Objective:To investigate the protective effects of Lepidium draba L.(L.draba)on cyclophosphamide(CP)-induced hepatotoxicity and nephrotoxicity in rats.Methods:A total of 36 rats were divided into six groups as follows...Objective:To investigate the protective effects of Lepidium draba L.(L.draba)on cyclophosphamide(CP)-induced hepatotoxicity and nephrotoxicity in rats.Methods:A total of 36 rats were divided into six groups as follows:the sham control group,the CP group(CP 100 mg/kg i.p.on days 1,7,14,21,28,and 35),the CP groups treated with L.draba extract(100,200 and 400 mg/kg of L.draba extract for 28 d),and the L.draba extract alone group(400 mg/kg of L.draba extract for 28 d).Serum parameters of renal and hepatic function,as well as pro-inflammatory and anti-inflammatory cytokines associated with liver and kidney damage were measured.Moreover,Bax,Bcl-2,and caspase-3 gene expression and histopathological changes were assessed.Results:L.draba extract alleviated CP-induced hepatotoxicity and nephrotoxicity by decreasing nitric oxide,TBARS,IL-6,TNF-α,and IL-1βlevels,as well as increasing superoxide dismutase,catalase and glutathione peroxidase activities,and FRAP,MIF,and TGF-βlevels.In addition,the extract downregulated the expression of pro-apoptotic genes(Bax and caspase-3)and mitigated the destruction of glomeruli and renal tubules as well as the degeneration of hepatocytes.Conclusions:L.draba extract can protect hepatic and renal structure and function against CP-induced toxicities,and may be used as a therapeutic agent for CP-induced hepatotoxicity and nephrotoxicity.展开更多
OBJECTIVES:To investigate the therapeutic effect of Huluan decotion(护卵汤,HLD)on cyclophosphamideinduced premature ovarian failure(POF)in mice and its regulatory mechanisms.METHODS:Female BALB/c mice were administere...OBJECTIVES:To investigate the therapeutic effect of Huluan decotion(护卵汤,HLD)on cyclophosphamideinduced premature ovarian failure(POF)in mice and its regulatory mechanisms.METHODS:Female BALB/c mice were administered cyclophosphamide and administered received different doses of HLD for 28 d.Levels of sex hormone,such as estradiol(E2),follicle stimulating hormone(FSH)and luteinizing hormone(LH)in the sera,were assessed using enzyme-linked immunosorbent assay(ELISA).Follicular structure variances were observed through hematoxylin and eosin(HE)staining,while Forkhead box L2(FOXL2)expression were analyzed via immuneohistochemical staining.The primary mechanism of POF were investigated through Western blot analysis.RESULTS:E2 levels decreased,and FSH and LH levels increased in POF model mice,but these trends were reversed with HLD or premarin administration,the expressions of WNT family member 4(Wnt4),β-Catenin and FOXL2 were downregulated in POF model mice,whereas high expression levels were observed in control mice and other groups.CONCLUSION:HLD effectively treats POF induced with cyclophosphamide in mice by enhancing expressions of Wnt4,β-Catenin and FOXL2.展开更多
Objective:To study the antioxidant protective effect and mechanism of melatonin on cyclophosphamide-induced premature ovarian failure model mice.Methods:Six-month sexually mature female Kunming mice were taken for one...Objective:To study the antioxidant protective effect and mechanism of melatonin on cyclophosphamide-induced premature ovarian failure model mice.Methods:Six-month sexually mature female Kunming mice were taken for one week of acclimatization and then randomly divided into a normal group,blank control group,drug control group,ovarian premature aging model group,and melatonin intervention low,medium,and high dose group,with 20 mice in each group.We observed the status and body mass of the mice in each group;observed and monitored the estrous cycle by HE staining;measured the diameter and size of the ovaries and weighed the wet weight of the ovaries;observed the morphological changes of the ovaries by HE staining and counted the developing follicles at all levels;detected the levels of serum estradiol(E2),follicle-stimulating hormone(FSH),and luteinizing hormone(LH)by ELISA;measured the levels of serum MDA,SOD,and GSH-PX by antioxidant kit;detected the levels of protein immunoblotting by ELISA;protein immunoblotting(Western blot)to examine the expression of DNA damage-related proteinsγH2AX,p53,and p21 in ovarian tissues.Results:Compared with the control group,mice in the premature ovarian failure model group showed reduced mobility,rough hair,decreased body weight,disorganized estrous cycle,decreased ovarian weight(P<0.05),decreased number of follicles at all levels of development(P<0.05),increased number of atretic follicles(P<0.05),significantly elevated levels of serum FSH and LH,significantly decreased levels of E2(P<0.05),significantly increased levels of serum MDA,significantly lower SOD and GSH-PX levels(P<0.05),and the expression of p53,p21,andγH2AX in ovarian tissues was increased(P<0.05).Compared with the model group of premature ovarian failure,melatonin improved the changes of the above indexes induced by cyclophosphamide-induced premature ovarian failure in mice.Conclusion:Melatonin can improve the changes of motility cycle disorders,abnormal follicular development,and abnormal serum hormone levels induced by cyclophosphamide-induced oxidative stress in mice with premature ovarian failure.At the same time,melatonin can improve the oxidative stress induced by cyclophosphamide and alleviate the role of oxidative stress-induced DNA damage in mouse ovaries by exerting its antioxidant effect.展开更多
Background:Allogeneic peripheral-blood stem-cell transplantation(SCT)from a matched related donor after myeloablative conditioning is the preferred curative treatment for patients with high-risk blood cancers.The comb...Background:Allogeneic peripheral-blood stem-cell transplantation(SCT)from a matched related donor after myeloablative conditioning is the preferred curative treatment for patients with high-risk blood cancers.The combination of a calcineurin inhibitor and an antimetabolite remains standard care for graft-versus-host disease(GVHD)prophylaxis in these patients.Data from two randomized trials have suggested that post-transplantation cyclophosphamide can reduce the risk of GVHD after SCT from a matched donor when it is added to or replaces the antimetabolite.展开更多
OBJECTIVE To investigate the damage effect and mechanisms of cyclophosphamide(CTX)and its active metabolite derivative 4-hydroperoxycyclophosphamide(4-HC)to human neuroblas⁃toma SH-SY5Y cells.METHODS SH-SY5Y cells wer...OBJECTIVE To investigate the damage effect and mechanisms of cyclophosphamide(CTX)and its active metabolite derivative 4-hydroperoxycyclophosphamide(4-HC)to human neuroblas⁃toma SH-SY5Y cells.METHODS SH-SY5Y cells were treated with CTX[0(cell control),0.01,0.1,1,5,10,20,40 and 80 mmol·L^(-1)]and 4-HC[0(cell control),0.01,0.1,1,5,10,20,40 and 80μmol·L^(-1)]for 48 h.Cell confluence and morphology were observed by the IncuCyte ZOOM system.Cell viability was assessed by CCK-8 assay.Lactate dehydrogenase(LDH)release was measured by LDH assay kit.SH-SY5Y cells were treated with CTX(0,1,5,10 and 20 mmol·L^(-1))and 4-HC(0,1,5,10 and 20μmol·L^(-1))for 48 h before cell proliferation was analyzed by 5-ethynyl-2′-deoxyuridine(EdU)staining assay.Immunofluorescence was employed to assess the levels of the DNA double-strand break markerγ-H2AX and to evaluate changes in mitochondrial membrane potential.SH-SY5Y cells were treated with CTX(0,1,5 and 10 mmol·L^(-1))and 4-HC(0,1,5 and 10μmol·L^(-1))for 48 h,and the alterations in glycolysis and oxidative phosphorylation levels were analyzed using the Seahorse XFe96 Analyzer.RESULTS Compared with the cell control group,cell confluence and cell viability were significantly reduced in the CTX and 4-HC groups(P<0.01),and the half-maximal inhibitory concentrations(IC50)for CTX and 4-HC were 4.44 mmol·L^(-1) and 4.78μmol·L^(-1),respectively.The release rate of LDH was signif⁃icantly increased while the percentage of EdU+cells was significantly reduced in the CTX and 4-HC groups(P<0.01).The percentage ofγ-H2AX+cells was significantly increased and mitochondrial membrane potential significantly decreased in the CTX and 4-HC group(P<0.05).Treatment with CTX and 4-HC resulted in reduced levels of maximum glycolytic capacity,glycolytic reserve,maximal respi⁃ration,and ATP production(P<0.05).CONCLUSION CTX and 4-HC exert significant cytotoxic effects on SH-SY5Y cells by disrupting cell membrane structure,impeding cell proliferation,and reducing cell viability.The mechanisms underlying these effects may involve intracellular DNA damage,disturbance of energy metabolism and mitochondrial dysfunction.展开更多
