Resveratrol ameliorates irinotecan chemoresistance of colorectal cancer cells by down-regulating EGFR/AKT/mTOR signaling pathway / 中国药理学通报

Aim To explore the possibility of resveratrol ( RES) combined with irinotecan ( IRI) in the treatment of colorectal cancer ( CRC ) and the underlying molecular mechanism of RES ameliorating IRI chemoresistance of CRC cells. Methods CRC cells used in this study were HT-29 and RKO cells. The effects of RES, IRI and their combination on the proliferation of CRC cells were analyzed by MTT assay and colony formation assay. The effects of RES,IRI and their combination on the migration of CRC cells were assessed by Wound-healing assay. On this basis,the role of RES in regulating IRI chemoresistance of CRC cells and the underlying molecular mechanisms were further explored. Results The proliferation and migration ability of CRC cells in the RES and IRI combined treatment group were significantly lower than those in the IRI treated group, which showed that RES could enhance the inhibiting effect of IRI on the proliferation and migration of CRC cells, indicating that RES was able to a-meliorate the chemoresistance of CRC cells to IRI. And remarkably lower marker proteins expression levels of EGFR/AKT/mTOR signaling pathway in the RES and IRI combined treatment group was observed. Moreover, both EGFR activator (NSC 228155) and AKT activator (SC79) could reverse the ameliorating effect of RES on IRI chemoresistance of CRC cells, whereas AKT inhibitor (MK2206 ) could partially reverse the effect of NSC 228155. Conclusions RES can inhibit the proliferation and migration of CRC cells by down-regulating EGFR/AKT/mTOR signaling pathway, so as to ameliorate the chemoresistance of CRC cells to IRI, suggesting that RES combined with IRI can be a promising novel treatment for CRC.

Full-profile pharmacokinetics, anticancer activity and toxicity of an extended release trivalent PEGylated irinotecan prodrug

Irinotecan is an anticancer topoisomerase I inhibitor that acts as a prodrug of the active metabolite, SN-38. Unfortunately, the limited utility of irinotecan is attributed to its pH-dependent stability, short half-life and dose-limiting toxicity. To address this problem, a novel trivalent PEGylated prodrug (PEG-[Irinotecan]3) has been synthesized and its full-profile pharmacokinetics, antitumor activity and toxicity compared with those of irinotecan. The results show that after intravenous administration to rats, PEG-[Irinotecan]3 undergoes stepwise loss of irinotecan to form PEG-[Irinotecan]3‒x (x = 1,2) and PEG-[linker] during which time the released irinotecan undergoes conversion to SN-38. As compared with conventional irinotecan, PEG-[Irinotecan]3 displays extended release of irinotecan and efficient formation of SN-38 with significantly improved AUC and half-life. In a colorectal cancer-bearing model in nude mice, the tumor concentrations of irinotecan and SN-38 produced by PEG-[Irinotecan]3 were respectively 86.2 and 2293 times higher at 48 h than produced by irinotecan. In summary, PEG-[Irinotecan]3 displays superior pharmacokinetic characteristics and antitumor activity with lower toxicity than irinotecan. This supports the view that PEG-[Irinotecan]3 is a superior anticancer drug to irinotecan and it has entered the phase II trial stage.

Molecular mechanism of resveratrol combined with irinotecan in treatment of colorectal cancer / 中国中药杂志

This study aimed to investigate the mechanism of resveratrol(RES) combined with irinotecan(IRI) in the treatment of colorectal cancer(CRC). The targets of RES, IRI, and CRC were obtained from databases, and the targets of RES combined with IRI in the treatment of CRC were acquired by Venn diagram. The protein functional cluster analysis, GO and KEGG enrichment analyses were performed. In addition, the protein-protein interaction(PPI) network was constructed. The core target genes were screened out and the target-signaling pathway network was set up. IGEMDOCK was used to dock the core target gene molecules. Besides, the relationship between the expression level of key target genes and the prognosis and immune infiltration of CRC was analyzed. Based on the in vitro cell experiment, the molecular mechanism of RES combined with IRI in the treatment of CRC was explored and analyzed. According to the results, 63 potential targets of RES combined with IRI were obtained for CRC treatment. Furthermore, cluster analysis revealed that protein functions included 23% transmembrane signal receptors, 22% protein modifying enzymes, and 14% metabolite converting enzymes. GO analysis indicated that BPs were mainly concentrated in protein autophosphorylation, CCs in receptor complex and plasma membrane, and MFs in transmembrane receptor protein tyrosine kinase activity. Moreover, KEGG signaling pathways were mainly enriched in central carbon metabolism in cancer. The key targets of RES combined with IRI in the treatment of CRC were PIK3CA, EGFR, and IGF1R, all of which were significantly positively correlated with the immune infiltration of CRC. As shown by the molecular docking results, PIK3CA had the most stable binding with RES and IRI. Compared with the results in the control group, the proliferation ability and EGFR protein expression of CRC cells in the RES-treated group, the IRI-treated group, and the RES+IRI treated group significantly decreased. Moreover, the cell proliferation ability and EGFR protein expression level of CRC cells in the RES+IRI treated group were remarkably lower than those in the IRI-treated group. In conclusion, PIK3CA, EGFR, and IGF1R are the key targets of RES combined with IRI in CRC treatment. In addition, RES can inhibit the proliferation of CRC cells and improve IRI chemoresistance by downregulating the EGFR signaling pathway.

