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cyclophosphamide-induced reproductive toxicity: Beneficial effects of Helichrysum odoratissimum(Asteraceae) in male Wistar rats

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Journal of Integrative Medicine 2019年第5期17卷 366-373页

作者： Pierre Watcho Ismaelle Rosine Mpeck Patrick Brice Deeh Defo Modeste Wankeu-Nya Esther Ngadjui Georges Romeo Bonsou Fozin Pierre Kamtchouing Albert Kamanyi Animal Physiology and Phytopharmacology Laboratory University of DschangP.O. BOX 67DschangCameroon Department of Animal Organisms Biology University of DoualaP.O. BOX 24157DoualaCameroon Department of Animal Biology and Physiology University of YaoundeP.O. BOX 812YaoundeCameroon

Objective: cyclophosphamide(CP) is commonly used to treat some cancers, but its clinical efficacy is also linked with testicular toxicity. We investigated the effects of aqueous extract(AE) and methanolic extract(ME) of Helichrysum odoratissimum for reducing CP-induced reproductive toxicity in male rats.Methods: In addition to a normal control(group 1), drugs or vehicles were administered orally to seven groups(n = 5) of rats that had already received 4-weeks of pre-treatment with CP(5 mg/[kgád], per oral administration);group 2 received CP + distilled water(10 m L/[kgád]);group 3 received CP + 5% tween 80(10 m L/[kgád]);group 4 received CP + clomiphene citrate(0.25 mg/[kgád]);groups 5 and 6 received CP + AE(50 and 100 mg/[kgád]) and groups 7 and 8 received CP + ME(50 and 100 mg/[kgád]). Animals were sacrificed on day 15, and body and sexual organ weights, sperm characteristics, testosterone level and testicular histology were evaluated.Results: The CP-treated group showed a significant reduction(P < 0.001) in the body and seminal vesicle weights, testosterone level, sperm count, sperm motility and sperm viability, but elevated(P < 0.001)sperm morphological abnormalities and testicular structure alterations, compared to the control group.Interestingly, these detrimental effects of CP were reversed by treatment with H. odoratissimum extracts.For instance, both extracts and all doses of H. odoratissimum significantly increased the sperm count(P < 0.001), sperm motility(AE, 50 mg/kg, P < 0.05;ME, 50 and 100 mg/kg, P < 0.05) and sperm viability(AE, 50 mg/kg, P < 0.001;ME, 50 and 100 mg/kg, P < 0.001) compared to the CP group. H. odoratissimum also improved plasmatic and intratesticular testosterone levels and prevented histological alterations of the testes.Conclusion: H. odoratissimum might be considered as an alternative drug to alleviate/prevent reproductive damage in cancer patients receiving CP chemotherapy.

关键词： Helichrysum odoratissimum cyclophosphamide Reproductive toxicity Rat

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cyclophosphamide abrogates the expansion of CD4^(+)Foxp3^(+) regulatory T cells and enhances the efficacy of bleomycin in the treatment of mouse B16-F10 melanomas

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Cancer Biology & Medicine 2021年第4期18卷 1010-1020页

作者： Ping Li Fengyang Chen Jingbin Zheng Yang Yang Yuan Li Yifei Wang Xin Chen State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical ScienceUniversity of MacaoMacao 999078China

Objective:Promotion of the proliferative expansion of CD4^(+)Foxp3^(+)regulatory T cells(Tregs)is one of the side effects that limits the use of bleomycin(BLM)in the treatment of tumors.In this study,we examined the hypothesis that cyclophosphamide(CY),a chemotherapeutic agent with the capacity to eliminate tumor infiltrating Tregs,abrogated BLM-induced expansion of Tregs and consequently resulted in a better anti-tumor effect.Methods:The in vitro effects of BLM,with or without mafosfamide(MAF,the active metabolite of CY),on both TGF-β-induced differentiation of Tregs(iTregs),and TNF-induced expansion of naturally occurring Tregs(nTregs)were assessed.The in vivo effect of low doses of BLM and CY on tumor-infiltrating Tregs,as well as on the growth of mouse B16-F10 melanomas,was also studied.Results:In vitro treatment with BLM promoted the differentiation of iTregs,as well as TNF-induced expansion of nTregs.These effects of BLM were completely abrogated by MAF.Furthermore,in the mouse B16-F10 melanoma model,treatment with low doses of BLM increased the number of tumor-infiltrating Tregs,and this effect of BLM was also abrogated by CY.Importantly,combination therapy with low doses of BLM and CY showed synergistic anti-tumor effects.Conclusions:CY abrogated the effect of BLM on the expansion of Tregs.The combination of these 2 chemotherapeutic agents may represent a safer and more effective therapy in the treatment of cancer patients,and thus merits future clinical evaluation.

