliplatin-induced neurotoxicity in traditional Chinese medicine (TCM) and western medical cognition and prevention and treatment by TCM / 中国中药杂志

Chemotherapy is one of the main options in clinical tumor treatment. Although chemotherapy drugs have a good therapeutic effect, they can also cause a series of adverse reactions, such as neurotoxicity. Chemotherapy-induced neurotoxicity is a dose-limi-ting adverse reaction that significantly affects patients' long-term treatment and quality of life. This article reviewed literature from 2000 to the present on chemotherapy-induced neurotoxicity and found that oxaliplatin was the most frequently used chemotherapy drug. Based on the clinical characteristics of oxaliplatin-induced neurotoxicity, this article summarized the understanding of its pathogenesis from both traditional Chinese medicine(TCM) and western medicine perspectives, discussed the role and mechanism of TCM compounds and monomeric components, and explored the research direction of using cutting-edge biotechnology to reveal the mechanism of oxaliplatin-induced neurotoxicity from a temporal-spatial perspective of intercellular communication and the application prospects of an interdisciplinary model combining TCM pathogenesis, western medicine manifestations, and artificial intelligence in precise intervention decision-making for TCM, aiming to provide research ideas for the prevention and treatment of oxaliplatin-induced neurotoxicity and the development of new drugs.

Efficacy and safety of radiotherapy combined with targeted therapy, immunotherapy and chemotherapy for unresectable intrahepatic cholangiocarcinoma / 中华放射医学与防护杂志

Objective:To evaluate the efficacy and safety of quadruple therapy involving radiotherapy (RT), lenvatinib, anti-PD-1 antibody and GEMOX (oxaliplatin and gemcitabine) chemotherapy (quadruple therapy) in treatment cohort of patients with unresectable intrahepatic cholangiocarcinoma (ICC).Methods:The patients with recurrent, metastatic, or unresectable ICC underwent quadruple therapy at Zhongshan Hospital, Fudan University between September 2018 and May 2022 were selected. The data about efficacy and safety of quadruple therapy were collected in the hospital electronic medical record system. All patients were followed up regularly to obtain the long-term prognostic data until December 31, 2022. The efficacy, prognosis, and toxicity data were collected and analyzed.Results:A total of 41 patients were included in the analysis. After a median follow-up period of 15 months, disease progression was diagnosed in 36 patients (18 patients died), while 3 patients were lost to follow-up. The causes of death included liver failure induced by intrahepatic tumor progression ( n=6), distant metastases (lungs or brain, n=6), abdominal lymph node metastases ( n=3), cancer cachexia ( n=2), and unknown cause ( n=1). The median progression-free survival (PFS) was 11 months (95% CI: 9.2-12.8), and the median overall survival (OS) was 35 months (95% CI: 17.0-52.0). All patients experienced treatment-related adverse events (AEs) during the study treatment period. Of the 41 patients, 13 patients experienced at least once grade 3 or worse treatment-related AE, but all were manageable with symptomatic treatment. No treatment-related deaths were reported during the follow-up period. Conclusions:Radiotherapy (RT), lenvatinib, anti-PD-1 antibody and GEMOX in the treatment of unresectable ICC shows significant efficacy and good safety, which is worthy of clinical application.

Correlation of OCTN2 with the chemosensitivity of prostate cancer cells to oxaliplatin / 中国药房