Carboxylesterase 1 family knockout alters drug disposition and lipid metabolism

The mammalian carboxylesterase 1 (Ces1/CES1) family comprises several enzymes that hydrolyze many xenobiotic chemicals and endogenous lipids. To investigate the pharmacological and physiological roles of Ces1/CES1, we generated Ces1 cluster knockout (Ces1 -/- ) mice, and a hepatic human CES1 transgenic model in the Ces1 -/- background (TgCES1). Ces1 -/- mice displayed profoundly decreased conversion of the anticancer prodrug irinotecan to SN-38 in plasma and tissues. TgCES1 mice exhibited enhanced metabolism of irinotecan to SN-38 in liver and kidney. Ces1 and hCES1 activity increased irinotecan toxicity, likely by enhancing the formation of pharmacodynamically active SN-38. Ces1 -/- mice also showed markedly increased capecitabine plasma exposure, which was moderately decreased in TgCES1 mice. Ces1 -/- mice were overweight with increased adipose tissue, white adipose tissue inflammation (in males), a higher lipid load in brown adipose tissue, and impaired blood glucose tolerance (in males). These phenotypes were mostly reversed in TgCES1 mice. TgCES1 mice displayed increased triglyceride secretion from liver to plasma, together with higher triglyceride levels in the male liver. These results indicate that the carboxylesterase 1 family plays essential roles in drug and lipid metabolism and detoxification. Ces1 -/- and TgCES1 mice will provide excellent tools for further study of the in vivo functions of Ces1/CES1 enzymes.

Combination of anlotinib and irinotecan in the second-line treatment of metastatic colorectal cancer: a multicenter phase 1/2 trial / 中华肿瘤杂志

Objective: To evaluate the safety and efficacy of anlotinib plus irinotecan in the second-line treatment of patients with metastatic colorectal cancer (mCRC). Methods: This prospective phase 1/2 study was conducted in 2 centers in China (Cancer Hospital of Chinese Academy of Medical Sciences and Jiangsu Province Hospital). We enrolled patients with mCRC whose disease had progressed after first-line systemic therapy and had not previously treated with irinotecan to receive anlotinib plus irinotecan. In the phase 1 of the trial, patients received anlotinib (8 mg, 10 mg or 12 mg, po, 2 weeks on/1 week off) in combination with fixed-dose irinotecan (180 mg/m(2), iv, q2w) to define the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). In the phase 2, patients were treated with the RP2D of anlotinib and irinotecan. The primary endpoints were MTD and objective response rate (ORR). Results: From May 2018 to January 2020, a total of 31 patients with mCRC were enrolled. Anlotinib was well tolerated in combination with irinotecan with no MTD identified in the phase 1, and the RP2D was 12 mg. Thirty patients were evaluable for efficacy analysis. Eight patients achieved partial response, and 21 had stable disease, 1 had progressive disease. The ORR was 25.8% and the disease control rate was 93.5%. With a median follow-up duration of 29.5 months, the median progression-free survival and overall survival were 6.9 months (95% CI: 3.7, 9.3) and 17.6 months (95% CI: 12.4, not evaluated), respectively. The most common grade 3 treatment-related adverse events (≥10%) were neutropenia (25.8%) and diarrhea (16.1%). There was no treatment-related death. Conclusion: The combination of anlotinib and irinotecan has promising anti-tumor activity in the second-line treatment of mCRC with a manageable safety profile.