Objective:To explore the effect of geraniol on cyclophosphamide-induced cardiotoxicity.Methods:Mice were divided into five groups:the control group,the cyclophosphamide group(200 mg/kg cyclophosphamide,i.p.on day 7),t...Objective:To explore the effect of geraniol on cyclophosphamide-induced cardiotoxicity.Methods:Mice were divided into five groups:the control group,the cyclophosphamide group(200 mg/kg cyclophosphamide,i.p.on day 7),the group treated with geraniol 100 and 200 mg/kg from day 1 to day 14,along with a single dose of cyclophosphamide on day 7,and the geraniol alone group(200 mg/kg geraniol from day 1 to day 14).At the end of the study,animals were sacrificed,and blood and heart were collected and analyzed for biochemical,histopathological,and immunohistochemical changes.Results:Treatment with 200 mg/kg geraniol significantly reduced the levels of cardiac injury markers,malondialdehyde,and inflammatory and apoptotic markers,while increasing antioxidant activities in mice with cyclophosphamide-induced cardiotoxicity.Moreover,it remarkably alleviated histopathological aberrations in cardiac tissue.Conclusions:Geraniol attenuates cyclophosphamide-induced cardiotoxicity via antioxidant,anti-inflammatory,and antiapoptotic effects.展开更多
OBJECTIVE:To investigate the effect of Ganoderma Lucidum Spore Oil(GLSO)on the tumor growth and survival of H22 tumor-bearing mice treated with cyclophosphamide(CTX),and explore the underlying mechanism.METHODS:Allogr...OBJECTIVE:To investigate the effect of Ganoderma Lucidum Spore Oil(GLSO)on the tumor growth and survival of H22 tumor-bearing mice treated with cyclophosphamide(CTX),and explore the underlying mechanism.METHODS:Allograft H22 hepatocellular carcinoma mouse model was applied to investigate the effect of GLSO on the tumor growth and survival of animals,and Kaplan-Meier survival analysis was used to analyze the life span.Plasma biochemical examination was used to determine the levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),urea(UREA)and creatinine(CRE).Western blot analysis was performed to detect Programmed Death-1(PD-1),Programmed Death Ligand 1(PD-L1),Janus Kinase 2(JAK2),phosphorylated Signal Transducer and Activator of Transcription 3(p-STAT3),and Signal Transducer and Activator of Transcription 3(STAT3)expression.RESULTS:GLSO increased the anti-tumor effect of CTX and prolonged the survival of H22 tumor-bearing mice treated with CTX.Meanwhile,GLSO increased the thymus index and showed no obvious toxicity to liver functions of animals.GLSO also decreased the level of UREA in H22 tumor-bearing mice treated with CTX.Furthermore,GLSO could inhibit the expression of PD-1 in spleen,which was independent of JAK2 expression and STAT3 phosphorylation.However,GLSO did not affect the expression of PD-L1,JAK2,and p-STAT3 in tumor tissue.CONCLUSION:GLSO could strengthen the anti-tumor effect of CTX and prolong the life span of H22 tumorbearing mice,while the underlying mechanism might be relevant to the amelioration effect of thymus function and inhibition of PD-1 expression in spleen.Furthermore,these findings implied the promising role of GLSO in combination with CTX to extend the survival of patients in clinical chemotherapy of hepatocellular carcinoma.展开更多
Objective: Unresectable hepatocellular carcinoma(uHCC) continues to pose effective treatment options. The objective of this study was to assess the efficacy and safety of combining low-dose cyclophosphamide with lenva...Objective: Unresectable hepatocellular carcinoma(uHCC) continues to pose effective treatment options. The objective of this study was to assess the efficacy and safety of combining low-dose cyclophosphamide with lenvatinib, pembrolizumab and transarterial chemoembolization(TACE) for the treatment of uHCC.Methods: From February 2022 to November 2023, a total of 40 patients diagnosed with uHCC were enrolled in this small-dose, single-center, single-arm, prospective study. They received a combined treatment of low-dose cyclophosphamide with lenvatinib, pembrolizumab, and TACE. Study endpoints included progression-free survival(PFS), objective response rate(ORR), and safety assessment. Tumor response was assessed using the modified Response Evaluation Criteria in Solid Tumors(mRECIST), while survival analysis was conducted through KaplanMeier curve analysis for overall survival(OS) and PFS. Adverse events(AEs) were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events(version 5.0).Results: A total of 34 patients were included in the study. The median follow-up duration was 11.2 [95% confidence interval(95% CI), 5.3-14.6] months, and the median PFS(mPFS) was 15.5(95% CI, 5.4-NA) months.Median OS(mOS) was not attained during the study period. The ORR was 55.9%, and the disease control rate(DCR) was 70.6%. AEs were reported in 27(79.4%) patients. The most frequently reported AEs(with an incidence rate >10%) included abnormal liver function(52.9%), abdominal pain(44.1%), abdominal distension and constipation(29.4%), hypertension(20.6%), leukopenia(17.6%), constipation(17.6%), ascites(14.7%), and insomnia(14.7%). Abnormal liver function(14.7%) had the most common grade 3 or higher AEs.Conclusions: A combination of low-dose cyclophosphamide with lenvatinib, pembrolizumab, and TACE is safe and effective for u HCC, showcasing a promising therapeutic strategy for managing uHCC.展开更多
Aplastic anemia(AA)is a rare but serious condition in which the bone marrow fails to produce sufficient new blood cells,leading to fatigue,increased susceptibility to infection,and uncontrolled bleeding.In this editor...Aplastic anemia(AA)is a rare but serious condition in which the bone marrow fails to produce sufficient new blood cells,leading to fatigue,increased susceptibility to infection,and uncontrolled bleeding.In this editorial,we review and comment on an article by Wang et al published in 2024.This study aimed to evaluate the potential therapeutic benefits of ginsenoside Rg1 in AA,focusing on its protective effects and uncovering the underlying mechanisms.Cyclophosphamide(CTX)administration caused substantial damage to the structural integrity of the bone marrow and decreased the number of hematopoietic stem cells,thereby establishing an AA model.Compared with the AA group,ginsenoside Rg1 alleviated the effects of CTX by reducing apoptosis and inflammatory factors.Mechanistically,treatment with ginsenoside Rg1 significantly mitigated myelosuppression in mice by inhibiting the mitogen activated protein kinase signaling pathway.Thus,this study indicates that ginsenoside Rg1 could be effective in treating AA by reducing myelosuppression,primarily through its influence on the mitogen activated protein kinase signaling pathway.We expect that our review and comments will provide valuable insights for the scientific community related to this research and enhance the overall clarity of this article.展开更多