OBJECTIVE To study the correlation of novel organic cation transporter 2 （OCTN2） with the chemosensitivity of prostate cancer cells to oxaliplatin. METHODS Tumor samples of patients receiving radical prostatectomy were collected， and OCTN2 protein was detected with immunohistochemistry； the primary cells of the specimen were cultivated to obtain prostate cancer cell line. Inductively coupled plasma mass spectrometry was used to detect the uptake of low concentration （0.1 μmol/L） of oxaliplatin by cancer cells. Real-time PCR and Western blot were used to detect the mRNA and protein expressions of OCTN2 in cancer cells； the prostate cancer cells with the highest and lowest expression of OCTN2 protein were selected， and IC50 of oxaliplatin to prostate cancer cells was analyzed by ATP-TCA method. The inhibitory rate of plasma peak concentration of oxaliplatin （50 μmol/L） to prostate cancer cells was detected by MTT assay. Spearman method was used to analyze the relationship of the uptake of oxaliplatin by prostate cancer cells with inhibitory rate of oxaliplatin to prostate cancer cells and 505916443@qq.com mRNA expressions of OCTN2. RESULTS OCTN2 was located on the membrane of cancer cells， and the uptake of zjdtztougao@163.com oxaliplatin by cancer cells was 0.283±0.264 （n＝12）mRNA and protein expression of OCTN2 varied significantly among different cancer cells. The sensitivity of cancer cells with high expression of OCTN2 to oxaliplatin （IC50 of 4.61 μmol/L） was higher than that of cancer cells with lower expression of OCTN2 （IC50 of 26.23 μmol/L）. The inhibitory rate of oxaliplatin to cancer cells was （25.4±10.8）% （n＝12）. There was a correlation between the uptake of oxaliplatin by prostate cancer cells and the inhibition rate of oxaliplatin to prostate cancer cells and mRNA expression of OCTN2 （P＜0.05）. CONCLUSIONS High-expressed OCTN2 may promote the uptake of oxaliplatin by prostate cancer cells， and its expression can serve as a reference for predicting the sensitivity of prostate cancer cells to oxaliplatin chemotherapy.

EGFR inhibitor AG1478 enhances oxaliplatin induced apoptosis in HCT116 cells / 中国药理学通报

Aim To investigate the effect of tyrosine kinase inhibitor AG1478 combined with oxaliplatin (OXA) on apoptosis of colorectal cancer HCT116 cells. Methods MTT assay was used to measure the effect of AG1478 combined with OXA on proliferation of HCT116 cells. RT-qPCR was used to detect the mRNA expression levels of p53, caspase-3, Bcl-2 and Bax. Western blot was used to detect the proteins expression of p53, caspase-3, cleaved-caspase 3, Bcl-2, Bax, p62, LC3 and IL-6. Results Both OXA and AG1478 inhibited the proliferation of HCT116 (P < 0. 01). IC

Synergistic effects of dendrosomal nanocurcumin and oxaliplatin on oncogenic properties of ovarian cancer cell lines by down-expression of MMPs

BACKGROUND: Contrary to the advantageous anticancer activities of curcumin (Cur), limited bioavailability and solubility hindered its efficacy. Here, nontoxic dendrosomal nano carrier with Cur was used to overcome these problems. Despite considerable antitumor properties of Oxaliplatin (Oxa), the limiting factors are drug resistance and adverse side-effects. The hypothesis of this study was to evaluate the possible synergism between dendrosomal nanocurcumin (DNC) and Oxa and these agents showed growth regulatory effects on SKOV3 and OVCAR3 cells. METHODS: and materials In the present study, colony formation, wound healing motility, cell adhesion, transwell invasion and migration assay and cell cycle arrest with or without DNC, Oxa and Combination were defined. In addition to, real time PCR and Western blot were used to analyze AKT, PI3K, PKC, JNK, P38 and MMPs mRNAs and proteins expressions. Docking of MMP-2-Cur, MMP-2-DNC and MMP-2-Oxa was performed and the results of all three complexes were simulated by molecular dynamics. RESULTS: Our findings illustrated that DNC had the greatest effect on cell death as compared to the Cur alone. Moreover, the growth inhibitory effects (such as cell death correlated to apoptosis) were more intense if Oxa was added followed by DNC at 4 h interval. However, insignificant effects were observed upon simultaneous addition of these two agents in both cell lines. Besides, a combination of agents synergistically alters the relative expression of MMP-9. CONCLUSIONS: The docking results showed that His70 and Asp100 may play a key role at the MMP-2 binding site. The matrigel invasion as well as cell viability of ovarian cancer cell lines SKOV3 and OVCAR3 by DNC alone or in combination with Oxa was inhibited significantly. The inhibitory effects of these agents were due to the differential expression levels of MMP 2 and MMP 9 regulated by multiple downstream signaling cascades. From the molecular dynamic simulation studies, it was confirmed that DNC established a strong interaction with MMP-2.

