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

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Acta Pharmaceutica Sinica B 2023年第8期13卷 3444-3453页

作者： Shiwen Song Dong Sun Hong Wang Jinliang Wang Huijing Yan Xuan Zhao John Paul Fawcett Xin Xu Deqi Cai Jingkai Gu Research Center for Drug Metabolism School of Life SciencesJilin UniversityChangchun 130012China Center for Food and Drug Inspection of NMPA Changchun 130012China Jen Kem Technology Co. Ltd.Tianjin 300450China State Key Laboratory of Supramolecular Structure and Materials College of ChemistryJilin UniversityChangchun 130012China Beijing Institute of Drug Metabolism Beijing 102209China

irinotecan is an anticancer topoisomerase I inhibitor that acts as a prodrug of the active metabolite,***,the limited utility of irinotecan is attributed to its pH-dependent stability,short half-life and dose-limiting *** 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 *** 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 *** compared with conventional irinotecan,PEG-[irinotecan]3 displays extended release of irinotecan and efficient formation of SN-38 with significantly improved AUC and *** 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 *** summary,PEG-[irinotecan]3 displays superior pharmacokinetic characteristics and antitumor activity with lower toxicity than *** supports the view that PEG-[irinotecan]3 is a superior anticancer drug to irinotecan and it has entered the phaseⅡtrial stage.

关键词： irinotecan SN-38 Trivalent PEGylated irinotecan Prodrug Full-profile pharmacokinetics

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Oxaliplatin plus irinotecan vs irinotecan as second-line treatment in pancreatic cancer patients:a randomized–controlled open-label Phase II study

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Gastroenterology Report 2023年第1期11卷 224-229页

作者： Hangyu Zhang Zhou Tong Lulu Liu Qihan Fu Xudong Zhu Xiaomeng Dai Xuanwen Bao Weijia Fang Yi Zheng Peng Zhao Department of Medical Oncology School of MedicineFirst Affiliated HospitalZhejiang UniversityHangzhouZhejiangP.R.China

Background:Limited second-line therapeutic options are available for metastasis pancreatic cancer(mPC).We aimed to explore the efficacy and safety of oxaliplatin plus irinotecan(IROX)in mPC ***:This is an open-label,Phase 2,randomized study of mPC patients(aged 18–75 years)who failed when using gemcitabine plus S-1 as first-line *** randomization with a block size of four was used to randomly assign patients(1:1)between October 2015 and December 2017 to receive either IROX(oxaliplatin 85mg/m2 and irinotecan 160mg/m2)or irinotecan monotherapy(irinotecan 180mg/m^(2))until disease progression,unacceptable adverse events,or consent *** primary end point was overall survival,and the secondary end points were progression-free survival,overall response rate,and adverse event ***:A total of 74 patients were enrolled in this study,including 44 males and 30 females,with an average age of 61 *** median overall survival was 10.2 and 6.7 months(adjusted hazard ratio[HR],0.7;95%confidence interval[CI],0.4–1.2;P=0.20)and the median progression-free survival was 5.1 and 2.3 months(adjusted HR,0.4;95%CI,0.2–0.6;Pirinotecan group,*** overall response rates were 18.4%(7/38)in the IROX group and 5.5%(2/36)in the irinotecan group(P=0.06).Grade 3–4 adverse events occurred in 34%(13/38)of patients in the IROX group and 19%(7/36)of patients in the irinotecan group(P=0.15).Conclusions:IROX had no significant survival benefit over irinotecan monotherapy in our ***,IROX reduced the risk of disease progression by 60%,with acceptable toxicity.

关键词： pancreatic cancer second-line chemotherapy randomized control trial irinotecan IROX

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A cellular chip-MS system for investigation of Lactobacillus rhamnosus GG and irinotecan synergistic effects on colorectal cancer

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Chinese Chemical Letters 2022年第4期33卷 2096-2100页

作者： Wanting Hu Dan Gao Zhaochen Su Rui Qian Yu Wang Qionglin Liang State Key Laboratory of Chemical Oncogenomics the Graduate School at ShenzhenTsinghua UniversityShenzhen 518055China Department of Chemistry Center for Synthetic and Systems BiologyKey Laboratory of Bioorganic Phosphorus Chemistry&Chemical Biology(Ministry of Education)Tsinghua UniversityBeijing 100084China

