Objective To investigate oxidative DNA damage in pharmacy technicians preparing antineoplastic drugs at the PIVAS （Pharmacy Intravenous Admixture Service） in two Chinese hospitals. Methods Urinary 8-OHdG served as a...Objective To investigate oxidative DNA damage in pharmacy technicians preparing antineoplastic drugs at the PIVAS （Pharmacy Intravenous Admixture Service） in two Chinese hospitals. Methods Urinary 8-OHdG served as a biomarker. 5-Fluorouracil （5-FU） concentrations in air, masks and gloves were determined. The spill exposure of each PIVAS technician to antineoplastic drugs was investigated. Eighty subjects were divided into exposed group t, II, and control group I, II. Results 5-FU concentration ratios for gloves and masks in exposed group I were significantly higher than those in exposed group II （P〈0.05 or P〈0.01）. The average urinary 8-OHdG concentrations in exposed group I, control group I, exposed group II, and control group II were 24.69＋0.93, 20.68＋1.07, 20.57＋0.55, and 12.96_＋0.73 ng/mg Cr, respectively. Urinary 8-OHdG concentration in exposed group I was significantly higher than that in control group I or that in exposed group 11 （P〈0.02）. There was a significant correlation between urinary 8-OHdG concentrations and spill frequencies per technician （P〈0.01）. Conclusion There was detectable oxidative DNA damage in PIVAS technicians exposed to antineoplastic drugs. This oxidative DNA damage may be associated with their spill exposure experience and contamination of their personal protective equipment.展开更多
Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attrac...Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attracting considerable attention in precise oncology therapy.Cetuximab(Cet)is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma(cSCC);however,its anti-tumor activity is limited to a single use.Cisplatin(CisPt)shows good curative effects;however,its adverse effects and non-tumor-targeting ability are major drawbacks.In this study,we designed and developed a new ADC based on a new cytotoxic platinum(IV)prodrug(C8Pt(IV))and Cet.The so-called antibody-platinum(IV)prodrugs conjugates,named Cet-C8Pt(IV),showed excellent tumor targeting in cSCC.Specifically,it accurately delivered C8Pt(IV)into tumor cells to exert the combined anti-tumor effect of Cet and CisPt.Herein,metabolomic analysis showed that Cet-C8Pt(IV)promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells,thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum(IV)prodrugs conjugates.展开更多
Aim: Recently, there is an increased average of developing cancers. Though, the chemotherapeutic-treatment is unfavorable during pregnancy due to its harmful effects on developing fetuses, physicians have two ways to ...Aim: Recently, there is an increased average of developing cancers. Though, the chemotherapeutic-treatment is unfavorable during pregnancy due to its harmful effects on developing fetuses, physicians have two ways to minimize these effects either by termination of the pregnancy or minimizing its side effects. The present work aimed to illustrate the susceptibility of cardiac, lung and dorsal aorta function to the widely applicable drugs doxorubicin and cisplatin as well as 5-flurouracil. Materials and Methods: Mother albino rats were arranged into four-groups (control, doxorubicin, cisplatin and 5-flurouracil-treated groups). Each pregnant rat received intraperitoneal administration of 0.2 mg/kg body weight at 10th and 14th day of gestation and sacrificed at parturition (two doses). At parturition, serum of mother rats used to assess troponin I, heat shock protein 70, 8-hydroxydeoxyguanosine, vascular endothelial growth factor and adhesion molecules (ICAM-1 & VCAM-1). Isoenzyme electrophoresis of alkaline and acid phosphatases, glucose-6-phosphate dehydrogenase and lactic dehydrogenase were estimated in serum, myocardium and dorsal aorta of mother rats. The myocardium and lung were processed for histopathological investigations for both mothers and their offspring. Single strand (comet assay) and double strand DNA damage were carried out in heart and dorsal aorta of mother rats. Results: The present finding revealed that there are detected alterations of myocardial markers and lung amino acid metabolism as well as disruption of myocardial isoenzymes. DNA damage of myocardium and dorsal aorta were observed. Conclusions: The authors concluded that the metabolic activity of heart and lung is highly susceptible to doxorubicin and cisplatin treatment compared to 5-flurouracil and the therapeutic doses must be degraded.展开更多