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)

Antitumor activity of irinotecan with ellagic acid in C6 glioma cells

SUMMARY OBJECTIVE: Irinotecan-based combination chemotherapies in malignant gliomas need to be examined. The aim of this study was to investigate the synergetic effect of ellagic acid, a natural polyphenolic antioxidant compound, with irinotecan, an inhibitor of topoisomerase I enzyme, on the growth, cadherin switch, and angiogenic processes of a glioma cell line. METHODS: A combination of 100 μM ellagic acid and 100 μM irinotecan was applied to rat C6 glioma cells for 24th, 48th, and 72nd h. The cell proliferation was evaluated by 5-bromo-2′-deoxyuridine immunocytochemistry. The expression levels of vascular endothelial growth factor, E-cadherin, and N-cadherin were measured using real-time polymerase chain reaction and their immunoreactivities using immunocytochemistry. RESULTS: The treatment of irinotecan with combining ellagic acid enhanced antitumor activity and the synergistic effect of these reduced the cell proliferation of C6 glioma by inhibiting the cadherin switch and promoting the antiangiogenic processes. CONCLUSIONS: Further research is required to prove a negative relationship between C6 glial cell proliferation and irinotecan with ellagic acid application. Our preliminary data suggest that even with the extremely short-term application, irinotecan with ellagic acid may affect glioma cells at the level of gene and protein expression.

Effects of irinotecan combined with XELOX regimen on prognosis and serum CD cells, miR-34a and let-7i in patients with advanced gastric cancer / 中国医师杂志

Objective:To investigate the effect of irinotecan combined with XELOX regimen on serum CD cells, miR-34a and let-7i in patients with advanced gastric cancer.Methods:A total of 72 patients with advanced gastric cancer treated in the Affiliated Hospital of Hubei University of Arts And Science from January 2015 to January 2020 were prospectively selected, and they were divided into control group and observation group with 36 cases in each group by random number table method. The control group was treated with XELOX regimen, while the observation group was treated with irinotecan on the basis of the control group. The efficacy, serum immune level, serum miR-34a and let-7i contents, incidence of toxic and side effects and life cycle of the two groups were compared.Results:The objective response rate (ORR) of the observation group was 33.33% , which were significantly higher than that of the control group (13.89%, χ 2=3.770, P>0.05). There was no significant difference in serum immune level, miR-34a and let-7i between the two groups before treatment (all P>0.05). After treatment, the levels of CD3 + , CD4 + and CD8 + in the two groups were significantly increased (all P<0.05), and the improvement of CD3 + , CD4 + and CD8 + in observation group was significantly better than that in control group (all P<0.05). After treatment, the serum miR-34a level increased significantly and serum let-7i level decreased significantly in the two groups (all P<0.05), and the serum miR-34a level in the observation group was higher than that in the control group, and the serum let-7i level was significantly lower than that in the control group (all P<0.05). Among the grade Ⅰ-Ⅱ adverse reactions, nausea and vomiting and leukocyte decline were the most common; The incidence of grade Ⅲ-Ⅳ leukopenia in the control group and the observation group were 5.56%(2/36) and 5.56%(2/36), respectively; The incidence of grade Ⅲ-Ⅳ thrombocytopenia was 5.56%(2/36) and 2.78%(1/36), respectively; One patient in the control group had grade Ⅲ-Ⅳ abnormal liver function, and one patient in the observation group had grade Ⅲ-Ⅳ nausea and vomiting. All patients with adverse reactions were effectively relieved after symptomatic treatment, and there were no treatment-related deaths. The progression free survival (PFS) of the observation group was 24.90 months (95% CI: 0.469-1.955), and that of the control group was 21.85 months (95% CI: 0.512-2.131). The PFS of the observation group was significantly longer than that of the control group (log rank=1.357, P=0.007). Conclusions:Irinotecan combined with XELOX regimen in the treatment of advanced gastric cancer can effectively improve the level of serum miR-34a and immune function, reduce the content of let-7i, and has good safety.

Clinical study of anlotinib combined with irinotecan in the third line treatment of metastatic esophageal cancer / 国际肿瘤学杂志