Evaluation of Gemcitabine-Cisplatin Vs Gemcitabine-Oxaliplatin in The Treatment of Advanced Biliary Tract Carcinoma: A Tertiary Care Hospital Study in Bangladesh

Background: Biliary tract carcinoma is highly fatal and one of the commonest cancers in Bangladesh. Chemotherapy is the mainstay of treatment as it is present in an advanced stage. Gemcitabine-Cisplatin association has been a standard of care for first-line regimens in advanced biliary tract cancer. Nevertheless, the Gemcitabine-Oxaliplatin regimen is frequently preferred. There has been no nationwide study to compare the effectiveness of these two platinum groups. Therefore, this study compared the efficacy and toxicities of Gemcitabine-Cisplatin (Gem-Cis) with Gemcitabine-Oxaliplatin (GEMOX) combination chemotherapy for the treatment of ABTC.Material & Methods:In this quasi-experimental study, a total number of eighty patients (40 patients in arm A and 40 patients in arm B), who had histopathologically or cytopathological proven ABTC with no history of previous treatment were included. The study has done between the periods of January 2019 to June 2020. The patients received Gemcitabine (1000 mg/m2 i.v. on day 1 and day 8) plus Cisplatin (25 mg/m2 i.v. on day 1 and 8) every 3 weeks for 6 cycles in Arm A. In another group, Gemcitabine (1000 mg/m2 i.v. on day 1) plus Oxaliplatin (100 mg/m2 i.v. on day 2) every 2 weeks for 6 cycles in Arm B was given. All the patients were followed up according to the set follow-up criteria up to 6 weeks after completion of treatment.Results:At the end of the treatment, Response rates (CR+PR+SD) were analyzed. No patient from both the arms showed Complete Response (CR). 37.5% and 45% of patients of the Arm A and Arm B groups showed Partial Response (PR) respectively. Meanwhile, 45% and 40% of patients from Arm A and B showed Stable Disease (SD) respectively. P-value was 0.410 (>0.05). Seven patients (17%) in Arm A and six patients (15%) in Arm B developed Progressive disease (PD). The most common treatment-related grade 3 toxicities were more experienced in the Arm A group. For Arm A versus Arm B that were as follows: neutropenia (15% versus 5%), anemia (15% versus 8%), thrombocytopenia (10% versus 2.5%), nausea (10% versus 5%), vomiting (5%versus 2.5%), peripheral neuropathy (0% versus 15%) and renal toxicity (7.5% versus 0%). For none of them, the p-value was <0.05 except for neutropenia, anemia, thrombocytopenia, renal toxicity, and peripheral neuropathy in which the p-value was 0.042, 0.001, 0.014, 0.0001, and 0.00001 respectively. For both Arms, there were no treatment-related Grade 4 toxicities.Conclusion:The study exhibited that treatment with the Gemcitabine-Oxaliplatin regimen was well tolerated, less toxic, and convenient with similar effectiveness compared to the Gemcitabine-Cisplatin regimen in loco regional control of advanced biliary tract cancer.

Oxaliplatin versus Irinotecan no câncer colorretal avançado / Oxaliplatin versus Irinotecan in advanced colorectal cancer

