Drug resistance poses a significant challenge to effective long-term treatment across various medical fields.This study proposed a feasible strategy to enhance lysosomal alkalinization by transporting mitochondria-tar...Drug resistance poses a significant challenge to effective long-term treatment across various medical fields.This study proposed a feasible strategy to enhance lysosomal alkalinization by transporting mitochondria-targeting quaternary ammonium salts into lysosomes,creating a deprotonated environment.This environment allows drugs to bypass protonation issues in lysosomes,thereby reversing drug resistance and improving therapeutic efficacy.As a proof of concept,a quaternary ammonium salt-based pH indicator was developed,berberrubine(BRB),enhancing the action of the anticancer drug hydroxycamptothecin(HCPT)in resistant cells.BRB-induced alkalinization increased lysosomal pH and deactivated lysosomal activity,enabling HCPT to bypass protonation constraints.This enhancement markedly improved the anticancer efficacy of HCPT in resistant cells,providing an innovative approach to address drug resistance and advancing therapeutic technologies.展开更多
Camptothecine （CPT） and hydroxycamptothecin （HCPT）, two kinds of anti-cancer alkaloids, were extracted from Camptotheca acuminata leaves using homogenate extraction technology under different conditions such as th...Camptothecine （CPT） and hydroxycamptothecin （HCPT）, two kinds of anti-cancer alkaloids, were extracted from Camptotheca acuminata leaves using homogenate extraction technology under different conditions such as the ratio of material to liquid, ethanol concentration, and homogenate time. The optimum technology parameters for homogenate extraction of CPT and HCPT from C acuminata leaves were determined as homogenate time at 8 rain, ethanol concentration at 55% and the ratio of material to liquid at 1：15 （g：mL）. By using the optimized parameters, we obtained 0.639‰ extraction rate for CPT and 0.437‰ for HCPT. The extraction yields of CPT and HCPT extracted by homogenating technology were higher than those by other extractive methods, such as ultrasonic, reflux, shaking in water bath. It is concluded that the homogenate extraction technology was an efficient method for extracting CPT and HCPT from C acuminata leaves, with characteristics of less extraction time and high yield.展开更多
The determination method of 10-hydroxycamptothecin in Camptotheca acuminata fruits by high-performance liquid chromatogram (HPLC) was studied. The HPLC analysis was performed on a HIQ sil C18(4.6×250 mm) column w...The determination method of 10-hydroxycamptothecin in Camptotheca acuminata fruits by high-performance liquid chromatogram (HPLC) was studied. The HPLC analysis was performed on a HIQ sil C18(4.6×250 mm) column with mobile phase of acetonitrilewater (3:7, V:V), flow rate 1 mLmin-1 and UV detective wavelength 266 nm. Extracting 10-hydroxycamptothecin by ultrasonic method from fruits of C. acuminata to prepare samples for analysis was systematically discussed. The optimal extraction condition was carried out by 60% alcohol solution at 60℃ for 50 minutes.展开更多
AIM To study the effects of arsenic trioxide andHCPT on different degrees of differentiated gastriccancer cells（SGC-7901,MKN-45,MKN-28）withrespect to both cytotoxicity and induction ofapoptosis in vitro.METHODS The ...AIM To study the effects of arsenic trioxide andHCPT on different degrees of differentiated gastriccancer cells（SGC-7901,MKN-45,MKN-28）withrespect to both cytotoxicity and induction ofapoptosis in vitro.METHODS The cytotoxicity of As<sub>2</sub>O<sub>3</sub> and HCPTon gastric cancer cells was determined by MTTassay.Morphologic changes of apoptosis ofgastric cancer cells were observed by lightmicroscopy and transmission electron microscopy.Apoptosis and cell cycle changes of gastric cancercells induced by HCPT and As<sub>2</sub>O<sub>3</sub> were investigatedby