BACKGROUND Oxaliplatin(Oxa)is the first-line chemotherapy drug for colorectal cancer(CRC),and Oxa resistance is crucial for treatment failure.Prostaglandin F_(2α)synthase(PGF 2α)(PGFS),an enzyme that catalyzes the p...BACKGROUND Oxaliplatin(Oxa)is the first-line chemotherapy drug for colorectal cancer(CRC),and Oxa resistance is crucial for treatment failure.Prostaglandin F_(2α)synthase(PGF 2α)(PGFS),an enzyme that catalyzes the production of PGF_(2α),is involved in the proliferation and growth of a variety of tumors.However,the role of PGFS in Oxa resistance in CRC remains unclear.AIM To explore the role and related mechanisms of PGFS in mediating Oxa resistance in CRC.METHODS The PGFS expression level was examined in 37 pairs of CRC tissues and paracancerous tissues at both the mRNA and protein levels.Overexpression or knockdown of PGFS was performed in CRC cell lines with acquired Oxa resistance(HCT116-OxR and HCT8-OxR)and their parental cell lines(HCT116 and HCT8)to assess its influence on cell proliferation,chemoresistance,apoptosis,and DNA damage.For determination of the underlying mechanisms,CRC cells were examined for platinum-DNA adducts and reactive oxygen species(ROS)levels in the presence of a PGFS inhibitor or its products.RESULTS Both the protein and mRNA levels of PGFS were increased in the 37 examined CRC tissues compared to the adjacent normal tissues.Oxa induced PGFS expression in the parental HCT116 and HCT8 cells in a dosedependent manner.Furthermore,overexpression of PGFS in parental CRC cells significantly attenuated Oxainduced proliferative suppression,apoptosis,and DNA damage.In contrast,knockdown of PGFS in Oxa-resistant HCT116 and HCT8 cells(HCT116-OxR and HCT8-OxR)accentuated the effect of Oxa treatment in vitro and in vivo.The addition of the PGFS inhibitor indomethacin enhanced the cytotoxicity caused by Oxa.Treatment with the PGFS-catalyzed product PGF_(2α)reversed the effect of PGFS knockdown on Oxa sensitivity.Interestingly,PGFS inhibited the formation of platinum-DNA adducts in a PGF_(2α)-independent manner.PGF_(2α)exerts its protective effect against DNA damage by reducing ROS levels.CONCLUSION PGFS promotes resistance to Oxa in CRC via both PGF_(2α)-dependent and PGF_(2α)-independent mechanisms.展开更多
OBJECTIVE:To investigate the inhibitory effect of Yiguanjian decoction(YD) on DNA damage in Concanavalin A(Con A)-induced liver injury mice model and to explain the possible mechanism.METHODS:Totally 120 male BALB/c m...OBJECTIVE:To investigate the inhibitory effect of Yiguanjian decoction(YD) on DNA damage in Concanavalin A(Con A)-induced liver injury mice model and to explain the possible mechanism.METHODS:Totally 120 male BALB/c mice were randomly divided into 6 groups,20 mice each:normal group,model group,Bifendate group,YD low dose group,YD middle dose group and YD high dose group.Except normal group,liver injury model induced by Con A was established.While modeling,each mouse in YD group was given YD(0.4 m L/20 g per day) by intragastric administration(0.13 g YD for YD low dose group;0.26 g for YD middle dose group;0.52 g for YD high dose group).Bifendate group was given Bifendate(0.2 gnd model·kg-1 grou·d-1) by gavage.Normal group ap were fed with same volume of physiological saline daily.After 8 weeks,the serum alanine transaminase(ALT)and aspartate transaminase(AST) were tested.The hematoxylin-eosin staining was used to evaluate the grade of liver inflammation and liver fibrosis stage.Hepatocellular DNA damage was detected by single cell gel electrophoresis technology.The protein expression of tumor necrosis factor-α(TNF-α),Bax and Mut T Homolog 1(MTH1) was detected by western blotting and enzyme linked immunosorbent assay.Bax m RNA and MTH1 m RNA were detected by Real-time Polymerase Chain Reaction(PCR).RESULTS:YD can improve the degree of liver inflammation and fibrosis in the liver of chronic hepatitis mice,the dose effect relationship is remarkable(P < 0.05).YD can reduce liver cell DNA damage.The difference between YD middle dose group and model group was statistically significant(P < 0.05).YD middle dose group had decreased the protein expression of TNF-α in the mice liver of immunological liver injury(P < 0.05).YD can increase the protein expression of Bax(P < 0.05).Compared with normal group,the protein expression of MTH1 was decreased(P < 0.05),but there was no statistical significance between YD group and model group(P >0.05).YD can increase the m RNA expression of Bax and MTH1(both P < 0.05).CONCLUSION:YD can effectively inhibit the DNA damage in immunological liver injury mice,the mechanism may be that it can decrease the TNF-αand increase the Bax and MTH1 expression.展开更多