O câncer colorretal é uma neoplasia com alta prevalência e letalidade. A razão desse elevado número de mortes é a detecção da doença em estágios metastáticos, de difícil cura e que necessitam de terapia quimioterápica adjuvante ou paliativa. Na atualidade, o principal tratamento quimioterápico dessa neoplasia tem como base as drogas Oxaliplatina ou Irinotecano, isolados ou combinados com outros medicamentos. O objetivo desta revisão sistemática é avaliar se há superioridade do esquema quimioterápico com Irinotecano sobre o regime com Oxaliplatina. Foi realizada a análise de ensaios clínicos randomizados, fase II ou III, nas bases de dados eletrônicas Central e PubMed. Critérios de inclusão: ensaios clínicos randomizados comparando regimes à base de irinotecano ou oxaliplatina como tratamentos de primeira linha para câncer colorretal metastático. O desfecho primário analisado foi a superioridade entre os quimioterápicos sobre a sobrevida global. Os desfechos secundários incluíram sobrevida livre de progressão, taxa de resposta e efeitos colaterais. Registro na PROSPERO: CRD42019130339. Não houve diferença significativa nos 13 estudos sobre a sobrevida dos pacientes. Sobre os efeitos colaterais dos medicamentos, os regimes baseados em irinotecano foram associados a uma alta incidência de neutropenia e diarreia grave. Já os associados com oxaliplatin cursaram com alta incidência de neuropatia sensitiva. Não houve diferença estatisticamente significativa sobre a sobrevida global, sobrevivência livre de progressão e na taxa de resposta quando comparamos os pacientes que receberam oxaliplatina e irinotecano (AU)

Colorectal cancer is a highly prevalent and lethal neoplasm. The reason for this high number of deaths is the detection of the disease in metastatic stages, which are difficult to cure and require adjuvant or palliative chemotherapy therapy. Currently, the main chemotherapeutic treatment of this neoplasm is based on the drugs Oxaliplatin or Irinotecan, alone or combined with other drugs. The objective of this systematic review is to evaluate whether there is superiority of the chemotherapy regimen with Irinotecan over that with Oxaliplatin. Analysis of randomized clinical trials, phase II or III, was performed in the electronic databases Central and PubMed. Inclusion criteria: randomized clinical trials comparing irinotecan- or oxaliplatin-based regimens as first-line treatments for metastatic colorectal cancer. The primary endpoint analyzed was the superiority between chemotherapies on overall survival. Secondary endpoints included progression-free survival, response rate, and side effects. PROSPERO registration: CRD42019130339. There was no significant difference in the 13 studies on patient survival. On drug side effects, irinotecan-based regimens were associated with a high incidence of neutropenia and severe diarrhea. Those associated with oxaliplatin were associated with a high incidence of sensory neuropathy. There was no statistically significant difference in overall survival, progression-free survival, and response rate when comparing patients receiving oxaliplatin and irinotecan (AU)

The Outcome of Gemcitabine-Cisplatin Versus Gemcitabine-Oxaliplatin in The Treatment of Advanced Biliary Tract Carcinoma