TUNEL method and flow cytometry.RESULTS As<sub>2</sub>O<sub>3</sub> and HCPT had remarkablecytotoxic effects on different degrees ofdifferentiated gastric cancer cells.The IC<sub>50</sub>ofAs<sub>2</sub>O<sub>3</sub> on well differentiated gastric cancer cellMKN-28,moderately differentiated gastric cancercell SGC-7901,and poorly differentiated gastriccancer cell MKN-28 were 8.91 μmol/L,10.57μmol/L,and 11.65 μmol/L,respectively.The IC<sub>50</sub>of HCPT on MKN-28,SGC-7901,and MKN-45 were9.35 mg/L,10.21 mg/L,and 12.63 mg/Lrespectively after 48 h treatment.After 12 h ofexposure to both drugs,gastric cancer cellsexhibited morphologic features of apoptosis,including cell shrinkage,nuclear condensation, and formation of apoptotic bodies.A typicalsubdiploid peak before G<sub>0</sub>/G<sub>1</sub> phase was observedby flow cytometry.The apoptotic rates of SGC-7901,MKN-45,and MKN-28 were 13.84%,22.52%,and 9.68%,respectively after 48 hexposure to 10 μmol/L As<sub>2</sub>O<sub>3</sub>.The apoptotic ratesof SGC-7901,MKN-45,and MKN-28 were 21.88%,12.35%,and 30.26%,respectively after 48 hexposure to 10 mg/L HCPT.The apoptotic indicewere 7%-15% as assessed by TUNEL method.The effect of As<sub>2</sub>O<sub>3</sub> on SGC-7901 showedremarkable cell cycle specificity,which inducedcell death in G<sub>1</sub> phase,and blocked G<sub>2</sub>/M phase.HCPT also showed a remarkable cell cyclespecificity,by inducing cell death and apoptosis inG<sub>1</sub> phase and arrest of proliferation at S phase.CONCLUSION As<sub>2</sub>O<sub>3</sub> and HCPT exhibitsignificant cytotoxicity on gastric cancer cells byinduction of apoptosis.As<sub>2</sub>O<sub>3</sub> and HCPT mighthave a promising prospect in the treatment ofgastric cancer,which needs to be further studied.展开更多
The improved 3 step preparation of a key antitumor agent, 7 ethyl 10 hydroxycamptothecin(SN 38), which consists of ethylation, oxidation and photo chemical rearrangement, is described. The proposed reaction mech...The improved 3 step preparation of a key antitumor agent, 7 ethyl 10 hydroxycamptothecin(SN 38), which consists of ethylation, oxidation and photo chemical rearrangement, is described. The proposed reaction mechanism is also discussed.展开更多
Objective： Although 5-fluarouracil-based chemotherapy has become a standard regimen for treatment of advanced colorectal cancer, the efficacy, as second line therapy, is not high. It is necessary to find a new regime...Objective： Although 5-fluarouracil-based chemotherapy has become a standard regimen for treatment of advanced colorectal cancer, the efficacy, as second line therapy, is not high. It is necessary to find a new regimen as a substitute for these patients. The study was to evaluate the short-time effects and toxicity of combination of HCPT plus L-OHP regimen in treatment of advanced colorectal cancer. Methods： Forty-seven patients with pathological evidence of advanced colorectal cancer were enrolled and were treated with HCPT plus L-OHP regimen for 86 cycles. All patients were treated with L-OHP 130 mg/m^2 day 1 and HCPT 6 mg/m^2day 1-4, the chemotherapy was repeated every 3 weeks as a cycle. The Short-time efficats and side effects were evaluated after 2 cycles for each patient. Results： 38 cases can be evaluated to short-time effects and achieved the overall response rate （CR＋PR） was 36.8%. KPS improved in 20 cases （52.6%）. In the total 86 cycles, the leucopenia occurred in 59 cycles （68.6%）,18 cycles （30.5%） in grade Ⅲ and Ⅳ and the diarrhea occurred in 48 cycles （55.8%）, 18 cycles （37.5%） in grade Ⅲ and Ⅳ. Conclusion： A satisfied response rate was obtained in advanced colorectal cancer patients treated by HCPT plus L-OHP regimen, especially who were the failure of first-line chemotherapy with 5-FU. The limited-dose toxicity was leucopenia and diarrhea.展开更多