BACKGROUND Parthenolide(PTL),a sesquiterpene lactone derived from the medicinal herb Chrysanthemum parthenium,exhibits various biological effects by targeting NF-kB,STAT3,and other pathways.It has emerged as a promisi...BACKGROUND Parthenolide(PTL),a sesquiterpene lactone derived from the medicinal herb Chrysanthemum parthenium,exhibits various biological effects by targeting NF-kB,STAT3,and other pathways.It has emerged as a promising adjunct therapy for multiple malignancies.AIM To evaluate the in vitro and in vivo effect of PTL on cyclophosphamide(CTX)metronomic chemotherapy.METHODS The cytotoxicity of PTL and CTX on Lewis lung cancer cells(LLC cells)was assessed by measuring cell activity and apoptosis.The anti-tumor efficiency was evaluated using a tumor xenograft mice model,and the survival of mice and tumor volume were monitored.Additionally,the collected tumor tissues were analyzed for tumor microenvironment indicators and inflammatory factors.RESULTS In vitro,PTL demonstrated a synergistic effect with CTX in inhibiting the growth of LLC cells and promoting apoptosis.In vivo,metronomic chemotherapy com-bined with PTL and CTX improved the survival rate of tumor-bearing mice and reduced tumor growth rate.Furthermore,metronomic chemotherapy combined with PTL and CTX reduced NF-κB activation and improved the tumor immune microenvironment by decreasing tumor angiogenesis,reducing Transforming growth factorβ,andα-SMA positive cells.CONCLUSION PTL is an efficient compound that enhances the metronomic chemotherapy effects of CTX both in vitro and in vivo,suggesting its potential as a supplementary therapeutic strategy in metronomic chemotherapy to improve the chemotherapy effects.展开更多
An experiment was conducted to compare the effects of two mouse thrombocytopenia models induced by cyclophosphamide at two different administration routes to determine a proper cyclophosphamide administration route th...An experiment was conducted to compare the effects of two mouse thrombocytopenia models induced by cyclophosphamide at two different administration routes to determine a proper cyclophosphamide administration route that could cause stable thrombocytopenia. A suitable drug dosage that could induce thrombocytopenia in mouse efficiently with the definite administration route was then investigated. BALB/c mice were randomly divided into Normal, Model A and Model B groups. To Model A, 200 mg/kg of cyclophosphamide was given by vena caudalis injection as first dose and 30 mg/kg as maintenance dose by intraperitoneal injection at the following 6 days. To Model B, 150 mg/kg of cyclophosphamide was given by subcutaneous injection once a day for consecutive 3 days. All groups were under investigation for 15 days. The result suggested that a decrease in the number of blood platelets of Model B at the 7th day were significantly than that of Normal. Other platelet related indices like platelet distribution width, mean platelet volume and platelet-large cell ratio of Model B increased significantly in comparison with those of Normal group. The platelets count was reduced but fluctuated greatly, and more than half of the mice died in Model A. Therefore, subcutaneous injection of cyclophosphamide for 3 days was used for the cyclophosphamide dosage test. BALB/c mice were randomly divided into Normal, cyclophosphamide low dose （100 mg/kg）, medium dose （120 mg/kg） and high dose （140 mg/kg） groups. All groups were under investigation for 11 days. Though all 3 dosages successfully initiated thrombocytopenia as the platelets number dropped at the 7th day, the low dose was considered to be a suitable one that was of high efficacy and low toxicity. Thus, BALB/c mice challenged by subcutaneous injection of cyclophosphamide 100 mg/kg per day for 3 consecutive day is one simple, feasible and stable mouse thrombocytopenia model that could be used for pharmacodynamic test of the drugs which are supposed to have platelets increasing effect.展开更多
A rapid and simple liquid chromatography method with on-line solid phase extraction was developed and validated for the quantitative determination of cyclophosphamide in rat plasma.The plasma sample was first extracte...A rapid and simple liquid chromatography method with on-line solid phase extraction was developed and validated for the quantitative determination of cyclophosphamide in rat plasma.The plasma sample was first extracted on an Acclaim？ Polar Advantage II C18 guard column（PA II C18,10 mm×4.6 mm,5 μm）,which was also the on-line Extraction Cartridge SPE column,by washing with 100% H2O for 1 min.The extracted sample was then eluted onto a PA II C18 column（150 mm×4.6 mm,5 μm） and separated by isocratic elution with acetonitrile-water（40：60,v/v）.The mobile phase was run at a flow rate of 1.0 mL/min,and the UV detector was set at 195 nm.Retention time of cyclophosphamide was 4.3 min and the total run-time was 6 min.The linear range of the standard curve was from 1.0 to 200 μg/mL（r2 = 0.9999）,and the limits of quantification and detection were 1.0 μg/mL（RSD10%,n = 5） and 0.3 μg/mL（RSD13%,n = 5）,respectively.Both intra-and inter-day variations were less than 5.6%.The developed method can be used for the therapeutic drug monitoring of cyclophosphamide in the clinic.展开更多
Hematological toxicity （bone marrow suppression） is the most common dose-limiting adverse effect of chemotherapies. The nuclear factor erythroid 2-related factor 2 （Nrf2） is a pivotal coordinator of cellular defen...Hematological toxicity （bone marrow suppression） is the most common dose-limiting adverse effect of chemotherapies. The nuclear factor erythroid 2-related factor 2 （Nrf2） is a pivotal coordinator of cellular defensive responses against chemical insults in many tissues including bone marrow. In the present study, the effects of tert-butylhydroquinone （tBHQ） on the expression of Nrf2-regulated genes in peripheral blood cells and cyclophosphamide （CTX）-induced hematotoxicity in mice were investigated. CTX induced apoptosis of peripheral blood nucleated cells and leukopenia in mice, accompanied by mobilization of bone marrow hematopoietic cells, tBHQ treatment induced the expression of Nrf2-regulated genes such as heine oxygenase 1 （HO1） and glutamate-cysteine ligase catalytic subtmit （GCLC） in RAW264.7 mouse macrophage cells and peripheral blood cells both in vitro and in vivo. Interestingly, pretreatment with tBHQ alleviated CTX-induced mouse peripheral blood cell apoptosis and leukopenia in vivo, indicating possible involvement of Nrf2 in the protection against CTX-induced hematotoxicity. This study provides new information on the chemotherapy-induced hematotoxicity, and suggests Nrf2 could serve as a target for the development of chemoprotectants against hematotoxicity.展开更多