Background: Biliary tract carcinoma is highly fatal and one of the commonest cancers in Bangladesh. Chemotherapy is the mainstay of treatment as it is present in an advanced stage. Gemcitabine-Cisplatin association has been a standard of care for first-line regimens in advanced biliary tract cancer. Nevertheless, the Gemcitabine-Oxaliplatin regimen is frequently preferred. There has been no nationwide study to compare the effectiveness of these two platinum groups. Therefore, this study compared the efficacy and toxicities of Gemcitabine-Cisplatin (Gem-Cis) with Gemcitabine-Oxaliplatin (GEMOX) combination chemotherapy for the treatment of ABTC.Material & Methods:In this quasi-experimental study, a total number of eighty patients (40 patients in arm A and 40 patients in arm B), who had histopathologically or cytopathologically proven ABTC with no history of previous treatment were included. The study has done between the periods of January 2019 to June 2020. The patients received Gemcitabine (1000 mg/m2 i.v. on day 1 and day 8) plus Cisplatin (25 mg/m2i.v. on day 1 and 8) every 3 weeks for 6 cycles in Arm A. In another group, Gemcitabine (1000 mg/m2 i.v. on day 1) plus Oxaliplatin (100 mg/m2 i.v. on day 2) every 2 weeks for 6 cycles in Arm B was given. All the patients were followed up according to the set follow-up criteria up to 6 weeks after completion of treatment.Results:At the end of the treatment, Response rates (CR+PR+SD) were analyzed. No patient from both the arms showed Complete Response (CR). 37.5% and 45% of patients of the Arm A and Arm B groups showed Partial Response (PR) respectively. Meanwhile, 45% and 40% of patients from Arm A and B showed Stable Disease (SD) respectively. P-value was 0.410 (>0.05). Seven patients (17%) in Arm A and six patients (15%) in Arm B developed Progressive disease (PD). The most common treatment-related grade 3 toxicities were more experienced in the Arm A group. For Arm A versus Arm B that were as follows: neutropenia (15% versus 5%), anemia (15% versus 8%), thrombocytopenia (10% versus 2.5%), nausea (10% versus 5%), vomiting (5%versus 2.5%), peripheral neuropathy (0% versus 15%) and renal toxicity (7.5% versus 0%). For none of them, the p-value was <0.05 except for neutropenia, anemia, thrombocytopenia, renal toxicity, and peripheral neuropathy in which the p-value was 0.042, 0.001, 0.014, 0.0001, and 0.00001 respectively. For both Arms, there were no treatment-related Grade 4 toxicities.Conclusion:The study exhibited that treatment with Gemcitabine-Oxaliplatin regimen was well tolerated, less toxic, and convenient with similar effectiveness compared to Gemcitabine-Cisplatin regimen in loco regional control of advanced biliary tract cancer.

Efficacy observation of continuous dosing or alternate-day dosing of apatinib combined with SOX regimen as first-line treatment for advanced gastric cancer / 肿瘤研究与临床

Objective:To compare the clinical efficacy and safety of continuous dosing or alternate-day dosing of apatinib combined with SOX regimen as first-line treatment for patients with advanced gastric cancer.Methods:A total of 52 patients with human epidermal growth factor receptor 2 (HER2) negative and inoperable locally advanced or advanced gastric cancer who were pathologically diagnosed from January 2018 to January 2021 in the Second Affiliated Hospital of Shandong First Medical University were collected. The patients were divided into continuous dosing group and alternate-day dosing group by random number table method. The continuous dosing group received apatinib (250 mg, once a day) combined with SOX regimen (S-1+oxaliplatin); the alternate-day dosing group received apatinib (250 mg, once every other day) combined with SOX regimen. Twenty-one days were a cycle, and the efficacy was evaluated after 2 cycles. After 4-6 cycles, patients with stable disease received apatinib and S-1 for maintenance therapy. The therapeutic effects and adverse reactions of the two groups were compared.Results:The curative effect could be evaluated in 51 patients, including 26 in the continuous dosing group and 25 in the alternate-day dosing group. The disease control rates in the continuous dosing group and the alternate-day dosing group were 84.6% (22/26) and 76.0% (19/25) ( χ2 = 0.60, P = 0.499), and the median progression-free survival time was 7.50 months (95% CI 6.17-8.83 months) and 8.30 months (95% CI 6.99-9.61 months) ( χ2 = 0.71, P = 0.401), and the median overall survival time was 15.50 months (95% CI 11.30-19.69 months) and 15.60 months (95% CI 13.63-17.57 months) ( χ2 = 1.82, P = 0.177). The main adverse reactions in the two groups were leukopenia, thrombocytopenia, hypertension, nausea, vomiting, fatigue, hand-foot syndrome, proteinuria, liver and kidney damage. The incidence rates of ≥grade 3 adverse reactions in the continuous dosing group and the alternate-day dosing group were 42.3% (11/26) and 12.0% (3/25), and the difference was statistically significant ( χ2 = 4.46, P = 0.035). Conclusions:The efficacy of continuous dosing or alternate-day dosing of apatinib combined with SOX regimen as first-line treatment for advanced gastric cancer is similar, but the incidence of ≥grade 3 adverse reactions in alternate-day dosing group is lower, which improves the compliance and tolerance of patients.