基金supported by the Scientific Research Fund of Health Bureau in Zhejiang Province (2009A089)Scientific Research Fund of Education Bureau in Zhejiang Province (Y200804934)
文摘Objective To investigate oxidative DNA damage in pharmacy technicians preparing antineoplastic drugs at the PIVAS （Pharmacy Intravenous Admixture Service） in two Chinese hospitals. Methods Urinary 8-OHdG served as a biomarker. 5-Fluorouracil （5-FU） concentrations in air, masks and gloves were determined. The spill exposure of each PIVAS technician to antineoplastic drugs was investigated. Eighty subjects were divided into exposed group t, II, and control group I, II. Results 5-FU concentration ratios for gloves and masks in exposed group I were significantly higher than those in exposed group II （P〈0.05 or P〈0.01）. The average urinary 8-OHdG concentrations in exposed group I, control group I, exposed group II, and control group II were 24.69＋0.93, 20.68＋1.07, 20.57＋0.55, and 12.96_＋0.73 ng/mg Cr, respectively. Urinary 8-OHdG concentration in exposed group I was significantly higher than that in control group I or that in exposed group 11 （P〈0.02）. There was a significant correlation between urinary 8-OHdG concentrations and spill frequencies per technician （P〈0.01）. Conclusion There was detectable oxidative DNA damage in PIVAS technicians exposed to antineoplastic drugs. This oxidative DNA damage may be associated with their spill exposure experience and contamination of their personal protective equipment.
基金the National Natural Science Foundation of China(Grant No.:51803120).
文摘Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attracting considerable attention in precise oncology therapy.Cetuximab(Cet)is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma(cSCC);however,its anti-tumor activity is limited to a single use.Cisplatin(CisPt)shows good curative effects;however,its adverse effects and non-tumor-targeting ability are major drawbacks.In this study,we designed and developed a new ADC based on a new cytotoxic platinum(IV)prodrug(C8Pt(IV))and Cet.The so-called antibody-platinum(IV)prodrugs conjugates,named Cet-C8Pt(IV),showed excellent tumor targeting in cSCC.Specifically,it accurately delivered C8Pt(IV)into tumor cells to exert the combined anti-tumor effect of Cet and CisPt.Herein,metabolomic analysis showed that Cet-C8Pt(IV)promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells,thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum(IV)prodrugs conjugates.
文摘Aim: Recently, there is an increased average of developing cancers. Though, the chemotherapeutic-treatment is unfavorable during pregnancy due to its harmful effects on developing fetuses, physicians have two ways to minimize these effects either by termination of the pregnancy or minimizing its side effects. The present work aimed to illustrate the susceptibility of cardiac, lung and dorsal aorta function to the widely applicable drugs doxorubicin and cisplatin as well as 5-flurouracil. Materials and Methods: Mother albino rats were arranged into four-groups (control, doxorubicin, cisplatin and 5-flurouracil-treated groups). Each pregnant rat received intraperitoneal administration of 0.2 mg/kg body weight at 10th and 14th day of gestation and sacrificed at parturition (two doses). At parturition, serum of mother rats used to assess troponin I, heat shock protein 70, 8-hydroxydeoxyguanosine, vascular endothelial growth factor and adhesion molecules (ICAM-1 & VCAM-1). Isoenzyme electrophoresis of alkaline and acid phosphatases, glucose-6-phosphate dehydrogenase and lactic dehydrogenase were estimated in serum, myocardium and dorsal aorta of mother rats. The myocardium and lung were processed for histopathological investigations for both mothers and their offspring. Single strand (comet assay) and double strand DNA damage were carried out in heart and dorsal aorta of mother rats. Results: The present finding revealed that there are detected alterations of myocardial markers and lung amino acid metabolism as well as disruption of myocardial isoenzymes. DNA damage of myocardium and dorsal aorta were observed. Conclusions: The authors concluded that the metabolic activity of heart and lung is highly susceptible to doxorubicin and cisplatin treatment compared to 5-flurouracil and the therapeutic doses must be degraded.
基金the S and T Program of Hebei,No.22377704DMedical Science Research Project of Hebei Province,No.20190510Postgraduate’s Innovation Fund Project of Hebei Province,No.CXZZBS2021077.