The protective effect of a kind of purified polysaccharides extracted from Radix of Phytolacca acinosa Roxb,with a molecular weight of 10 KDa,on hematopoiesis was investigated.Average survival time of mice treated wit...The protective effect of a kind of purified polysaccharides extracted from Radix of Phytolacca acinosa Roxb,with a molecular weight of 10 KDa,on hematopoiesis was investigated.Average survival time of mice treated with cyclophosphamide (CY) 300 mg/kg once alone was 13.3 ± 7.2d(n=7) however,average survival time of mice treated with CY 300 mg/kg in com-bination with PAP-1 10 mg/kg,3 times/wk was 36.7± 16.4d(n=7,P<0.01).PAP-1,ip had benefi-cial effect on the recovery of the CY induced decrease of peripheral leukocyte number,and the nu-cleated bone marrow cell(BMC)number and[3￣H]TdR uptaken by BMC induced by rmGM-CSF in S180 bearing mice treated with CY,In mice,after the first ip treatment with CY 100 mg/kg on d7,the peripheral leukocyte number decreased on d9 and recovered to normal level about d13 to d15. Such recovery was accelerated by administrating PAP-1,10mg/kg, 3 times/wk.A significant in-crease of the activity to form colony in spleen(colony-forming unit in spleen, CFU-S_8, CUF-S12) in mice irradiated with 550 rad 6O￣Co γ-rays and an enhancement of proliferative response of BMC to rmGM-CSF treated with PAP-1,10mg/kg,3 times/wk, ip were observed.After PAP-1,10 mg/kg,ip once,a significant increase in the number of peripheral blood leukocytes and a rise in the serum of colony stimulating factor(CSF) were also confirmed.The types of CSF in serum were M-CSF and other hematopoietic growth factors,which were confirmed by using McAb of IL-3, GM-CSF and PcAb of M-CSF. These beneficial effects of PAP-1 on hematopoiesis may be related to its activityinducing CSFs and other hematopoietic growth factors and warrant further evaluation of its use-fulness.展开更多
Novel prodrugs of cyclophosphamide 1a and 1b, which comprised the galactosyl moiety, the key fraction of cyclophosphamide derivates, and the linker 4-hydroxy benzaldehyde, were synthesized. These compounds were antici...Novel prodrugs of cyclophosphamide 1a and 1b, which comprised the galactosyl moiety, the key fraction of cyclophosphamide derivates, and the linker 4-hydroxy benzaldehyde, were synthesized. These compounds were anticipated to exhibit amplified anti-tumor activity and targeting ability.展开更多
Aim:To study the detrimental effects of cyclophosphamide on the testicular androgenic and gametogenic activities through endocrine inhibition and/or induction of oxidative stress in male albino rats and to evaluate th...Aim:To study the detrimental effects of cyclophosphamide on the testicular androgenic and gametogenic activities through endocrine inhibition and/or induction of oxidative stress in male albino rats and to evaluate the protective effect of ascorbic acid.Methods:The testicular△^(5),3β-hydroxysteroid dehydrogenase(HSD),17β-HSD,peroxidase and catalase activities along with the levels of malondialdehyde(MDA)and conjugated dienes in testicular tissue were measured for the evaluation of testicular oxidative stress.The plasma testosterone(T)level was measured by immunoassay.Various germ cells at stageⅦof spermatogenic cycle were quantified from testicular stained sections.Results:Cyclophosphamide treatment results in a significant inhibition in the testicular△^(5),3β-HSD and 17β-HSD activities,a decrease in plasma T level and a diminution in the counts of various germ cells.Moreover,this treatment was also associated with a significant inhibition of the peroxidase and catalase activities along with high levels of MDA and conjugated dienes in the testis.All these changes were reversed by ascorbic acid co-administration.Conclusion:Cyclophosphamide treatment at the dosage used caused testicular gametogenic and androgenic disorders as well as induced testicular oxidative stress that can be reversed by ascorbic acid co-administration.展开更多
Based on the principle of association, a novel class of cyclophosphamide bis-spiropiperazinium compounds was designed and synthesized. A new method of synthesis, separation and purification for this kind of compounds ...Based on the principle of association, a novel class of cyclophosphamide bis-spiropiperazinium compounds was designed and synthesized. A new method of synthesis, separation and purification for this kind of compounds was also developed.展开更多
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) ...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.展开更多
OBJECTIVE: To investigate the therapeutic effects of Jiazhu decoction (JZD) in combination with cyclophosphamide (CTX) on the growth of breast cancer in mice and to explore the possible molecular mechanisms of action....OBJECTIVE: To investigate the therapeutic effects of Jiazhu decoction (JZD) in combination with cyclophosphamide (CTX) on the growth of breast cancer in mice and to explore the possible molecular mechanisms of action. METHODS: BALB/c mice were randomly divided into four groups of 10 (untreated model group, JZD group, CTX group, and JZD + CTX group) and subcutaneously injected with 4T1 mouse breast cancer cells. Tumors were allowed to establish for ~7 d before initiation of treatment with CTX (100 mg/kg every week by intraperitoneal injection) and/or JZD (0.015 mL of 1.65 g/mL crude drug, administered daily by gavage). The model group received equivalent volumes of vehicle on the same schedules. Tumor volumes were measured every 3 d. Mice were sacrificed after 3 weeks of treatment, and tumors were excised and subjected to RT-qPCR and western blot analysis to evaluate expression of the Wnt/β-catenin signaling pathway components β-catenin, c-Myc, and cyclin D1 at the mRNA and protein levels. RESULTS: The mean tumor volume was smaller and the growth rate was slower in the CTX and JZD + CTX groups compared with the model group (P < 0.05), and in the JZD + CTX group compared with the CTX and JZD groups (P < 0.05). Tumor growth was inhibited by 35.4% and 48.1% by CTX and JZD + CTX treatment, respectively (P < 0.001). The expression of β-catenin, c-Myc, and cyclin D1 mRNA and protein in tumors was significantly lower in mice treated with JZD or JZD + CTX compared with the untreated mice (P < 0.05), and was significantly lower in mice treated with JZD + CTX compared with either JZD or CTX alone (P < 0.05). CONCLUSION: JZD inhibited the growth of mouse breast cancer cells in vivo, possibly by reducing the expression of β-catenin, c-Myc, and cyclin D1. Combination therapy with JZD plus CTX had a more potent inhibitory effect on breast cancer growth compared with either agent alone.展开更多
In this study, freeze-dried water extract from the leaves of Myristica fragrans （Houtt.） was tested for mutagenic and antimutagenic potentials using the Allium cepa assay. Freeze-dried water extract alone and its co...In this study, freeze-dried water extract from the leaves of Myristica fragrans （Houtt.） was tested for mutagenic and antimutagenic potentials using the Allium cepa assay. Freeze-dried water extract alone and its combination with cyclophosphamide （CP） （50 mg/kg） were separately dissolved in tap water at 500, 1000, 2000, and 4000 mg/kg. Onions （A. cepa） were suspended in the solutions and controls for 48 h in the dark. Root tips were prepared for microscopic evaluation. 2,2-Diphenyl-l-picrylhydrazyl （DPPH） free radicals＇ scavenging power of the extract was tested using butylated hydroxyanisole （BHA） and butylated hydroxytoluene （BHT） as standards. Water extract of Myristica fragrans scavenged free radicals better than BHA, but worse than BHT. The extract alone, as well as in combination with CP suppressed cell division, and induced chromosomal aberrations that were insignificantly different from the negative control （P≤0.05）. However, cytotoxic and mutagenic actions of CP were considerably suppressed. The observed effects on cell division and chromosomes of A. cepa may be principally connected to the antioxidant properties of the extract. The obtained results suggest mitodepressive and antimutagenic potentials of water extract of the leaves of M. fragrans as desirable properties of a promising anticancer agent.展开更多
基金supported by the Basic Research Joint Special General Project of Yunnan Provincial Local Universities(part)(No:202301BA070001-029,202301BA070001-044)Yunnan Province High-level Scientific and Technological Talents and Innovation Team Selection Special Young and Middle-aged Academic and Technical Leaders Reserve Talent Project(No:202405AC350067).