Protective Mechanism of Electroacupuncture on Peripheral Neurotoxicity Induced by Oxaliplatin in Rats / 中国结合医学杂志

OBJECTIVE@#To study the effect of electroacupuncture (EA) on oxaliplatin-induced peripheral neuropathy (OIPN) in rats.@*METHODS@#Male Sprague-Dawley rats were equally divided into 3 groups using a random number table: the control group, the OIPN group, and the EA (OIPN + EA) group, with 10 rats in each. The time courses of mechanical, cold sensitivity, and microcirculation blood flow intensity were determined. The morphology of the dorsal root ganglion (DRG) was observed by electron microscopic examination. The protein levels of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and the transient receptor potential (TRP) protein family in DRGs were assayed by Western blot.@*RESULTS@#EA treatment significantly reduced mechanical allodynia and cold allodynia in OIPN rats (P<0.01). Notably, oxaliplatin treatment resulted in impaired microcirculatory blood flow and pathomorphological defects in DRGs (P<0.01). EA treatment increased the microcirculation blood flow and attenuated the pathological changes induced by oxaliplatin (P<0.01). In addition, the expression levels of Nrf2 and HO-1 were down-regulated, and the TRP protein family was over-expressed in the DRGs of OIPN rats (P<0.01). EA increased the expression levels of Nrf2 and HO-1 and decreased the level of TRP protein family in DRG (P<0.05 or P<0.01).@*CONCLUSION@#EA may be a potential alternative therapy for OIPN, and its mechanism may be mainly mediated by restoring the Nrf2/HO-1 signaling pathway.

Expression of ENO3 and Its Effect on Sensitivity of Hepatocellular Carcinoma Cells to Oxaliplatin / 肿瘤防治研究

Objective To investigate the expression of ENO3 gene in hepatocellular carcinoma and its effect on the sensitivity of hepatocellular carcinoma cell lines to OXA, and to explore the possible mechanism. Methods qRT-PCR and immunohistochemical analysis were used to detect the expression of ENO3 in 48 pairs of hepatocellular carcinoma tissues and normal liver tissues.Overexpression plasmid was constructed and transfected into MHCC97H and HepG2 cells.The experiments were divided into empty group (Vector group), ENO3 overexpression group (ENO3 group), empty+OXA group (Vector+OXA group) and ENO3 overexpression+OXA group (ENO3+OXA group).The proliferation ability of MHCC97H and HepG2 cells were detected by CCK-8 assay and cell colony formation assay.The apoptosis rate was determined by flow cytometry assay.Protein expressions of Bcl-2, Bax and Caspase-3 were detected by Western blot assay. Results The expression of ENO3 was significantly decreased in hepatocellular carcinoma tissues, compared with normal liver tissues adjacent to the carcinoma.The expression of ENO3 gene in the ENO3 overexpression group was significantly higher than that in the empty group.Compared with the Vector+OXA group, cell viability was decreased, apoptosis rate was increased, Bcl-2 protein expression was decreased, Bax and Caspase-3 protein expression were increased in the ENO3+OXA group. Conclusion The expression of ENO3 is down-regulated in hepatocellular carcinoma tissues, and the overexpression of ENO3 can enhance the sensitivity of hepatocellular carcinoma cell lines to oxaliplatin by promoting cell apoptosis.

Preparation and targeting evaluation of reductant-sensitive oxaliplatin-loaded Fe3O4 nanoparticles / 药学学报