OBJECTIVE To estimate effects, survival rate after the short-time efficacy, side the treatment of combining chemotherapy of oxaliplatin or 5-fluorouracil/leucovorin with hydroxycamptothecine （HCPT） for the patients ...OBJECTIVE To estimate effects, survival rate after the short-time efficacy, side the treatment of combining chemotherapy of oxaliplatin or 5-fluorouracil/leucovorin with hydroxycamptothecine （HCPT） for the patients with advanced colorectal cancer. METHODS From January 2002 to November 2005, 59 patients with advanced colorectal cancer confirmed by pathology were enrolled into this study in the department of medical oncology, in the Sixth People＇s Hospital of Shanghai Jiaotong University, Shanghai. Patients＇ characteristics in two groups were similarly confirmed by statistic. All 37 patients in OH group received oxalip21atin （130 mg/m^2 d1） plus hydroxycamptothecine （6 mg/m d1-4）, and all 22 patients in the HLF group received hydroxycamptothecine （6 mg/m^2 d1-4） plus leucovorin （300 mg d1-5） and 5-fluorouracil （0.375 g/m^2 d1-5）. The regimens in both groups were 21-day cycle that was repeated three weeks. The side effects were evaluated. The efficacy was estimated after two cycles of chemotherapy for each patient. RESULTS The efficacy of the treatment in the OH group with 37 patients and in the HLF group with 22 patients was estimated. The overall response rate （CR ＋ PR） was 32.4% in the OH group and 22.7% in the HLF group. There was no complete response （CR） and there was no statistical significantly difference （%2= 0.876, P = 0.704） in two groups. The 1-year survival rate was 30.98% in the OH group and 15.02% in the HLF group, and it had no significant difference between the two groups. The median PSF and OS were 5.83 months and 11.17 months in the OH group vs. 7.40 months and 10.48 months in the HLF group, and it had no significant differences between the two groups （P 〉 0.05）. The major side effects of grade III and IV in the two groups were myelosuppression and gastrointestinal reactions. The statistically significant difference in side effects appeared in leukopenia （χ^2= 17.173, P = 0.001）, nausea/vomiting （χ^2= 6.426, P = 0.039）, diarrhea （χ^2= 16.245, P = 0.000） and peripheral neuropathy. CONCLUSION The efficacy was almost equal between the OH and the HLF groups, and the two regimens can be used as the second-line treatments for the patients with colorectal cancer. Leucopenia, nausea, diarrhea and peripheral neuropathy appeared more in OH group, and anemia and thrombocytopenia were almost equal between the OH and the HLF groups.展开更多
Camptothecine(CPT) and hydroxycamptothecin(HCPT), two kinds of anti-cancer alkaloids, were extracted from Camptotheca acuminata leaves using homogenate extraction technology under different conditions such as the rati...Camptothecine(CPT) and hydroxycamptothecin(HCPT), two kinds of anti-cancer alkaloids, were extracted from Camptotheca acuminata leaves using homogenate extraction technology under different conditions such as the ratio of material to liquid, ethanol concentration, and homogenate time.The optimum technology parameters for homogenate extraction of CPT and HCPT from C.acuminata leaves were determined as homogenate time at 8 min, ethanol concentration at 55% and the ratio of material to liquid at 1:15(g:mL).By using the optimized parameters, we obtained 0.639‰ extraction rate for CPT and 0.437‰ for HCPT.The extraction yields of CPT and HCPT extracted by homogenating technology were higher than those by other extractive methods, such as ultrasonic, reflux, shaking in water bath.It is concluded that the homogenate extraction technology was an efficient method for extracting CPT and HCPT from C.acuminata leaves, with characteristics of less extraction time and high yield.展开更多