Objective:To investigate the clinical efficacy and adverse reactions of anlotinib combined with irinotecan in the third line treatment of metastatic esophageal cancer.Methods:From October 2018 to October 2019, 52 patients with metastatic esophageal cancer who had developed distant metastasis after receiving standard concurrent chemoradiotherapy and failed second-line chemotherapy were selected from Lu′an Hospital of Traditional Chinese Medicine of Anhui Province. The patients were divided into experimental group and control group by random number table method, with 26 cases in each group. The control group was given intravenous chemotherapy with irinotecan. The experimental group was treated with oral erlotinib combined with intravenous chemotherapy of irinotecan. The clinical efficacy and adverse reactions of the two groups were evaluated after 2 cycles of treatment.Results:Before treatment, there was no significant difference in Karnofsky performance status (KPS) score between the experimental group and the control group (76.15±7.52 vs. 74.62±8.59, t=-0.137, P=0.892). After treatment, there was no significant difference between the two groups (70.77±6.28 vs. 72.69±8.74, t=-1.761, P=0.084). However, after treatment, the KPS score in the experimental group was lower than that before treatment ( t=3.035, P=0.006). There was no statistical significance in the KPS scores of the control group before and after treatment ( t=1.000, P=0.327). Adverse reactions in the two groups were mainly grade 1-2. The incidences of grade 1-2 myelosuppression and diarrhea in the experimental group were 61.5% (16/26) and 46.2% (12/26), which were significantly higher than those in the control group (19.2%, 5/26 and 19.2%, 5/26), with statistically significant differences ( χ2=9.665, P=0.002; χ2=4.282, P=0.039). The disease control rate of the experimental group was 73.1% (19/26), which was significantly higher than that of the control group (46.2%, 12/26), and there was a statistically significant difference between the two groups ( χ2=3.914, P=0.048). The median progression-free survival of the experimental group and the control group was 52 days and 45 days, respectively, and there was a statistically significant difference ( χ2=4.692, P=0.032). Conclusion:Anlotinib combined with irinotecan in the third-line treatment of metastatic esophageal cancer has obvious efficacy, but to a certain extent, it increases the incidence of grade 1-2 myelosuppression and diarrhea, and the KPS score is lower compared with before treatment.

Analysis of Mechanism of Chloroform Extract of Gegen Qinliantang on Alleviating Enterotoxicity Induced by Irinotecan / 中国实验方剂学杂志

Objective:Considering the efficacy of Gegen Qinliantang （GQT） in releasing exterior and clearing interior to alleviate dampness-heat dysentery， we analyzed the mechanism of the chloroform extract of GQT in alleviating enterotoxicity caused by irinotecan to provide an experimental basis for the development of GQT. Method:Kunming mice （<italic>n</italic>=60） were randomly divided into a blank group， a model group， a loperamide group （positive drug of loperamide hydrochloride capsule， 0.4 mg·kg^-1）， and high- （2.3 g·kg^-1） and low-dose （1.16 g·kg^-1） GQT chloroform extract groups. The mouse model of delayed diarrhea was established by intraperitoneal injection of irinotecan hydrochloride （CPT-11， 55 mg·kg^-1） for four consecutive days， meanwhile， the mice in the blank group only received the same volume of normal saline. Corresponding drugs were administered by gavage on the fifth day， respectively， while the ones in the blank group and model group were given distilled water for five consecutive days. The general condition of mice in each group was observed， and diarrhea indexes of mice were recorded. Pathological changes in colon tissues of mice were observed by hematoxylin-eosin （HE） staining. The tumor necrosis factor （TNF）-<italic>α</italic>， interleukin （IL）-1<italic>β</italic>， cyclooxygenase （COX）-2， intercellular adhesion molecule （ICAM）-1， glutathione peroxidase （GSH-Px）， superoxide dismutase （SOD）， malondialdehyde （MDA） and nitric oxide （NO） levels in colon tissues were detected with the assay kits. Furthermore， the expression levels of Kelch sample epoxy chloropropane associated protein 1 （Keap1）， nuclear factor E₂ related factor 2 （Nrf2）， tight junction protein-1 （ZO-1）， heme oxygenase-1 （HO-1） and tight junction protein （Occludin） were detected by Western blot. Result:Compared with the blank group， the model group showed declined body weight and reduced contents of GSH-Px and SOD （<italic>P</italic><0.01）， whereas increased diarrhea indexes and TNF-<italic>α</italic>， IL-1<italic>β</italic>， COX-2， ICAM-1， MDA and NO levels （<italic>P</italic><0.01）. Abundant inflammatory cells and colonic mucosa with defects， swelling， bleeding， and inflammatory exudation were revealed by HE staining in the mice of the model group. The expression levels of Keap1， Nrf2， ZO-1， HO-1 and Occludin in colon tissues significantly declined （<italic>P</italic><0.01）. Compared with the model group， the loperamide group and the high- and low-dose GQT chloroform extract groups exhibited improved weight loss， reduced diarrhea indexes， diminished TNF-<italic>α</italic>，<italic> </italic>IL-1<italic>β</italic>， COX-2， ICAM-1， MDA and NO， and elevated GSH-Px and SOD. HE staining indicated that the cells were compactly arranged with clear nuclei in the high- and low-dose GQT chloroform extract groups， and the expression levels of Keap1， Nrf2， HO-1， Occludin， and ZO-1 were up-regulated. Conclusion:GQT chloroform extract may alleviate CPT-11-induced delayed diarrhea by regulating inflammation and oxidative stress for enhancing the intestinal barrier function. These findings are expected to provide a reference for exploring the toxicity-attenuating effect of Chinese medicinals on chemotherapy drugs and for developing famous classical formulas.