The non-specific accumulation and release of drugs are the main factors affecting the therapeutic effect as well as causing toxic side effects of chemotherapeutic drugs. Nowadays, the application of nanotechnology and responsive drug release is an important strategy to improve the tumor-specific accumulation of drugs and reduce their side effects. In this study, an α-enolase targeted peptide (ETP)-modified polyethylene glycol poly-lysine block copolymer loaded with oxaliplatin prodrug was synthesized first, and then, polymer-coating Fe3O4 nanoparticles were prepared by phase transfer dialysis method to improve the blood circulation stability and tumor targeting of oxaliplatin. At the same time, the physicochemical properties, reductant-responsive drug release, cellular uptake, tumor targeting and other biological functions of ETP modified oxaliplatin-loaded Fe3O4 nanoparticles were studied in vitro and in vivo. First, the results of reductant-triggered drug release study showed that the drug-loaded nanoparticles could achieve rapid release of more than 80% of the prototype oxaliplatin within 3 h under the reduction conditions simulating the tumor cytoplasmic microenvironment. Secondly, the results of flow cytometry showed that the modification of ETP could increase the ratio of cellular uptake of drug-loaded nanoparticles in tumor cells, and the way that drug-loaded nanoparticles endocytosed by tumor cells were mainly through the energy-dependent and receptor protein and fossin-mediated endocytosis pathway. The animal procedures were approved by the Institutional Animal Care and Use Committee of School of Pharmacy of Fudan University. Moreover, the results of pharmacokinetic experiment showed that the area under the curve (AUC0-∞) of oxaliplatin could be significantly increased by nano-formulation which was about 5 times than that of free oxaliplatin. Besides, the pharmacokinetic results also showed that the drug-loaded Fe3O4 nanoparticles constructed by covalent linkage and chelation had good overall stability in vivo. Finally, the in vivo imaging results showed that ETP modification could increase tumor accumulation of drug-loaded nanoparticles, which would be conducive to the efficacy of oxaliplatin in tumor lesions. In summary, the oxaliplatin-loaded Fe3O4 nanoparticles with the capability of reductant-responsive drug release have good drug release characteristics, blood circulation stability and tumor targeting ability, and have the potential to improve the anti-tumor therapeutic effect of oxaliplatin.

Clinical observation of albumin-bound paclitaxel combined with oxaliplatin in the first-line treatment of advanced gastric cancer / 中国药房

OBJECTIVE To observe the ther apeutic efficacy and safety of albumin-bound paclitaxel combined with oxaliplatin in the first-line treatment of advanced gastric cancer （GC）. METHODS A total of 90 advanced unresectable GC patients were randomized into observation group and control group ，with 45 patients in each group. Control group was given oxaliplatin combined with tegafur ，and observation group was given albumin-bound paclitaxel combined with oxaliplatin. A chemotherapy cycle last for 21 days，and both groups received 6 cycles of chemotherapy ，and then the follow-up observation was conducted every 2 weeks. Short-term efficacy （after 2 chemotherapy cycles ），mid-term efficacy （after 6 chemotherapy cycles ），tumor marker，long-term efficacy （after follow-up ），quality of life ，the occurrence of ADRs were compared between 2 groups. RESULTS After 2 cycles of treatment ，objective remission rate （ORR）of observation group was significantly higher than that of control group （60.00％ vs. 37.78％，P＜0.05）；there was no statistical significance in disease control rate between the two groups （P＞0.05）. After 6 chemotherapy cycles ，ORR of observation group was significantly higher than that of control group （55.56％ vs. 31.11％，P＜0.05）；there was no statistical significance in disease control rate between the two groups （P＞0.05）；the levels of tumor markers [carcinoembryonic antigen ， carbohydrate antigen （CA）724， CA199， CA242] in observation group were significantly lower than those of control group （P＜0.05）. After the follow-up period ，the median progression-free survival [ 8.78 （95％CI：6.94-11.01）months] and the median overall survival [ 13.02（95％CI：12.78-15.62）months] of observation group were significantly longer than those [ 6.99（95％CI：3.67-10.88）months and 10.42（95％CI：8.72-13.22）months] of control group （P＜ 0.05）. The score of body dimension in the observation group was significantly higher than that in the control group （P＜0.05）. Except for peripheral neurotoxicity ，there was no significant difference in the incidence of ADR between 2 groups（P＞0.05）. CONCLUSIONS Albumin-bound paclitaxel combined with oxaliplatin has a good effect and safety in the first-line treatment of advanced unresectable GC.