文摘Objective:To investigate the protective effects of Lepidium draba L.(L.draba)on cyclophosphamide(CP)-induced hepatotoxicity and nephrotoxicity in rats.Methods:A total of 36 rats were divided into six groups as follows:the sham control group,the CP group(CP 100 mg/kg i.p.on days 1,7,14,21,28,and 35),the CP groups treated with L.draba extract(100,200 and 400 mg/kg of L.draba extract for 28 d),and the L.draba extract alone group(400 mg/kg of L.draba extract for 28 d).Serum parameters of renal and hepatic function,as well as pro-inflammatory and anti-inflammatory cytokines associated with liver and kidney damage were measured.Moreover,Bax,Bcl-2,and caspase-3 gene expression and histopathological changes were assessed.Results:L.draba extract alleviated CP-induced hepatotoxicity and nephrotoxicity by decreasing nitric oxide,TBARS,IL-6,TNF-α,and IL-1βlevels,as well as increasing superoxide dismutase,catalase and glutathione peroxidase activities,and FRAP,MIF,and TGF-βlevels.In addition,the extract downregulated the expression of pro-apoptotic genes(Bax and caspase-3)and mitigated the destruction of glomeruli and renal tubules as well as the degeneration of hepatocytes.Conclusions:L.draba extract can protect hepatic and renal structure and function against CP-induced toxicities,and may be used as a therapeutic agent for CP-induced hepatotoxicity and nephrotoxicity.
基金Fujian Natural Science:Study on Potential Protein Targets of Huluan Decotion in the Intervention of Premature Ovarian Failure(No.2021J011173)Major Project Cultivation Plan Project of Ningde Normal University:the Effect of Huluan Decotion on the Decreased Ovarian Reserve Function Induced by Cyclophosphamide is Studied based on Forkhead box L2(No.2019ZDK06)。
文摘OBJECTIVES:To investigate the therapeutic effect of Huluan decotion(护卵汤,HLD)on cyclophosphamideinduced premature ovarian failure(POF)in mice and its regulatory mechanisms.METHODS:Female BALB/c mice were administered cyclophosphamide and administered received different doses of HLD for 28 d.Levels of sex hormone,such as estradiol(E2),follicle stimulating hormone(FSH)and luteinizing hormone(LH)in the sera,were assessed using enzyme-linked immunosorbent assay(ELISA).Follicular structure variances were observed through hematoxylin and eosin(HE)staining,while Forkhead box L2(FOXL2)expression were analyzed via immuneohistochemical staining.The primary mechanism of POF were investigated through Western blot analysis.RESULTS:E2 levels decreased,and FSH and LH levels increased in POF model mice,but these trends were reversed with HLD or premarin administration,the expressions of WNT family member 4(Wnt4),β-Catenin and FOXL2 were downregulated in POF model mice,whereas high expression levels were observed in control mice and other groups.CONCLUSION:HLD effectively treats POF induced with cyclophosphamide in mice by enhancing expressions of Wnt4,β-Catenin and FOXL2.
基金2023 Special Project for Serving the National Development Strategy with Basic Scientific Research Fees from Central Universities(No.31920230188)2023 Northwestern Minzu University College-Level Innovation and Entrepreneurship Training Program(No.X202310742289)2024 National College Students’Innovation and Entrepreneurship Training Program(No.202410742005)。
文摘Objective:To study the antioxidant protective effect and mechanism of melatonin on cyclophosphamide-induced premature ovarian failure model mice.Methods:Six-month sexually mature female Kunming mice were taken for one week of acclimatization and then randomly divided into a normal group,blank control group,drug control group,ovarian premature aging model group,and melatonin intervention low,medium,and high dose group,with 20 mice in each group.We observed the status and body mass of the mice in each group;observed and monitored the estrous cycle by HE staining;measured the diameter and size of the ovaries and weighed the wet weight of the ovaries;observed the morphological changes of the ovaries by HE staining and counted the developing follicles at all levels;detected the levels of serum estradiol(E2),follicle-stimulating hormone(FSH),and luteinizing hormone(LH)by ELISA;measured the levels of serum MDA,SOD,and GSH-PX by antioxidant kit;detected the levels of protein immunoblotting by ELISA;protein immunoblotting(Western blot)to examine the expression of DNA damage-related proteinsγH2AX,p53,and p21 in ovarian tissues.Results:Compared with the control group,mice in the premature ovarian failure model group showed reduced mobility,rough hair,decreased body weight,disorganized estrous cycle,decreased ovarian weight(P<0.05),decreased number of follicles at all levels of development(P<0.05),increased number of atretic follicles(P<0.05),significantly elevated levels of serum FSH and LH,significantly decreased levels of E2(P<0.05),significantly increased levels of serum MDA,significantly lower SOD and GSH-PX levels(P<0.05),and the expression of p53,p21,andγH2AX in ovarian tissues was increased(P<0.05).Compared with the model group of premature ovarian failure,melatonin improved the changes of the above indexes induced by cyclophosphamide-induced premature ovarian failure in mice.Conclusion:Melatonin can improve the changes of motility cycle disorders,abnormal follicular development,and abnormal serum hormone levels induced by cyclophosphamide-induced oxidative stress in mice with premature ovarian failure.At the same time,melatonin can improve the oxidative stress induced by cyclophosphamide and alleviate the role of oxidative stress-induced DNA damage in mouse ovaries by exerting its antioxidant effect.
文摘Background:Allogeneic peripheral-blood stem-cell transplantation(SCT)from a matched related donor after myeloablative conditioning is the preferred curative treatment for patients with high-risk blood cancers.The combination of a calcineurin inhibitor and an antimetabolite remains standard care for graft-versus-host disease(GVHD)prophylaxis in these patients.Data from two randomized trials have suggested that post-transplantation cyclophosphamide can reduce the risk of GVHD after SCT from a matched donor when it is added to or replaces the antimetabolite.
文摘OBJECTIVE To investigate the damage effect and mechanisms of cyclophosphamide(CTX)and its active metabolite derivative 4-hydroperoxycyclophosphamide(4-HC)to human neuroblas⁃toma SH-SY5Y cells.METHODS SH-SY5Y cells were treated with CTX[0(cell control),0.01,0.1,1,5,10,20,40 and 80 mmol·L^(-1)]and 4-HC[0(cell control),0.01,0.1,1,5,10,20,40 and 80μmol·L^(-1)]for 48 h.Cell confluence and morphology were observed by the IncuCyte ZOOM system.Cell viability was assessed by CCK-8 assay.Lactate dehydrogenase(LDH)release was measured by LDH assay kit.SH-SY5Y cells were treated with CTX(0,1,5,10 and 20 mmol·L^(-1))and 4-HC(0,1,5,10 and 20μmol·L^(-1))for 48 h before cell proliferation was analyzed by 5-ethynyl-2′-deoxyuridine(EdU)staining assay.Immunofluorescence was employed to assess the levels of the DNA double-strand break markerγ-H2AX and to evaluate changes in mitochondrial membrane potential.SH-SY5Y cells were treated with CTX(0,1,5 and 10 mmol·L^(-1))and 4-HC(0,1,5 and 10μmol·L^(-1))for 48 h,and the alterations in glycolysis and oxidative phosphorylation levels were analyzed using the Seahorse XFe96 Analyzer.RESULTS Compared with the cell control group,cell confluence and cell viability were significantly reduced in the CTX and 4-HC groups(P<0.01),and the half-maximal inhibitory concentrations(IC50)for CTX and 4-HC were 4.44 mmol·L^(-1) and 4.78μmol·L^(-1),respectively.The release rate of LDH was signif⁃icantly increased while the percentage of EdU+cells was significantly reduced in the CTX and 4-HC groups(P<0.01).The percentage ofγ-H2AX+cells was significantly increased and mitochondrial membrane potential significantly decreased in the CTX and 4-HC group(P<0.05).Treatment with CTX and 4-HC resulted in reduced levels of maximum glycolytic capacity,glycolytic reserve,maximal respi⁃ration,and ATP production(P<0.05).CONCLUSION CTX and 4-HC exert significant cytotoxic effects on SH-SY5Y cells by disrupting cell membrane structure,impeding cell proliferation,and reducing cell viability.The mechanisms underlying these effects may involve intracellular DNA damage,disturbance of energy metabolism and mitochondrial dysfunction.