A four-component combination derived from Huang-Qin Decoction significantly enhances anticancer activity of irinotecan / 中国天然药物

Huang-Qin Decoction (HQD) is a classic prescription for diarrhea in Chinese medicine treatment. Recent studies have demonstrated that HQD and its modified formulation PHY906 could ameliorate irinotecan (CPT-11) induced gastrointestinal (GI) toxicity and enhance its anticancer therapeutic efficacy. Nevertheless, which constituents in HQD are effective is still unclear so far. The study aims to screen out the key bioactive components combination from HQD that could enhance the anticancer effect of CPT-11. First, the potential bioactive constituents were obtained through system pharmacology strategy. Then the bioactivity of each constituent was investigated synthetically from the aspects of NCM460 cell migration, TNF-α release of THP-1-derived macrophage and MTT assay in HCT116 cell. The contribution of each constituent in HQD was evaluated using the bioactive index E

Analysis of the Efficacy of Irinotecan in the Second-line Treatment of Refractory and Relapsed Small Cell Lung Cancer / 中国肺癌杂志

BACKGROUND@#Among malignant tumors, lung cancer has the highest mortality rate. Small cell lung cancer (SCLC) is a kind of malignant lung cancer. Its doubling time is very fast. Patients are prone to drug resistance during treatment, and their condition often deteriorates rapidly after recurrence. Except for topotecan, there is a lack of effective second-line single-agent chemotherapy. This study aims to analysis the efficacy and safety of irinotecan (CPT-11) in the second-line treatment of refractory and relapsed SCLC.@*METHODS@#A total of 107 SCLC patients were collected from the Department of Oncology, Jilin Guowen Hospital, who were diagnosed from April 2012 to March 2020, relapsed within 6 months after first-line treatment, and received second-line chemotherapy with single-agent CPT-11. Follow-up until November 2020, calculate the patient's progression free survival (PFS) and overall survival (OS), and summarize the effects and adverse reactions of CPT-11 chemotherapy.@*RESULTS@#The patient's median PFS was 3.8 (3.4-4.4) months, median OS was 8.1 (6.5-10.9) months, objective response rate (ORR) was 16.82% (18/107), and DCR was 55.14% (59/107). The incidence of grade 3-4 adverse reactions in patients was relatively low. Among them, neutropenia was 13.08%, delayed diarrhea was 7.48%, nausea and vomiting was 17.76%, and liver function impairment was 6.54%. The influencing factors of PFS in single-agent CPT-11 second-line chemotherapy were gender (P=0.001), NSE (P=0.029), and effusion (P=0.040). While the influencing factors of OS were NSE level only (P=0.033).@*CONCLUSIONS@#For patients with refractory relapsed SCLC, CPT-11 single-agent second-line chemotherapy has a certain effect, is well tolerated, and is worthy of promotion.
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Efficacy and safety analysis of dose-modified FOLFOXIRI as first-line chemotherapy in advanced gastric cancer / 中国肿瘤临床

Objective: To evaluate the efficacy and safety of dose-modified FOLFOXIRI as first-line chemotherapy in advanced gastric cancer patients. Methods: Twenty patients without prior chemotherapy were enrolled between July 2016 and March 2019 at the Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Treatment consisted of oxaliplatin 85 mg/m2 on day 1, irinotecan 120 mg/m2 on day 1, leucovorin 200 mg/m2 on day 1, and 5-fluorouracil 2400 mg/m2 as a 44-h continuous infusion starting on day 1; treatment was repeated every two weeks. The primary endpoint was objective response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DOR), and safety. Results: The median number of treatment cycles was eight. ORR and DCR were 50% and 95%, respectively. The median time to response was 1.6 months, and the median DOR reached 8.7 months. The median follow-up was 19.5 months, the median PFS was 9.5 months (95% CI: 7.309-11.691), and the median OS was 19.9 months (95% CI: 9.754-30.046). The most common adverse enents (AEs) were leukopenia, elevation of ALT and AST, and diarrhea. Grade 3 neutropenia, diarrhea, and elevation of ALT occurred in 50%, 10%, and 5% patients, respectively. No Grade 4/5 AEs were observed. Conclusion: The dose-modified FOLFOXIRI showed promising antitumor activity and was well tolerated by advanced gastric cancer patients without previous treatment.