关键词： Bleomycin cyclophosphamide tumor necrosis factor Tregs TNFR2

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cyclophosphamide loaded thermo-responsive hydrogel system synergize with a hydrogel cancer vaccine to amplify cancer immunotherapy in a prime-boost manner

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Bioactive Materials 2021年第10期6卷 3036-3048页

作者： Fan Yang Kun Shi Ying Hao Yanpeng Jia Qingya Liu Yu Chen Meng Pan Liping Yuan Yongyang Yu Zhiyong Qian State Key Laboratory of Biotherapy and Cancer Center Collaborative Innovation Center for BiotherapyWest China HospitalSichuan UniversityChengdu610041PR China Department of Gastrointestinal Surgery West China HospitalSichuan UniversityChengdu610041PR China

Although neoantigen-based cancer vaccines show great potential in cancer immunotherapy due to their ability to induce effective and long-lasting anti-tumor immunity,their development is hindered by the limitations of neoantigens identification,low immunogenicity,and weak immune response.cyclophosphamide(CTX)not only directly kills tumors but also causes immunogenic cell death,providing a promising source of antigens for cancer vaccines.Herein,a combined immunotherapy strategy based on temperature-sensitive PLEL hydrogel is designed.First,CTX-loaded hydrogel is injected intratumorally into CT26 bearing mice to prime anti-tumor immunity,and then 3 days later,PLEL hydrogels loaded with CpG and tumor lysates are subcutaneously injected into both groins to further promote anti-tumor immune responses.The results confirm that this combined strategy reduces the toxicity of CTX,and produces the cytotoxic T lymphocyte response to effectively inhibit tumor growth,prolong survival,and significantly improve the tumor cure rate.Moreover,a long-lasting immune memory response is observed in the mice.About 90%of the cured mice survive for at least 60 days after being re-inoculated with tumors,and the distant tumor growth is also well inhibited.Hence,this PLEL-based combination therapy may provide a promising reference for the clinical promotion of chemotherapy combined with cancer vaccines.

关键词： Immunotherapy Thermo-responsive hydrogels Immunogenic cell death Cancer vaccine cyclophosphamide

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Exosomes derived from BMSCs ameliorate cyclophosphamide-induced testosterone deficiency by enhancing the autophagy of Leydig cells via the AMPK-mTOR signaling pathway

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Asian Journal of Andrology 2023年第4期25卷 474-483页

作者： Hao-Yu Liang Fan Peng Min-Jia Pan Sen-Lin Liao Cun Wei Guan-Yang Wei Xiao Xie Kang-Yi Xue Ming-Kun Chen Jian-Kun Yang Wen-Bin Guo Cun-Dong Liu Qi-Zhao Zhou Department of Urology The Third Affiliated Hospital of Southern Medical UniversityGuangzhou 510630China The Third School of Clinical Medicine Southern Medical UniversityGuangzhou 510515China The First School of Clinical Medicine Southern Medical UniversityGuangzhou 510515China

cyclophosphamide-induced testosterone deficiency (CPTD) during the treatment of cancers and autoimmune disorders severelyinfluences the quality of life of patients. Currently, several guidelines recommend patients suffering from CPTD receive testosteronereplacement therapy (TRT). However, TRT has many disadvantages underscoring the requirement for alternative, nontoxictreatment strategies. We previously reported bone marrow mesenchymal stem cells-derived exosomes (BMSCs-exos) could alleviatecyclophosphamide (CP)-induced spermatogenesis dysfunction, highlighting their role in the treatment of male reproductive disorders.Therefore, we further investigated whether BMSCs-exos affect autophagy and testosterone synthesis in Leydig cells (LCs). Here,we examined the effects and probed the molecular mechanisms of BMSCs-exos on CPTD in vivo and in vitro by detecting theexpression levels of genes and proteins related to autophagy and testosterone synthesis. Furthermore, the testosterone concentrationin serum and cell-conditioned medium, and the photophosphorylation protein levels of adenosine monophosphate-activatedprotein kinase (AMPK) and mammalian target of rapamycin (mTOR) were measured. Our results suggest that BMSCs-exos couldbe absorbed by LCs through the blood–testis barrier in mice, promoting autophagy in LCs and improving the CP-induced low serumtestosterone levels. BMSCs-exos inhibited cell death in CP-exposed LCs, regulated the AMPK-mTOR signaling pathway to promoteautophagy in LCs, and then improved the low testosterone synthesis ability of CP-induced LCs. Moreover, the autophagy inhibitor,3-methyladenine (3-MA), significantly reversed the therapeutic effects of BMSCs-exos. These findings suggest that BMSCs-exospromote LC autophagy by regulating the AMPK-mTOR signaling pathway, thereby ameliorating CPTD. This study provides novelevidence for the clinical improvement of CPTD using BMSCs-exos.