Colorectal cancer(CRC) is still the leading cause of cancer death worldwide, but the clinical effect of drug therapy such as irinotecan is not an ideal way at present. In recent years, probiotics have attracted much attention, and the combination of probiotics may play an important role in the prevention and treatment of CRC. This work proposed a cellular chip-MS system, to study the synergistic effects of probiotic Lactobacillus rhamnosus GG(***) and irinotecan on HCT116 cells by cell viability and on-line mass spectrometry(MS) analysis. The double-layer chip sandwiched with a polycarbonate membrane can coculture HCT116 cells and ***. And the solid phase microextraction chip can be used for desalination and concentration. Finally, the extracted chemicals were entered the electrospray ionization quadrupole time-of-flight MS to detect irinotecan metabolites. The results showed that with the increasing concentration of co-cultured ***, the percentage of living HCT116 cells decreased, but the relative amount of metabolized SN-38 by HCT116 cells increased. Therefore, the microfluidic system can be used to detect and monitor the synergistic effect of *** combination on HCT116 cells. In summary, our study provided experimental evidence for the first time with potential applications of *** combination in CRC treatment, and the cellular chip-MS system as a powerful tool can be used in the experiments of probiotics as new drugs.

关键词： irinotecan Lactobacillus rhamnosus Microfluidics Mass spectrometry Colorectal cancer

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Short-term efficacy and influencing factors of conventional chemotherapy combined with irinotecan in patients with advanced gastric cancer

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World Journal of Gastrointestinal Oncology 2023年第1期15卷 143-154页

作者： Jun-Ping Wang Jian-Lei Du Ya-Ying Li Pharmacy Department Zhumadian Central HospitalZhumadian 463000Henan ProvinceChina

BACKGROUND Gastric cancer is one of the most common cancers worldwide, with a 5-year survival rate of only 20%. The age of onset of gastric cancer is in line with the general rule of cancer. Most of them occur after middle age, mostly between 40and 60 years old, with an average age of about 50 years old, and only 5% of patients are under 30 years old. The incidence of male is higher than that of *** To investigate the short-term efficacy and influencing factors of chemotherapy combined with irinotecan in patients with advanced gastric *** Eighty patients with advanced gastric cancer who were treated in our hospital from January 2019 to January 2022 were selected. The patients were divided into an observation group(n = 40) and control group(n = 40) by the envelope *** control group was given preoperative routine chemotherapy. The observation group was treated with irinotecan in addition to the chemotherapy given to the control group. The short-term efficacy of treatment in the two groups, as well as tumor marker levels and quality of life before and after treatment were *** The short-term treatment effect in the observation group was better than that in the control group(P < 0.05), and the total effective rate was 57.50%. The age and proportion of tumor node metastasis(TNM) stage IV patients with ineffective chemotherapy in the observation group were(65.12 ± 5.71) years and 52.94%,respectively, which were notably higher than those of patients with effective chemotherapy(P < 0.05), while the Karnofsky Performance Scale score was(67.70± 3.83) points, which was apparently lower than that of patients with effective chemotherapy(P <0.05). After 3 mo of treatment, the SF-36 scale scores of physiological function, energy, emotional function, and mental health in the observation group were 65.12 ± 8.14, 54.76 ± 6.70, 47.58 ± 7.22,and 66.16 ± 8.11 points, respectively, which were considerably higher than those in the control group(P < 0.

关键词： Advanced gastric cancer Conventional chemotherapy irinotecan Efficacy Quality of life

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irinotecan therapy and molecular targets in colorectal cancer: A systemic review

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World Journal of Gastroenterology 2009年第29期15卷 3597-3602页

作者： Jessica Weekes Alfred King-Yin Lam Sabe Sebesan Yik-Hong Ho Discipline of Surgery (School of Medicine) and North Queensland Centre for Cancer Research (Australian Institute of Tropical Medicine) James Cook University Townsville Queensland 4811 Australia Discipline of Pathology Griffith Medical School Medicine and Oral Health Centre Gold Coast Campus Gold Coast Queensland 4222 Australia Medical Oncology Townsville Hospital Townsville Queensland 4811 Australia