Comparison of two methods for the determination of sucrose octasulfate concentration in irinotecan hydrochloride liposomes / 药学学报

HPLC-RID and HPIC-CD methods were established for the determination of sucrose octasulfate content in irinotecan hydrochloride liposomes for injection. HPLC-RID: This method was performed on a Kromasil 100-5-NH2 column (250 mm×4.6 mm, 5 μm) with a mobile phase of 0.8 mol·L-1 ammonium sulfate buffer (pH 3.5)-acetonitrile (83∶17). The flow rate, column temperature and detector temperature were maintained at 1 mL·min-1, 30 ℃ and 30 ℃ respectively. HPIC-CD: This method was performed on an anion exchange column Dionex InPacTM AS11-HC (250 mm×4 mm, 9 μm) with an eluent of 30 mmol·L-1 sodium hydroxide solution. The flow rate was 1.5 mL·min-1, the column temperature was 30 ℃ and the detector temperature was 35 ℃. The HPLC-RID method and HPIC-CD method were validated with respects to specificity, limit of detection, limit of quantitation, linearity, precision, accuracy, stability and robustness and met the validation requirements. There were no significant differences between the HPIC-CD and HPLC-RID methods according to T-test analysis, both of which were applicable for the measurement of sucrose octasulfate concentration in irinotecan hydrochloride liposomes for injection. However, the HPLC-CD was better at the following aspects: higher detection sensitivity, simpler sample pretreatment, lower time and money spent, better environmental protection.

Risk Factors of Chemotherapy-Induced Neutropenia associated with FOLFOX, FOLFIRI, and FOLFOXIRI Regimens used in Patients with Advanced and Metastatic Colorectal Cancer

Background: Since the introduction of oxaliplatin and irinotecan, they have been the mainstay chemotherapies in the fluorouracil-based regimens, FOLFOX, FOLFIRI, and FOLFOXIRI, used in the treatment of advanced and/or metastatic colorectal cancer (CRC). These regimens are effective and usually well-tolerated in patients. However, they have been associated with neutropenia in some patients. Objective: The aim of this study was to assess risk factors of chemotherapy-induced neutropenia associated with the regimens used in CRC patients. Methods: A retrospective analysis was conducted of all CRC patients’ records who had been treated with the aforementioned regimens between January 2016 and February 2019 at the oncology clinics in a tertiary referral hospital in Riyadh, Saudi Arabia. Results: A total of 136 patients treated with the standard CRC regimens were identified. The majority of CRC patients (63.2%) had stage IV with extensive metastases. Twenty-two patients (16.2%) had developed neutropenia. However, only 13 of the neutropenic patients (59.1%) had shown symptoms of infections or fever. Most neutropenia occurred between the third and the fourth cycle of the used regimen. A significant increase in neutropenia was found in females (p=0.0273) and in patients with stage IV (p=0.0378). However, 53 CRC patients (39.0%) who received filgrastim had shown a significantly lower incidence of neutropenia (p=0.0027). Conclusion: Despite the effectiveness of the CRC chemotherapy regimens, the risk of neutropenia is still considerably elevated. The use of granulocyte colonystimulating factors such as filgrastim is an effective intervention to reduce neutropenia, hence infections, in high-risk CRC patients

Genomic DNA detection frequently-used chemotherapeutic drugs and their adverse drug reactions in children with rhabdomyosarcoma / 中华实用儿科临床杂志