Correlation between organic cation transporter gene polymorphisms and the toxicities and clinical response of oxaliplatin / 中国临床药理学与治疗学

AIM: To investigate the relationship between genotypes of rs628031, rs650284, rs683369 of SLC22A1 gene and the toxicities and clinical response of oxaliplatin in patients with colorectal cancer. METHODS: A total of 72 patients diagnosed as colorectal cancer during January 2018 to June 2018 were selected and all patients received oxaliplatin treatment. Their peripheral venous blood was collected and genotyping was conducted by using SNaPshot. The toxicities including gastrointestinal toxicity, hematological toxicity and peripheral neurotoxicity were evaluated according to the Common Terminology Criteria Adverse Events (CTCAE) Version 5.0. Clinical response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1). RESULTS: The results of Chi-test showed that different genotypes of SLC22A1 SNP sites rs628031 and rs683369 may be related to the toxicities and clinical response of oxaliplatin significantly. Specifically, when compared with the patients with GG type of rs628031, the patients with the GA or AA type had a lower incidence of grade 3 nausea and vomiting (P=0.017) and may also be less responsive to efficacy (P=0.008). When compared with the patients with CC type of rs683369, the patients with the GC or GG type had a lower incidence of grade 3 nausea and vomiting (P=0.002) and may also be less responsive to efficacy (P=0.014).CONCLUSION: The polymorphisms of SLC22A1 gene are closely related to the toxicities and clinical response of oxaliplatin in patients with colorectal cancer, which may be helpful for improving clinical treatment.

Foot drop - an uncommon presentation of FOLFOX toxicity

A quimioterapia com FOLFOX (oxaliplatina, leucovorina e 5-fluorouracilo) é frequentemente utilizada em doentes com cancro colorretal. Os sais de platina são conhecidos por serem uma classe de quimioterápicos que comumente induzem neurotoxicidade periférica. Na toxicidade induzida pela oxaliplatina, os sintomas sensitivos são os mais frequentes. Neste artigo, apresentamos dois casos clínicos de pacientes com adenocarcinoma de cólon, ambos submetidos à quimioterapia com FOLFOX4, e que desenvolveram neurotoxicidade incomum, apresentando pé pendente após o terceiro ciclo de tratamento. Esta manifestação clínica pode ser explicada por dano axonal nos neurônios motores periféricos do nervo peroneal comum (fibular), que fornece inervação motora aos músculos do pé. A paralisia do nervo fibular causa fraqueza súbita nos músculos do pé, que parece ser temporária. Ambos os doentes recuperaram completamente do evento sem necessidade de ajustes no tratamento, nem introdução de medicamentos diferentes. A apresentação de pé pendente como toxicidade da quimioterapia ainda é pouco compreendida. Os casos relatados mostram o pé pendente como uma manifestação grave e incomum de neuropatia induzida por FOLFOX, que pode ser transitória, e não requer necessariamente intervenção específica.

Chemotherapy based on FOLFOX (oxaliplatin, leucovorin, and 5-fluorouracil) regimen is frequently used in colorectal cancer patients. Oxaliplatin and other platinum agents are known to be a class of chemotherapy drugs that commonly induce peripheral neurotoxicity. The most frequent oxaliplatin related neurotoxicity is sensitive symptoms. Here, we present two cases of patients with colon adenocarcinoma, both undergoing chemotherapy with FOLFOX4, who developed uncommon neurotoxicity, presenting with foot drop after the third treatment cycle. Foot drop may be explained by axonal damage of peripheral motor neurons of the common peroneal (fibular) nerve, which provides motor innervation to the foot muscles. Peroneal nerve palsy causes sudden weakness in the muscles of the foot that seems to be temporary. Both patients completely recovered from the event. There was no need for treatment adjustments, neither introduction of different drugs. Foot drop as chemotherapy toxicity is still poorly understood. The reported cases show foot drop as a severe and uncommon manifestation of FOLFOX-induced neuropathy, that might be transitory, and does not necessarily requires specific intervention.