关键词： autophagy bone marrow mesenchymal stem cells cyclophosphamide exosomes Leydig cells testosterone deficiency

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cyclophosphamide,fluorouracil and low-dose interleukin-2 and salvage combination chemotherapy in advanced cutaneous squamous cell carcinoma

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Journal of Cancer Metastasis and Treatment 2020年第1期6卷 168-176页

作者： Giovanni Lo Re Paolo Doretto Francesco Lo Re Fabio Matrone Anna Ermacora Wally Marus Maria Antonietta Pizzichetta Sandro Sulfaro Medical Oncology and Immune-Related Tumors Centro di Riferimento Oncologico di Aviano(CRO)IRCCSAvianoPN 33081Italy Clinical Pathology AAS5 PordenonesePN 33170Italy Pharmacology and Clinical Toxicology University of MilanMilanMI 20129Italy Radiotherapy Unit Centro di Riferimento Oncologico di Aviano(CRO)IRCCSAvianoPN 33081Italy Internal Medicine AAS5 PordenonesePN 33170Italy Pathology AAS5 PordenonesePN 33170Italy Medical oncology and Cancer prevention Centro di Riferimento Oncologico di Aviano(CRO)IRCCSAvianoPN 33081Italy

A 70-year-old female with metastatic cutaneous squamous cell carcinoma(cSCC)and low-grade non-Hodgkin’s lymphoma,not amenable to cisplatin combination therapy,was treated with cyclophoshamide(Cyc)-fluorouracil(FU)-interleukin-2(IL-2)in light of high tumor immunogenicity and the potential activity of this regimen.Cyc 300 mg/m^(2)and FU 500 mg/m^(2)intravenously on day 1 and IL-24.5 MIU/day on days 3-6 and 17-20 subcutaneously every 4 weeks;Carboplatin(C)AUC 2 and paclitaxel(P)85 mg/m^(2)on days 1,8 and 15±capecitabine(Cape)every 4 weeks.After partial remission(PR)of lung metastases and local control with two cycles of first therapy followed by PR with five cycles of CP±Cape,right mastectomy was performed with evidence of viable tumor.Subsequently,the patient underwent 3 cycles of chlorambucil and is alive after 13 months of follow-up.Safety and activity of chemo-immunotherapy and salvage treatment can be achieved in cSCC.

关键词： Cutaneous squamous cell carcinoma cyclophosphamide fluorouracil interleukin-2 regulatory T cells myeloid-derived suppressor cells

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cyclophosphamide-associated enteritis: A rare association with severe enteritis

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World Journal of Gastroenterology 2016年第39期22卷 8844-8848页

作者： Linda S Yang Karla Cameron Tim Papaluca Chamara Basnayake Louise Jackett Penelope McKelvie David Goodman Barbara Demediuk Sally J Bell Alexander J Thompson Department of Gastroenterology St. Vincent’s HospitalFitzroy Department of Pathology St. Vincent’s HospitalFitzroy Department of Nephrology St. Vincent’s HospitalFitzroy

cyclophosphamide is a potent cytotoxic agent used in many clinical settings. The main risks of cyclophosphamide therapy include hematological disorders, infertility, hemorrhagic cystitis and malignancies. Gastrointestinal side effects reported to date are often non-specific and not severe. We present the first case of a fatal small bowel enteritis and pan-colitis which appears to be associated with cyclophosphamide. We aim to raise the readers' awareness of this significant adverse event to facilitate clinical suspicion and early recognition in potential future cases.

关键词：肠炎大肠炎 cyclophosphamide 小肠平底锅大肠炎

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Salvadora persica extract attenuates cyclophosphamide-induced hepatorenal damage by modulating oxidative stress, inflammation and apoptosis in rats

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Journal of Integrative Medicine 2022年第4期20卷 348-354页

作者： Talat Albukhari Bassem Refaat El-Sayed Bakr Sameh Baz Bodour Rajab Hossam Gadalla Mohamed El-Boshy Department of Immunology and Hematology Faculty of MedicineUmm Al-Qura UniversityMakkah 21955Saudi Arabia Department of Laboratory Medicine Faculty of Applied Medical SciencesUmm Al-Qura UniversityMakkah 7607Saudi Arabia Clinical Nutrition Department Faculty of Applied Medical Sciences Umm Al-Qura UniversityMakkah 7607Soudi Arabia Clinical Pathology Department Faculty of Veterinary MedicineMansoura UniversityMansoura 35516Egypt