文摘BACKGROUND Oxaliplatin(Oxa)is the first-line chemotherapy drug for colorectal cancer(CRC),and Oxa resistance is crucial for treatment failure.Prostaglandin F_(2α)synthase(PGF 2α)(PGFS),an enzyme that catalyzes the production of PGF_(2α),is involved in the proliferation and growth of a variety of tumors.However,the role of PGFS in Oxa resistance in CRC remains unclear.AIM To explore the role and related mechanisms of PGFS in mediating Oxa resistance in CRC.METHODS The PGFS expression level was examined in 37 pairs of CRC tissues and paracancerous tissues at both the mRNA and protein levels.Overexpression or knockdown of PGFS was performed in CRC cell lines with acquired Oxa resistance(HCT116-OxR and HCT8-OxR)and their parental cell lines(HCT116 and HCT8)to assess its influence on cell proliferation,chemoresistance,apoptosis,and DNA damage.For determination of the underlying mechanisms,CRC cells were examined for platinum-DNA adducts and reactive oxygen species(ROS)levels in the presence of a PGFS inhibitor or its products.RESULTS Both the protein and mRNA levels of PGFS were increased in the 37 examined CRC tissues compared to the adjacent normal tissues.Oxa induced PGFS expression in the parental HCT116 and HCT8 cells in a dosedependent manner.Furthermore,overexpression of PGFS in parental CRC cells significantly attenuated Oxainduced proliferative suppression,apoptosis,and DNA damage.In contrast,knockdown of PGFS in Oxa-resistant HCT116 and HCT8 cells(HCT116-OxR and HCT8-OxR)accentuated the effect of Oxa treatment in vitro and in vivo.The addition of the PGFS inhibitor indomethacin enhanced the cytotoxicity caused by Oxa.Treatment with the PGFS-catalyzed product PGF_(2α)reversed the effect of PGFS knockdown on Oxa sensitivity.Interestingly,PGFS inhibited the formation of platinum-DNA adducts in a PGF_(2α)-independent manner.PGF_(2α)exerts its protective effect against DNA damage by reducing ROS levels.CONCLUSION PGFS promotes resistance to Oxa in CRC via both PGF_(2α)-dependent and PGF_(2α)-independent mechanisms.
基金Supported by Beijing Natural Science Foundation-funded Project(Yiguanjian on the Regulation of Microenvironment and Signal Pathway of Reactive Oxygen Species in Mouse with Immunological Liver Injury,No.7122024)
文摘OBJECTIVE:To investigate the inhibitory effect of Yiguanjian decoction(YD) on DNA damage in Concanavalin A(Con A)-induced liver injury mice model and to explain the possible mechanism.METHODS:Totally 120 male BALB/c mice were randomly divided into 6 groups,20 mice each:normal group,model group,Bifendate group,YD low dose group,YD middle dose group and YD high dose group.Except normal group,liver injury model induced by Con A was established.While modeling,each mouse in YD group was given YD(0.4 m L/20 g per day) by intragastric administration(0.13 g YD for YD low dose group;0.26 g for YD middle dose group;0.52 g for YD high dose group).Bifendate group was given Bifendate(0.2 gnd model·kg-1 grou·d-1) by gavage.Normal group ap were fed with same volume of physiological saline daily.After 8 weeks,the serum alanine transaminase(ALT)and aspartate transaminase(AST) were tested.The hematoxylin-eosin staining was used to evaluate the grade of liver inflammation and liver fibrosis stage.Hepatocellular DNA damage was detected by single cell gel electrophoresis technology.The protein expression of tumor necrosis factor-α(TNF-α),Bax and Mut T Homolog 1(MTH1) was detected by western blotting and enzyme linked immunosorbent assay.Bax m RNA and MTH1 m RNA were detected by Real-time Polymerase Chain Reaction(PCR).RESULTS:YD can improve the degree of liver inflammation and fibrosis in the liver of chronic hepatitis mice,the dose effect relationship is remarkable(P < 0.05).YD can reduce liver cell DNA damage.The difference between YD middle dose group and model group was statistically significant(P < 0.05).YD middle dose group had decreased the protein expression of TNF-α in the mice liver of immunological liver injury(P < 0.05).YD can increase the protein expression of Bax(P < 0.05).Compared with normal group,the protein expression of MTH1 was decreased(P < 0.05),but there was no statistical significance between YD group and model group(P >0.05).YD can increase the m RNA expression of Bax and MTH1(both P < 0.05).CONCLUSION:YD can effectively inhibit the DNA damage in immunological liver injury mice,the mechanism may be that it can decrease the TNF-αand increase the Bax and MTH1 expression.