基金The Deanship of Scientific Research at King Abdulaziz University,Jeddah,Saudi Arabia has funded this project under grant no.RG-21-166-43.
文摘Objective:To explore the effect of geraniol on cyclophosphamide-induced cardiotoxicity.Methods:Mice were divided into five groups:the control group,the cyclophosphamide group(200 mg/kg cyclophosphamide,i.p.on day 7),the group treated with geraniol 100 and 200 mg/kg from day 1 to day 14,along with a single dose of cyclophosphamide on day 7,and the geraniol alone group(200 mg/kg geraniol from day 1 to day 14).At the end of the study,animals were sacrificed,and blood and heart were collected and analyzed for biochemical,histopathological,and immunohistochemical changes.Results:Treatment with 200 mg/kg geraniol significantly reduced the levels of cardiac injury markers,malondialdehyde,and inflammatory and apoptotic markers,while increasing antioxidant activities in mice with cyclophosphamide-induced cardiotoxicity.Moreover,it remarkably alleviated histopathological aberrations in cardiac tissue.Conclusions:Geraniol attenuates cyclophosphamide-induced cardiotoxicity via antioxidant,anti-inflammatory,and antiapoptotic effects.
基金the Ministry of Science and Technology of China:Evaluation,Re-examination,Promotion and Demonstration of Complete Sets of Technical Equipment for Efficient and Energy-Saving Extraction and Separation of Traditional Chinese Medicine(No.2017YFC1703104)the Key Laboratory Project of Pharmaceutical Lipids in Guangdong Province:Assessment of Enterprise-Class Key Laboratory of Guangdong Province(No.2020B1212070024)the Guangdong Province Key Areas Research and Development Program Project:Research and Development on Innovative Key Technologies and Intelligent Production Equipment about Processing,Decoction,Extraction and Separation of Traditional Chinese Medicine(No.2020B1111120002)。
文摘OBJECTIVE:To investigate the effect of Ganoderma Lucidum Spore Oil(GLSO)on the tumor growth and survival of H22 tumor-bearing mice treated with cyclophosphamide(CTX),and explore the underlying mechanism.METHODS:Allograft H22 hepatocellular carcinoma mouse model was applied to investigate the effect of GLSO on the tumor growth and survival of animals,and Kaplan-Meier survival analysis was used to analyze the life span.Plasma biochemical examination was used to determine the levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),urea(UREA)and creatinine(CRE).Western blot analysis was performed to detect Programmed Death-1(PD-1),Programmed Death Ligand 1(PD-L1),Janus Kinase 2(JAK2),phosphorylated Signal Transducer and Activator of Transcription 3(p-STAT3),and Signal Transducer and Activator of Transcription 3(STAT3)expression.RESULTS:GLSO increased the anti-tumor effect of CTX and prolonged the survival of H22 tumor-bearing mice treated with CTX.Meanwhile,GLSO increased the thymus index and showed no obvious toxicity to liver functions of animals.GLSO also decreased the level of UREA in H22 tumor-bearing mice treated with CTX.Furthermore,GLSO could inhibit the expression of PD-1 in spleen,which was independent of JAK2 expression and STAT3 phosphorylation.However,GLSO did not affect the expression of PD-L1,JAK2,and p-STAT3 in tumor tissue.CONCLUSION:GLSO could strengthen the anti-tumor effect of CTX and prolong the life span of H22 tumorbearing mice,while the underlying mechanism might be relevant to the amelioration effect of thymus function and inhibition of PD-1 expression in spleen.Furthermore,these findings implied the promising role of GLSO in combination with CTX to extend the survival of patients in clinical chemotherapy of hepatocellular carcinoma.
基金financially supported by the Science and Technology Plan Project of Guangzhou (No. 202102010171)National Natural Science Foundation Cultivation Project of the Third Affiliated Hospital of Sun Yat-sen University (No. 2020GZRPYMS11)+2 种基金Natural Science Foundation of Guangdong Province (No. 2018A030313641)Natural Science Foundation of Guangdong Province (No. 2016A030313848)Science and Technology Plan Project of Guangzhou (No. 201704020175)。
文摘Objective: Unresectable hepatocellular carcinoma(uHCC) continues to pose effective treatment options. The objective of this study was to assess the efficacy and safety of combining low-dose cyclophosphamide with lenvatinib, pembrolizumab and transarterial chemoembolization(TACE) for the treatment of uHCC.Methods: From February 2022 to November 2023, a total of 40 patients diagnosed with uHCC were enrolled in this small-dose, single-center, single-arm, prospective study. They received a combined treatment of low-dose cyclophosphamide with lenvatinib, pembrolizumab, and TACE. Study endpoints included progression-free survival(PFS), objective response rate(ORR), and safety assessment. Tumor response was assessed using the modified Response Evaluation Criteria in Solid Tumors(mRECIST), while survival analysis was conducted through KaplanMeier curve analysis for overall survival(OS) and PFS. Adverse events(AEs) were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events(version 5.0).Results: A total of 34 patients were included in the study. The median follow-up duration was 11.2 [95% confidence interval(95% CI), 5.3-14.6] months, and the median PFS(mPFS) was 15.5(95% CI, 5.4-NA) months.Median OS(mOS) was not attained during the study period. The ORR was 55.9%, and the disease control rate(DCR) was 70.6%. AEs were reported in 27(79.4%) patients. The most frequently reported AEs(with an incidence rate >10%) included abnormal liver function(52.9%), abdominal pain(44.1%), abdominal distension and constipation(29.4%), hypertension(20.6%), leukopenia(17.6%), constipation(17.6%), ascites(14.7%), and insomnia(14.7%). Abnormal liver function(14.7%) had the most common grade 3 or higher AEs.Conclusions: A combination of low-dose cyclophosphamide with lenvatinib, pembrolizumab, and TACE is safe and effective for u HCC, showcasing a promising therapeutic strategy for managing uHCC.