Objective: Salvadora persica(SP) is used as a food additive and is a common ingredient in folk medicine.This study investigates the antioxidant, anti-inflammatory, and beneficial effects of SP against cyclophosphamide(CYP) toxicity in rats.Methods: In a 10-day study, 32 male rats were equally allocated into 4 groups(8 rats/group) as follows:the normal control(NC group), normal rats that only received oral aqueous extract of SP(100 mg/[kg·d];SP group), animals treated with intraperitoneal CYP injections(30 mg/[kg·d];CYP group), and the CYP + SP group that concurrently received CYP with SP aqueous extract. Serum samples were collected to measure the liver and renal biochemical profiles, as well as antioxidant and oxidative stress markers and the concentrations of interleukin-1β(IL-1β), IL-6, IL-10, tumor necrosis factor-a(TNF-a), nuclear factor-κB(NF-κB) and adenosine 5’-monophosphate-activated protein kinase(AMPK). Hepatic and renal tissues were also harvested for histopathology and to measure apoptosis using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling technique, alongside tissue levels of oxidative stress markers.Results: Liver enzymes, total bilirubin, creatinine and urea, as well as serum IL-1β, IL-6, TNF-a and NF-κB increased significantly, whilst total protein, albumin, calcium, IL-10 and AMPK declined in serum of the CYP group relative to the NC group. The hepatorenal concentrations of glutathione, glutathione peroxidase and catalase declined markedly in the CYP group, whereas malondialdehyde, protein adducts, and apoptosis index increased compared with the NC group. By contrast, the hepatorenal biochemistry and apoptosis index of the SP group were comparable to the NC group. Interestingly, the CYP + SP group had significant improvements in the liver and renal biochemical parameters, enhanced anti-oxidative and anti-inflammatory effects, and marked declines in hepatic and renal apoptosis relative to the CYP group. Moreover, all monitored parameters were statistically indistingui

关键词： cyclophosphamide Salvadora persica Cytokine NF-κB AMP-activated protein kinases Antioxidants Anti-inflammatory agents

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He-Wei Granule enhances anti-tumor activity of cyclophosphamide by changing tumor microenvironment

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Chinese Herbal Medicines 2022年第1期14卷 79-89页

作者： Jianxiu Zhai Zehai Song Hang Chang Yuwei Wang Na Han Zhihui Liu Jun Yin Key Laboratory of Northeast Plant Materials Department of Pharmacognosy and UtilizationSchool of Traditional Chinese MedicineShenyang Pharmaceutical UniversityShenyang 110016China

Objective:He-Wei Granule(HWKL)is a modern product derived from the modified formulation of traditional Chinese medicine Banxia Xiexin Decoction(BXD),which remarkedly enhanced the anti-proliferation activity of cyclophosphamide(CTX)on HepG2 and SGC-7901 cell lines in vitro in our previous research.The aim of the study was to investigate the synergistic effects of HWKL and CTX using a transplanted H22 hepatocellular carcinoma mouse model.Methods:The CTX-toxic-reducing efficacy of HWKL was evaluated by hematology indexes,organ indexes and marrow DNA detection.To investigate the underlying mechanisms,histopathology test,immunohistochemistry test and TUNEL staining were conducted.The efficacy of HWKL on the micro-vessel density(MVD)in tumor tissue was also evaluated by measuring CD34 level.Results:High dose HWKL(6.75 g/kg)markedly attenuated CTX-induced hepatotoxicity and myelosuppression while significantly enhanced CTX anticancer efficacy in vivo.Further mechanism investigation suggested that high dose HWKL significantly increased cleaved Caspase 3 level and promoted apoptosis in tumor tissue by up-regulating Bax expression and down-regulating Bcl-2 and FasL expressions.Compared with CTX alone group,the decrease in LC-3B and Beclin 1 levels suggested that the autophagy in H22 carcinoma was significantly inhibited with addition of high dose HWKL.ELISA assay results indicated that the autophagy inhibition was achieved by decreasing p53 expression,blocking PI3K/AKT/mTOR pathway and recovering Th1/Th2 cytokine balance.In addition,CD34 and EGFR immunohistochemistry assay suggest that high dose HWKL could significantly decrease micro-vessel density(MVD)and inhibit angiogenesis in H22 carcinoma.Conclusion:It can be concluded that high-dose HWKL enhanced CTX efficacy by promoting apoptosis,inhibiting autophagy and angiogenesis in tumor tissue while significantly alleviated CTX-induced toxicity,and could be applied along with CTX in clinical treatment as a supplement agent.