Objective To analyze and summarize the results of genomic DNA test findings of chemotherapeutic drugs commonly used in pediatric rhabdomyosarcoma (RMS) in children,and to analyze the relationship between adverse reactions to chemotherapy toxicity and genomic DNA polymorphisms,so as to provide evidence for guiding treatment.Methods Retrospective analysis was conducted in RMS children admitted at Hematology Oncology Center,Beijing Children's Hospital,Capital Medical University from January 2017 to June 2018.The criteria for enrollment were definite diagnosis of RMS,regular treatment and follow-up at Hematology Oncology Center,Beijing Children's Hospital,Capital Medical University,and detection of peripheral blood DNA fluorescence hybridization sequence for several commonly chemotherapy drugs.The toxicity of chemotherapeutic drugs was detected based on the National Cancer Institute routine toxicity criteria (NCI-CTCAE version 4.0).Summary and analysis indicators included primary and metastatic site,size,international RMS clinical stage (TNM-UICC),Intergroup Rhabdomyosarcoma Study (IRS) Clinical Grouping Classification,risk grouping,pathological type,changes in major organ functions,as well as processes of surgery,chemotherapy and radiotherapy,and the association between toxicity and DNA polymorphism of drug genes was analyzed.SPSS 22.0 software was used for x2 test.Results A total of 32 children were enrolled,and 20 cases were male and 12 cases were female,their median age was 50 months (15-120 months).The primary tumor of 9 cases were sited in the chest,abdomen and basin,8 cases in the head and neck (non-meningeal),7 cases in bladder prostate,3 cases in limbs,2 cases in the meningeal area,1 case in urogenital tract (non-bladder prostate),2 cases in other parts.Seventeen cases were embryonic type and 15 cases were alveolar type.Five cases were TNM-Ⅰ stage,5 cases were TNM-Ⅱ stage,10 cases TNM-Ⅲ stage,12 cases were TNM-Ⅳ stage,21 cases were IRS-Ⅲ,11 cases were IRS-Ⅳ.Twenty-two cases were moderate-risk (MR),10 cases were high-risk (HR).Twenty-two cases were detected UGT1A1 * 6 gene,18 cases in GG type,13 cases in GA type,and 1 case in AA type.ABCB1 gene monitoring was performed in 27 children,14 cases of CT type and 13 cases of TT type;29 cases were detected GSTP1 gene,7 cases of GA type and 2 cases of GG type,19 cases of AA type,1 case of AG type;30 cases were detected CYP3A5 gene,2 cases of GA type,13 cases of GG type,AG 15 cases.All patients were treated according to the BCH-RMS-2007 protocol using VAC (Vincristine,Doxorubicin,and Cyclophosphamide) as the basis for chemotherapy.From 2017,VAC and Ⅵ regimen (Vincristine,Irinotecan) were defined as the standard of backbone chemotherapeutic regimen for MR.Nine cases underwent surgery before chemotherapy and 10 cases had surgery after chemotherapy,among them,5 cases underwent twice operation.Local radiotherapy was performed on the 12th week of chemotherapy,and the central nervous system involvement cases started in the first week.Hematological toxicity was mainly caused by neutropenia,with 2 cases of grade 3 and 30 cases of grade 4.Liver function damage of grade 2 was 6 cases,grade 3 was 3 cases.Four patients with grade 1 diarrhea,3 patients with grade 2,5 patients with grade 3,3 patients with grade 4.There was significant difference between the severity of diarrhea and UGT1A1 * 6 genotype polymorphism (P ＜ 0.05).Conclusions Chemotherapy for RMS patients is highly safety.If the genomic DNA test of chemotherapy drugs show a slow metabolism type,the dose of chemotherapy should be reduced,and the toxicity of chemotherapy drugs should be monitored dynamically.

Randomized Open Label Phase III Trial of Irinotecan Plus Capecitabine versus Capecitabine Monotherapy in Patients with Metastatic Breast Cancer Previously Treated with Anthracycline and Taxane: PROCEED Trial (KCSG BR 11-01) / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: We investigated whether irinotecan plus capecitabine improved progression-free survival (PFS) compared with capecitabine alone in patients with human epidermal growth factor 2 (HER2) negative and anthracycline and taxane pretreated metastatic breast cancer (MBC). MATERIALS AND METHODS: A total of 221 patients were randomly assigned to irinotecan (80 mg/m2, days 1 and 8) and capecitabine (1,000 mg/m2 twice a day, days 1-14) or capecitabine alone (1,250 mg/m2 twice a day, days 1-14) every 3 weeks. The primary endpoint was PFS. RESULTS: There was no significant difference in PFS between the combination and monotherapy arm (median, 6.4 months vs. 4.7 months; hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.63 to 1.11; p=0.84). In patients with triple-negative breast cancer (TNBC, n=90), the combination significantly improved PFS (median, 4.7 months vs. 2.5 months; HR, 0.58; 95% CI, 0.37 to 0.91; p=0.02). Objective response rate was numerically higher in the combination arm, though it failed to reach statistical significance (44.4% vs. 33.3%, p=0.30). Overall survival did not differ between arms (median, 20.4 months vs. 24.0 months; p=0.63). While grade 3 or 4 neutropenia was more common in the combination arm (39.6% vs. 9.0%), hand-foot syndrome was more often observed in capecitabine arm. Quality of life measurements in global health status was similar. However, patients in the combination arm showed significantly worse symptom scales especially in nausea/vomiting and diarrhea. CONCLUSION: Irinotecan plus capecitabine did not prove clinically superior to single-agent capecitabine in anthracycline- and taxane-pretreated HER2 negative MBC patients. Toxicity profiles of the two groups differed but were manageable. The role of added irinotecan in patients with TNBC remains to be elucidated.