文摘Aplastic anemia(AA)is a rare but serious condition in which the bone marrow fails to produce sufficient new blood cells,leading to fatigue,increased susceptibility to infection,and uncontrolled bleeding.In this editorial,we review and comment on an article by Wang et al published in 2024.This study aimed to evaluate the potential therapeutic benefits of ginsenoside Rg1 in AA,focusing on its protective effects and uncovering the underlying mechanisms.Cyclophosphamide(CTX)administration caused substantial damage to the structural integrity of the bone marrow and decreased the number of hematopoietic stem cells,thereby establishing an AA model.Compared with the AA group,ginsenoside Rg1 alleviated the effects of CTX by reducing apoptosis and inflammatory factors.Mechanistically,treatment with ginsenoside Rg1 significantly mitigated myelosuppression in mice by inhibiting the mitogen activated protein kinase signaling pathway.Thus,this study indicates that ginsenoside Rg1 could be effective in treating AA by reducing myelosuppression,primarily through its influence on the mitogen activated protein kinase signaling pathway.We expect that our review and comments will provide valuable insights for the scientific community related to this research and enhance the overall clarity of this article.
基金Supported by Joint Funding of Yunnan Ministry of Science and Technology,No.2019FF002-048and Beijing Heathco Clinical Oncology Research Foundation,No.Y-Q201802-048.
文摘BACKGROUND Parthenolide(PTL),a sesquiterpene lactone derived from the medicinal herb Chrysanthemum parthenium,exhibits various biological effects by targeting NF-kB,STAT3,and other pathways.It has emerged as a promising adjunct therapy for multiple malignancies.AIM To evaluate the in vitro and in vivo effect of PTL on cyclophosphamide(CTX)metronomic chemotherapy.METHODS The cytotoxicity of PTL and CTX on Lewis lung cancer cells(LLC cells)was assessed by measuring cell activity and apoptosis.The anti-tumor efficiency was evaluated using a tumor xenograft mice model,and the survival of mice and tumor volume were monitored.Additionally,the collected tumor tissues were analyzed for tumor microenvironment indicators and inflammatory factors.RESULTS In vitro,PTL demonstrated a synergistic effect with CTX in inhibiting the growth of LLC cells and promoting apoptosis.In vivo,metronomic chemotherapy com-bined with PTL and CTX improved the survival rate of tumor-bearing mice and reduced tumor growth rate.Furthermore,metronomic chemotherapy combined with PTL and CTX reduced NF-κB activation and improved the tumor immune microenvironment by decreasing tumor angiogenesis,reducing Transforming growth factorβ,andα-SMA positive cells.CONCLUSION PTL is an efficient compound that enhances the metronomic chemotherapy effects of CTX both in vitro and in vivo,suggesting its potential as a supplementary therapeutic strategy in metronomic chemotherapy to improve the chemotherapy effects.
基金Supported by the 211 Project of Jinan Universitythe Team Project of Natural Science Foundation of Guangdong Province (8351063201000003)+3 种基金the Popular Science Foundation of Science & Technology Bureau of Guangzhou City (2008KP055)the Natural Science Foundation of Guangdong Province (06025198)the Jinan University Natural Science Foundation (51204017)the Science and Technology Innovation Project for Undergraduates (cx08120)
文摘An experiment was conducted to compare the effects of two mouse thrombocytopenia models induced by cyclophosphamide at two different administration routes to determine a proper cyclophosphamide administration route that could cause stable thrombocytopenia. A suitable drug dosage that could induce thrombocytopenia in mouse efficiently with the definite administration route was then investigated. BALB/c mice were randomly divided into Normal, Model A and Model B groups. To Model A, 200 mg/kg of cyclophosphamide was given by vena caudalis injection as first dose and 30 mg/kg as maintenance dose by intraperitoneal injection at the following 6 days. To Model B, 150 mg/kg of cyclophosphamide was given by subcutaneous injection once a day for consecutive 3 days. All groups were under investigation for 15 days. The result suggested that a decrease in the number of blood platelets of Model B at the 7th day were significantly than that of Normal. Other platelet related indices like platelet distribution width, mean platelet volume and platelet-large cell ratio of Model B increased significantly in comparison with those of Normal group. The platelets count was reduced but fluctuated greatly, and more than half of the mice died in Model A. Therefore, subcutaneous injection of cyclophosphamide for 3 days was used for the cyclophosphamide dosage test. BALB/c mice were randomly divided into Normal, cyclophosphamide low dose （100 mg/kg）, medium dose （120 mg/kg） and high dose （140 mg/kg） groups. All groups were under investigation for 11 days. Though all 3 dosages successfully initiated thrombocytopenia as the platelets number dropped at the 7th day, the low dose was considered to be a suitable one that was of high efficacy and low toxicity. Thus, BALB/c mice challenged by subcutaneous injection of cyclophosphamide 100 mg/kg per day for 3 consecutive day is one simple, feasible and stable mouse thrombocytopenia model that could be used for pharmacodynamic test of the drugs which are supposed to have platelets increasing effect.
基金National Natural Science Foundation of China(Grant No.81072612)the Natural Science Foundation of Beijing(Grant No.7102107)+1 种基金the Open Foundation of State Key Laboratory of Natural and Biomimetic Drugs(Grant No.K20110109)Specialized Research Fund for the Doctoral Program of Higher Education(Grant No.20110001110021)
文摘A rapid and simple liquid chromatography method with on-line solid phase extraction was developed and validated for the quantitative determination of cyclophosphamide in rat plasma.The plasma sample was first extracted on an Acclaim？ Polar Advantage II C18 guard column（PA II C18,10 mm×4.6 mm,5 μm）,which was also the on-line Extraction Cartridge SPE column,by washing with 100% H2O for 1 min.The extracted sample was then eluted onto a PA II C18 column（150 mm×4.6 mm,5 μm） and separated by isocratic elution with acetonitrile-water（40：60,v/v）.The mobile phase was run at a flow rate of 1.0 mL/min,and the UV detector was set at 195 nm.Retention time of cyclophosphamide was 4.3 min and the total run-time was 6 min.The linear range of the standard curve was from 1.0 to 200 μg/mL（r2 = 0.9999）,and the limits of quantification and detection were 1.0 μg/mL（RSD10%,n = 5） and 0.3 μg/mL（RSD13%,n = 5）,respectively.Both intra-and inter-day variations were less than 5.6%.The developed method can be used for the therapeutic drug monitoring of cyclophosphamide in the clinic.
基金National Natural Science Foundation(Grant No.81272468 and 21001011)the Scientific Research Foundation for the Returned Overseas Chinese Scholars,Ministry of Education
文摘Hematological toxicity （bone marrow suppression） is the most common dose-limiting adverse effect of chemotherapies. The nuclear factor erythroid 2-related factor 2 （Nrf2） is a pivotal coordinator of cellular defensive responses against chemical insults in many tissues including bone marrow. In the present study, the effects of tert-butylhydroquinone （tBHQ） on the expression of Nrf2-regulated genes in peripheral blood cells and cyclophosphamide （CTX）-induced hematotoxicity in mice were investigated. CTX induced apoptosis of peripheral blood nucleated cells and leukopenia in mice, accompanied by mobilization of bone marrow hematopoietic cells, tBHQ treatment induced the expression of Nrf2-regulated genes such as heine oxygenase 1 （HO1） and glutamate-cysteine ligase catalytic subtmit （GCLC） in RAW264.7 mouse macrophage cells and peripheral blood cells both in vitro and in vivo. Interestingly, pretreatment with tBHQ alleviated CTX-induced mouse peripheral blood cell apoptosis and leukopenia in vivo, indicating possible involvement of Nrf2 in the protection against CTX-induced hematotoxicity. This study provides new information on the chemotherapy-induced hematotoxicity, and suggests Nrf2 could serve as a target for the development of chemoprotectants against hematotoxicity.