关键词： cyclophosphamide He-Wei Granule H22 carcinoma synergistic effect toxicity

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UPLC-Q-TOF/MS-based metabolomics reveals modulatory effects of Mesona chinensis Benth polysaccharide in liver injury mice induced by cyclophosphamide

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Food Science and Human Wellness 2023年第2期12卷 584-595页

作者： Yuzhen Hong Mingyue Shen Qiang Yu Yi Chen Jianhua Xie State Key Laboratory of Food Science and Technology Nanchang UniversityNanchang 330047China

The main purpose of this study was to investigate the improvement effect of Mesona chinensis Benth polysaccharide(MP)on cyclophosphamide(CTX)induced liver injury in mice.To explore metabolic profile of liver tissue and feces among normal group,CTX-induced group and MP management group based on metabolomics method by using UPLC-Q-TOF/MS.The results showed that MP could alleviate liver injury and promote the production of short chain fatty acids(SCFAs),with the best dose of 200 mg/kg·body weight(bw).The principal component analysis(PCA)and orthogonal partial least squares discriminant analysis(OPLSDA)scores plots of the liver and feces samples showed a clear separation among normal,model and highdose of MP(MPH).There were 18 endogenous metabolites in liver and 29 endogenous metabolites in feces,which were mainly involved in 8 metabolic pathways:taurine and hypotaurine metabolism,phenylalanine metabolism,α-linolenic acid metabolism,tricarboxylic acid(TCA)cycle,phenylalanine,tyrosine and tryptophan biosynthesis,arachidonic acid metabolism,sphingolipid metabolism as well as tryptophan metabolism.Moreover,a common metabolite arachidonic acid was observed in liver and feces samples.These endogenous metabolites may be considered to be MP’s response to liver protection.It will help to further understand the mechanism of MP and provide a basis for further research.

关键词： Metabolomics Polysaccharide Liver injury cyclophosphamide

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Treatment outcome analysis of bevacizumab combined with cyclophosphamide and oxaliplatin in advanced pseudomyxoma peritonei

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World Journal of Gastrointestinal Surgery 2023年第6期15卷 1149-1158页

作者： Ying Zhang Xin Zhao Chao Gao Lin-Yu Lin Yan Li Department of Peritoneal Cancer Surgery Beijing Shijitan HospitalCapital Medical UniversityBeijing 100038China

BACKGROUND Pseudomyxoma peritonei(PMP)is a rare peritoneal malignant tumor syndrome.Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy is its standard treatment.However,there are few studies and insufficient evidence regarding systemic chemotherapy of advanced PMP.Regimens for colorectal cancer are often used clinically,but there is no uniform standard for late-stage treatment.AIM To determine if bevacizumab combined with cyclophosphamide and oxaliplatin(Bev+CTX+OXA)is effective for treatment of advanced PMP.The primary study endpoint was progression-free survival(PFS).METHODS Retrospective analysis was conducted on the clinical data of patients with advanced PMP who received Bev+CTX+OXA regimen(bevacizumab 7.5 mg/kg ivgtt d1,oxaliplatin 130 mg/m2 ivgtt d1 and cyclophosphamide 500 mg/m2 ivgtt d1,q3w)in our center from December 2015 to December 2020.Objective response rate(ORR),disease control rate(DCR)and incidence of adverse events were evaluated.PFS was followed up.Kaplan-Meier method was used to draw survival curve,and log-rank test was used for comparison between groups.Multivariate Cox proportional hazards regression model was used to analyze the independent influencing factors of PFS.RESULTS A total of 32 patients were enrolled.After 2 cycles,the ORR and DCR were 3.1%and 93.7%,respectively.The median follow-up time was 7.5 mo.During the follow-up period,14 patients(43.8%)had disease progression,and the median PFS was 8.9 mo.Stratified analysis showed that the PFS of patients with a preoperative increase in CA125(8.9 vs 2.1,P=0.022)and a completeness of cytoreduction score of 2-3(8.9 vs 5.0,P=0.043)was significantly longer than that of the control group.Multivariate analysis showed that a preoperative increase in CA125 was an independent prognostic factor for PFS(HR=0.245,95%CI:0.066-0.904,P=0.035).CONCLUSION Our retrospective assessment confirmed that the Bev+CTX+OXA regimen is effective in second-or posterior-line treatment of advanced PMP and that adverse reactions can be tolera

关键词： Pseudomyxoma peritonei Bevacizumab Oxaliplatin cyclophosphamide

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