irinotecan is the second line chemotherapy for advanced stage colorectal cancer (CRC) after failure of first line chemotherapy with oxaliplatin and 5-fluorouracil. The aim of this review is to analyse the data on irinotecan as second line chemotherapy for advanced CRC and the potential roles of the molecular markers, p53 and vascular endothelial growth factor (VEGF) in the management of advanced CRC. Thus, the English literature from 1980 to 2008 concerning irinotecan, p53, VEGF and CRC was reviewed. On review, Phase and clinical trials showed thatirinotecan improves pain-free survival, quality of life, 1-year survival, progression-free survival and overall survival in advanced CRC. p53 and VEGF were expressed in CRC and had a predictive power of aggressive clinical behaviour in CRC. irinotecan sensitizes p53 wild type, mutant and null cells to Fasmediated cell apoptosis in CRC cells. Wild type p53 cells were more sensitive to irinotecan than mutated p53. irinotecan has an anti-VEGF effect inhibiting endothelial cell proliferation, increasing apoptosis and reducing microvascular density which is onlylimited by irinotecan toxicity levels. To conclude, irinotecan improves the patient's quality of life and the survival rates of patients with advanced CRC. p53 and VEGF status of the patients' tumour is likely to affect the responsiveness of CRC to irinotecan. It is recommended that studies of the expression of these molecular markers in relation to chemoresponsiveness ofirinotecan should be carried out for better management of patients with advanced CRC.

关键词： Colorectal cancer irinotecan Molecular p53 Vascular endothelial growth factor

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irinotecan or oxaliplatin combined with 5-fluorouracil and leucovorin as first-line therapy for advanced colorectal cancer： a meta-analysis

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Chinese Medical Journal 2010年第22期123卷 3314-3318页

作者： LIANG Xiao-bo HOU Sheng-huai Li Yao-ping WANG Li-chun ZHANG Xin YANG Jun Department of Colorectal Surgery Shanxi Cancer Hospital Taiyuan Shanxi 030013 China

Background To compare clinical efficacy and toxicity of irinotecan combined with 5-fluorouracil and leucovorin with those of oxatiplatin combined with 5-fluorouracil and leucovorin as first-line therapy for advanced colorectal cancer. Methods Literature search was performed by keywords ＂irinotecan＂, ＂oxaliplatin＂ and ＂colorectal cancer＂ on all randomized controlled trails reported on irinotecan versus oxaliplatin combined with 5-fluorouracil and leucovorin as first-line therapy for advanced colorectal cancer in MEDLINE, OVID, Springer, Cochrane Controlled Trials Register （CCTR） and CBMdisc （Chinese Biology and Medicine disc） before January 2010. Two authors drew the details of trial design, characteristics of patients, outcomes, and toxicity from the studies included. Data analysis was performed by RevMan 4.2. Results According to the screening criteria, 7 clinical studies with 2095 participants of advanced colorectal cancer were included in this meta analysis. The baseline characteristics of irinotecan group were similar to those of oxaliplatin group. The response rate of oxaliplatin group was higher than that of irinotecan group （relative risk （RR）=0.82, 95% confidence interval （95%C/）（0.70, 0.96）, P=0.01）, and the median overall survival of oxaliplatin group was longer by 2.04 months than that of irinotecan group （95%C/（-3.54, -0.54）, P=0.008）. In the comparison of grade 3-4 toxicity between the two groups, the incidences of nausea, emesis, diarrhoea and alopecia in irinotecan group were higher than those in oxaliplatin group （RR=1.94, 95%C/（1.22, 3.09）, P=0.005; 1.71, 95%C/（1.34, 2.18）, P 〈0.001; 14.56, 95%C/（4.11, 51.66）, P 〈0.0001）, respectively. However, the incidence of neurotoxicity, neutropenia and thrombocytopenia in irinotecan group were lower than those in oxaliplatin group （RR=0.06, 95%CI（0.03, 0.14）, P 〈0.00001; 0.70, 95%CI （0.55, 0.91）, P=0.006; 0.18, 95%CI（0.05, 0.61）, P=0.006）, respectively. Conclusions Both irinotecan and oxaliplatin combined wit

关键词： colorectal neoplasms irinotecan oxaliplatin meta-analysis

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irinotecan plus S-1 versus S-1 in patients with previously treated recurrent or metastatic esophageal cancer(ESWN 01):a prospective randomized,multicenter,open-labeled phase 3 trial

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Cancer Communications 2019年第1期39卷 151-160页