Randomized Phase III Trial of Irinotecan Plus Cisplatin versus Etoposide Plus Cisplatin in Chemotherapy-Naïve Korean Patients with Extensive-Disease Small Cell Lung Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: This randomized phase III study was designed to compare the efficacy and safety of irinotecan plus cisplatin (IP) over etoposide plus cisplatin (EP) in Korean patients with extensive-disease small-cell lung cancer (SCLC). MATERIALS AND METHODS: Patients were randomly assigned to receive IP, composed of irinotecan 65 mg/m2 intravenously on days 1 and 8+cisplatin 70 mg/m2 intravenously on day 1 every 3 weeks, or EP, composed of etoposide 100 mg/m2 intravenously on days 1, 2, 3+cisplatin 70 mg/m2 intravenously on day 1, every 3 weeks for a maximum of six cycles, until disease progression, or until unacceptable toxicity occurred. The primary endpoint was overall survival. RESULTS: A total of 362 patients were randomized to IP (n=173) and EP (n=189) arms. There were no significant differences between IP and EP arms for the median overall survival (10.9 months vs. 10.3 months, p=0.120) and the median progression-free survival (6.5 months vs. 5.8 months, p=0.115). However, there was a significant difference in response rate (62.4% vs. 48.2%, p=0.006). The pre-planned subgroup analyses showed that IP was associated with longer overall survival in male (11.3 months vs. 10.1 months, p=0.036), < 65 years old (12.7 months vs. 11.3 months, p=0.024), and Eastern Cooperative Oncology Group performance status 0/1 (12.4 months vs. 10.9 months, p=0.040) patient groups. The severity of treatment-related adverse events such as grade 3/4 anemia, nausea and diarrhea was more frequent in patients treated with IP. CONCLUSION: The IP chemotherapy did not significantly improve the survival compared with EP chemotherapy in Korean patients with extensive-disease SCLC.

Efficacy observation of irinotecan combined with capecitabine or tegafur-gimeracil-oteracil potassium in the second-line treatment of advanced colorectal cancer / 肿瘤研究与临床

Objective To observe the clinical efficacy of irinotecan combined with capecitabine or tegafur-gimeracil-oteracil potassium in the second-line treatment of advanced colorectal cancer. Methods The clinical data of 19 patients with advanced colorectal cancer who were admitted to the Cancer Hospital of Chinese Academy of Medical Sciences and Peking Union Medical College from October 2014 to December 2017 were retrospectively analyzed, and these patients failed the first-line chemotherapy regimen. All patients were treated with irinotecan plus capecitabine or tegafur-gimeracil-oteracil potassium. The patient's short-term efficacy, adverse reactions, progression-free survival, and overall survival were analyzed. Results After treatment, the efficacy in 18 of the 19 patients with advanced colorectal cancer was evaluable, including partial remission in 3 patients, stable disease in 13 patients, and disease progression in 2 patients. The objective remission rate was 16.7％ (3/18), the disease control rate was 88.9％ (16/18), the median progression-free survival time was 7.6 months, and the median overall survival time was 23.3 months. All of the patients were well tolerated , and the grade 4 adverse reaction was presented as grade 4 neutropenia (1 case), grade 3 leukopenia (2 cases) and thrombocytopenia (1 case), grade 2 diarrhea (1 case), and grade 1 diarrhea (3 cases), and grade 1-2 liver injury (3 cases) and nephrotoxicity (2 cases). Conclusion Irinotecan combined with capecitabine or tegafur-gimeracil-oteracil potassium in the treatment of advanced colorectal cancer is effective and safe, which is worthy of clinical promotion.

Evaluation of tolerance and pharmacodynamics of nano-micelle irinotecan formulation / 中国药科大学学报

@#This study aimed to investigate the improvement of tolance and pharmacodynamics of nano-micelle irinotecan formulation compared with irinotecan hydrochloride injection(Campto). The toxic effects of the two formulations on colorectal cancer cells COLO205, HT-29, HCT-8 and SW480 were tested in vitro. COLO205 tumor-bearing mouse model was constructed. The two preparations were given via tail vein injection to investigate the maximum tolerance dose(MTD)of tumor-bearing mice to the two preparations, and then to explore the improvement of anti-tumor efficacy of nano-micelle irinotecan formulation near the MTD. The results showed that there was no significant difference in the inhibitory effect of the two formulations on the four colorectal cancer cells in vitro. The MTD of nano-micelle irinotecan formulation and Campto was 432. 0 and 276. 5 mg/m2 respectively. Both of the two formulations showed significant anti-tumor effect in vivo, and the relative tumor proliferation rate and tumor wet weight inhibition rate of nano-micelle irinotecan formulation at high dose(345. 6 mg/m2)were significantly better than those of Campto at two doses(177. 0 and 221. 2 mg/m2)(P< 0. 05).