文摘The protective effect of a kind of purified polysaccharides extracted from Radix of Phytolacca acinosa Roxb,with a molecular weight of 10 KDa,on hematopoiesis was investigated.Average survival time of mice treated with cyclophosphamide (CY) 300 mg/kg once alone was 13.3 ± 7.2d(n=7) however,average survival time of mice treated with CY 300 mg/kg in com-bination with PAP-1 10 mg/kg,3 times/wk was 36.7± 16.4d(n=7,P<0.01).PAP-1,ip had benefi-cial effect on the recovery of the CY induced decrease of peripheral leukocyte number,and the nu-cleated bone marrow cell(BMC)number and[3￣H]TdR uptaken by BMC induced by rmGM-CSF in S180 bearing mice treated with CY,In mice,after the first ip treatment with CY 100 mg/kg on d7,the peripheral leukocyte number decreased on d9 and recovered to normal level about d13 to d15. Such recovery was accelerated by administrating PAP-1,10mg/kg, 3 times/wk.A significant in-crease of the activity to form colony in spleen(colony-forming unit in spleen, CFU-S_8, CUF-S12) in mice irradiated with 550 rad 6O￣Co γ-rays and an enhancement of proliferative response of BMC to rmGM-CSF treated with PAP-1,10mg/kg,3 times/wk, ip were observed.After PAP-1,10 mg/kg,ip once,a significant increase in the number of peripheral blood leukocytes and a rise in the serum of colony stimulating factor(CSF) were also confirmed.The types of CSF in serum were M-CSF and other hematopoietic growth factors,which were confirmed by using McAb of IL-3, GM-CSF and PcAb of M-CSF. These beneficial effects of PAP-1 on hematopoiesis may be related to its activityinducing CSFs and other hematopoietic growth factors and warrant further evaluation of its use-fulness.
基金National Natural Science Foundation of China (Grant No.20732001,90713004)
文摘Novel prodrugs of cyclophosphamide 1a and 1b, which comprised the galactosyl moiety, the key fraction of cyclophosphamide derivates, and the linker 4-hydroxy benzaldehyde, were synthesized. These compounds were anticipated to exhibit amplified anti-tumor activity and targeting ability.
基金The authors gratefully acknowledge the financial assistance from the Major Research Project(Project No.F-3/50/99 dated 3l-3-99)provided by the University Grants Commission(UGC),New Delhi,India
文摘Aim:To study the detrimental effects of cyclophosphamide on the testicular androgenic and gametogenic activities through endocrine inhibition and/or induction of oxidative stress in male albino rats and to evaluate the protective effect of ascorbic acid.Methods:The testicular△^(5),3β-hydroxysteroid dehydrogenase(HSD),17β-HSD,peroxidase and catalase activities along with the levels of malondialdehyde(MDA)and conjugated dienes in testicular tissue were measured for the evaluation of testicular oxidative stress.The plasma testosterone(T)level was measured by immunoassay.Various germ cells at stageⅦof spermatogenic cycle were quantified from testicular stained sections.Results:Cyclophosphamide treatment results in a significant inhibition in the testicular△^(5),3β-HSD and 17β-HSD activities,a decrease in plasma T level and a diminution in the counts of various germ cells.Moreover,this treatment was also associated with a significant inhibition of the peroxidase and catalase activities along with high levels of MDA and conjugated dienes in the testis.All these changes were reversed by ascorbic acid co-administration.Conclusion:Cyclophosphamide treatment at the dosage used caused testicular gametogenic and androgenic disorders as well as induced testicular oxidative stress that can be reversed by ascorbic acid co-administration.
基金National Natural Science Foundation of China(Grant No.20472008)the Major State Basic Research Development Program(Grant No.2004CB719900).
文摘Based on the principle of association, a novel class of cyclophosphamide bis-spiropiperazinium compounds was designed and synthesized. A new method of synthesis, separation and purification for this kind of compounds was also developed.
文摘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.
基金Supported by Research Topic of Traditional Chinese Medicine and Ethnic Medicine Technology in Guizhou Provincial Administration of Traditional Chinese Medicine(No.QZYY2017-005)Guiyang Science and Technology Bureau Fund National Base Cultivation Project(Zhuke Contract[2017] 30-39)the Foundation of Innovation and Talent Team of the Higher Education of Guizhou province(No.2015 51)
文摘OBJECTIVE: To investigate the therapeutic effects of Jiazhu decoction (JZD) in combination with cyclophosphamide (CTX) on the growth of breast cancer in mice and to explore the possible molecular mechanisms of action. METHODS: BALB/c mice were randomly divided into four groups of 10 (untreated model group, JZD group, CTX group, and JZD + CTX group) and subcutaneously injected with 4T1 mouse breast cancer cells. Tumors were allowed to establish for ~7 d before initiation of treatment with CTX (100 mg/kg every week by intraperitoneal injection) and/or JZD (0.015 mL of 1.65 g/mL crude drug, administered daily by gavage). The model group received equivalent volumes of vehicle on the same schedules. Tumor volumes were measured every 3 d. Mice were sacrificed after 3 weeks of treatment, and tumors were excised and subjected to RT-qPCR and western blot analysis to evaluate expression of the Wnt/β-catenin signaling pathway components β-catenin, c-Myc, and cyclin D1 at the mRNA and protein levels. RESULTS: The mean tumor volume was smaller and the growth rate was slower in the CTX and JZD + CTX groups compared with the model group (P < 0.05), and in the JZD + CTX group compared with the CTX and JZD groups (P < 0.05). Tumor growth was inhibited by 35.4% and 48.1% by CTX and JZD + CTX treatment, respectively (P < 0.001). The expression of β-catenin, c-Myc, and cyclin D1 mRNA and protein in tumors was significantly lower in mice treated with JZD or JZD + CTX compared with the untreated mice (P < 0.05), and was significantly lower in mice treated with JZD + CTX compared with either JZD or CTX alone (P < 0.05). CONCLUSION: JZD inhibited the growth of mouse breast cancer cells in vivo, possibly by reducing the expression of β-catenin, c-Myc, and cyclin D1. Combination therapy with JZD plus CTX had a more potent inhibitory effect on breast cancer growth compared with either agent alone.
文摘In this study, freeze-dried water extract from the leaves of Myristica fragrans （Houtt.） was tested for mutagenic and antimutagenic potentials using the Allium cepa assay. Freeze-dried water extract alone and its combination with cyclophosphamide （CP） （50 mg/kg） were separately dissolved in tap water at 500, 1000, 2000, and 4000 mg/kg. Onions （A. cepa） were suspended in the solutions and controls for 48 h in the dark. Root tips were prepared for microscopic evaluation. 2,2-Diphenyl-l-picrylhydrazyl （DPPH） free radicals＇ scavenging power of the extract was tested using butylated hydroxyanisole （BHA） and butylated hydroxytoluene （BHT） as standards. Water extract of Myristica fragrans scavenged free radicals better than BHA, but worse than BHT. The extract alone, as well as in combination with CP suppressed cell division, and induced chromosomal aberrations that were insignificantly different from the negative control （P≤0.05）. However, cytotoxic and mutagenic actions of CP were considerably suppressed. The observed effects on cell division and chromosomes of A. cepa may be principally connected to the antioxidant properties of the extract. The obtained results suggest mitodepressive and antimutagenic potentials of water extract of the leaves of M. fragrans as desirable properties of a promising anticancer agent.