作者： Jing Huang Binghe Xu Ying Liu Junxing Huang Ping Lu Yi Ba Lin Wu Yuxian Bai Shu Zhang Jifeng Feng Ying Cheng Jie Li Lu Wen Xianglin Yuan Changwu Ma Chunhong Hu Qingxia Fan Xi Wang Department of Medical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeNo 17 Panjiayuan NanliChaoyang DistrictBeijing 100021P.R.China Department of Medical Oncology Henan Cancer HospitalZhengzhou 450008HenanP.R.China Department of Medical Oncology Taizhou People’s HospitalTaizhou 225300JiangsuP.R.China Department of Medical Oncology First Affiliated Hospital of Xinxiang Medical UniversityXinxiang 453100HenanP.R.China Department of Medical Oncology Tianjin Cancer HospitalTianjin 300060P.R.China Department of Medical Oncology Hunan Cancer HospitalChangsha 410006HunanP.R.China Department of Medical Oncology Harbin Medical University Cancer HospitalHarbin 150040HeilongjiangP.R.China Department of Medical Oncology Shandong Cancer HospitalJinan 250117ShandongP.R.China Department of Medical Oncology Jiangsu Cancer HospitalNanjing 210009JiangsuP.R.China Department of Medical Oncology Jilin Cancer HospitalChangchun 130012JilinP.R.China Department of Radiotherapy Shanxi Cancer HospitalTaiyuan 030013ShanxiP.R.China Department of Medical Oncology Shanxi Cancer HospitalTaiyuan 030013ShanxiP.R.China Department of Medical Oncology Tongji HospitalWuhan 430030HubeiP.R.China Department of Medical Oncology Chifeng Municipal HospitalChifeng 024000Inner MongoliaP.R.China Department of Oncology The Second Xiangya Hospital of Central South UniversityChangsha 410011HunanP.R.China Department of Oncology The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052HenanP.R.China

Background:The benefit of systemic treatments in esophageal squamous cell carcinoma(ESCC)which has pro-gressed after chemotherapy is still uncertain and optimal regimens based on randomized trials have not yet been *** aimed to compare the efficacy of irinotecan plus S-1 with S-1 monotherapy in recurrent or metastatic ESCC patients who had resistance to platinum-or taxane-based ***:We conducted a prospective randomized,multicenter,open-label,phase 3 trial in 15 centers across *** patients were adults with histologically confirmed recurrent or metastatic ESCC,and were randomly assigned(ratio,1:1)to receive either irinotecan plus S-1(intravenous infusion of irinotecan[160 mg/m2]on day 1 and oral S-1[80-120 mg]on days 1-10,repeated every 14 days)or oral S-1 monotherapy(80-120 mg/day on days 1-14,repeated every 21 days)using a central computerized minimization *** primary endpoint was progression-free survival(PFS).Results:Between December 23,2014 and July 25,2016,we screened 148 patients and randomly assigned 123 patients to receive either irinotecan plus S-1 regimen(n=61)or S-1 monotherapy(n=62).After a median follow-up of 29.2 months(95%confidence interval[CI]17.5-40.9 months),the median PFS was significantly longer in the irinotecan plus S-1 group than in the S-1 monotherapy group(3.8 months[95%CI 2.9-4.3 months]vs.1.7 months[95%CI 1.4-2.7 months],hazard ratio=0.58,95%CI 0.38-0.86,P=0.006).The objective response rates were 24.6%in the irinotecan plus S-1 group and 9.7%in the S-1 monotherapy group(P=0.002).The patients in the irinotecan plus S-1 group presented with increased rates of grade 3-4 leukopenia(16.4%vs.0%),neutropenia(14.8%vs.1.6%),and nausea(4.9%vs.0%).No significant difference in grade 3-4 diarrhea and no treatment-related deaths were observed in both ***: The combination of irinotecan with S-1 was similarly tolerable but significantly prolonged PFS compared to S-1 monotherapy as a second- o

关键词： Esophageal squamous cell carcinoma Recurrent Metastasis Multicenter open-label randomized trial irinotecan S-1 Overall survival Progression-free survival Objective response rate Disease control rate

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Pharmacometabolomic prediction of individual differences of gastrointestinal toxicity complicating myelosuppression in rats induced by irinotecan

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Acta Pharmaceutica Sinica B 2019年第1期9卷 157-166页

作者： Yiqiao Gao Wei Li Jiaqing Chen Xu Wang Yingtong Lv Yin Huang Zunjian Zhang Fengguo Xu Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education) State Key Laboratory of Natural MedicineChina Pharmaceutical University Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University

Pharmacometabolomics has been already successfully used in toxicity prediction for one specific adverse effect. However in clinical practice, two or more different toxicities are always accompanied with each other, which puts forward new challenges for pharmacometabolomics. Gastrointestinal toxicity and myelosuppression are two major adverse effects induced by irinotecan(CPT-11),and often show large individual differences. In the current study, a pharmacometabolomic study was performed to screen the exclusive biomarkers in predose serums which could predict late-onset diarrhea and myelosuppression of CPT-11 simultaneously. The severity and sensitivity differences in gastrointestinal toxicity and myelosuppression were judged by delayed-onset diarrhea symptoms, histopathology examination, relative cytokines and blood cell counts. Mass spectrometry-based non-targeted and targeted metabolomics were conducted in sequence to dissect metabolite signatures in predose serums. Eventually,two groups of metabolites were screened out as predictors for individual differences in late-onset diarrhea and myelosuppression using binary logistic regression, respectively. This result was compared with existing predictors and validated by another independent external validation set. Our study indicates the prediction of toxicity could be possible upon predose metabolic profile. Pharmacometabolomics can be a potentially useful tool for complicating toxicity prediction. Our findings also provide a new insight into CPT-11 precision medicine.

关键词： irinotecan Individual differences Complicating toxicity Prediction Metabolomics Gastrointestinal toxicity Biomarkers Diarrhea

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Visible-Light-Induced Radical Cascade Cyclization： Synthesis of（20S）-Camptothecin, SN-38 and irinotecan

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Chinese Journal of Chemistry 2018年第11期36卷 1035-1040页

作者： Yao Yuan Wuheng Dong Xiaoshuang Gao Xiaomin Xie Dennis P. Curran Zhaoguo Zhang Shanghai Key Laboratory for Molecular Engineering Of Chiral Drugs School of Chemistry and Chemical Engineering Shanghai Jiao Tong Uni- versity 800 Dongchuan Road Shanghai 200240 China Department of Chemistry University of Pittsburgh Pittsburgh Pennsyl-vania PA 15260 USA

(20 S )‐Camptothecin, irinotecan and SN‐38 were successfully synthesized by a photocatalyzed radical cascade cyclization from an N ‐propargyl iodopyridinone and an arylisonitrile under visible light with a ruthenium catalyst. This synthetic method provided a useful entry into composing camptothecin family of antitumor agents in good yields under mild reaction conditions without the use of heavy metal reagents.

关键词： photocatalysis radicals camptothecin irinotecan SN‐38 ruthenium

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Chemotherapy with or without irinotecan in patients with advanced or recurrent gastric cancer： a meta-analysis of randomized controlled trials

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Chinese Medical Journal 2014年第5期127卷 951-956页

作者： Zeng Chao Zhou Hang Wei Yang Wang Liyang Xie Hua Yao Wenxiu Department of Gastroenterology Third People&#39 s Hospital of Chengdu Chengdu Sichuan 610031 China

Background Studies have shown that irinotecan can improve survival in patients with advanced or recurrent gastric cancer,but the overall benefit of irinotecan in the treatment of advanced or recurrent gastric cancer remains *** aim of this study was to evaluate the benefits and risks of irinotecan for survival in patients with advanced or recurrent gastric *** We searched PubMed,EmBase,the Cochrane Central Register of Controlled Trials,reference lists of articles,and proceedings of major conferences for relevant clinical *** included randomized controlled trials that reported on the efficacy and safety of irinotecan in patients with advanced or recurrent gastric *** were analyzed by survival rate,objective response rate （ORR）,and ***,the analysis was further stratified by factors that could affect the treatment *** Eight trials recruiting 1 546 patients with advanced or recurrent gastric cancer were included in the ***,irinotecan therapy was associated with a 6％ improvement in survival rate,but this difference was not statistically significant （odds ratio （OR） 0.94; 95％ confidence interval （95％ CI） 0.70-1.27; P=-0.69）.However,irinotecan therapy had more frequent ORR than irinotecan-free arm （OR 1.70; 95％ CI 1.34-2.17; P ＜0.001）.Furthermore,irinotecan therapy was associated with a clinically and statistically significant increase in the risk for declined hemoglobin,hyponatremia,and diarrhea,but it also protected against thrombocytopenia risk when compared with irinotecan-free *** There is no evidence to support the use of irinotecan therapy in patients with advanced or recurrent gastric cancer; however,given the significant advantage in ORR irinotecan therapy using combination regimens may be considered for further evaluation in subsets of patients who may benefit from this treatment.

关键词： irinotecan gastric cancer meta-analysis

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