A novel camptothecin analogue, 9-methyl-10-hydroxycamptothecin （4）, was unexpectedly synthesized from 10-hydroxycamptothecin in two steps. The key step included an efficient Mannich-type reaction. The overall yield ...A novel camptothecin analogue, 9-methyl-10-hydroxycamptothecin （4）, was unexpectedly synthesized from 10-hydroxycamptothecin in two steps. The key step included an efficient Mannich-type reaction. The overall yield was 47.2%. An ether analogue of 4, 9-methyl-10-benzylaminomethoxycamptothecin （5）, was also prepared. These new camptothecin analogues were evaluated for in vitro cytotoxicity against four human cancer cell lines, and exhibited more potent antitumor activities than contrals camptothecin and topotecan against several cancer cells.展开更多
Hydroxycamptothecin is a potent antineoplastic agent that has shown efficacy against multiple tumor lines in vitro. This is the first study to investigate the release, distribution, and efficacy of hydroxycamptothecin...Hydroxycamptothecin is a potent antineoplastic agent that has shown efficacy against multiple tumor lines in vitro. This is the first study to investigate the release, distribution, and efficacy of hydroxycamptothecin which was incorporated into the biodegradable polymer Polylactic Acid (PLA), and implant into brain directly. In vitro release curve generated showed that a large initial release occurred over the first three days and was followed by a steady, but considerably slower rate of release over the next 25 days. After implanting the discs into 40 male SD rats, the animals were followed up to 28 days, where the concentration in brain tissue was far higher than that in peripheral blood at the each of the eight time-points evaluated, and it was also within the therapeutic range for C6 cells tested in vitro. The in vivoefficacy of the discs was evaluated with rats inoculated intracranially with C6 glioma and treated with hydroxycamptothecin polymer compared to intravenous as well as intratumoral injections;the median survival is 21.1, 13.9, 14.9 days, respectively. Given these data, we conclude that the biodegradable polymer PLA releases hydroxycamptothecin, producing tumoricidal levels in brain tissues and prolonging survival in a rat glioma model.展开更多
The binding reaction between 10-hydroxycamptothecin （10-HCPT） and human serum albumins （HSA） is studied by means of fluorescence spectroscopy, UV-Vis absorption spectrum, IH NMR spectrum, and molecular simulation....The binding reaction between 10-hydroxycamptothecin （10-HCPT） and human serum albumins （HSA） is studied by means of fluorescence spectroscopy, UV-Vis absorption spectrum, IH NMR spectrum, and molecular simulation. The results indicate that the binding reaction of 10-HCPT and HSA is a single static quenching process, and the binding equilibrium constant for 10-HCPT binding with HSA is estimated K0-4.93×10^4 L · mol-I at 25 ℃ with the molar ratio of I ： 1. The distance （r） and energy transfer efficiency（E） between donor （HSA） and acceptor （10-HCPT） are obtained as follows, r=3.51 nm; E-0.27. The enthalpy change （△Hφ） and entropy change （△Sφ） are calcu- lated at different temperatures, and the hydrophobic force and shidipole force are the functions in the reaction. The results show that 10-HCPT binds within the subdomain II A of HSA by the hydrophobic force, and the 10-OH and 20-OH of 10-HCPT bind with both residue Leu-238 of HSA and Ala 291 of HSA by hydrogen bonds.展开更多
The present method gives a detailed description for the development and validation of a simple stability indicating reverse phase liquid chromatographic method for 10-hydroxycamptothecin(10-HCTN) in the presence of it...The present method gives a detailed description for the development and validation of a simple stability indicating reverse phase liquid chromatographic method for 10-hydroxycamptothecin(10-HCTN) in the presence of its impurities namely Imp A and Imp B along with degradation products generated from forced degradation studies. The drug was subjected to stress conditions of hydrolysis (acid, base and neutral), oxidative, photolytic and thermal stress degradation. Degradation was observed when subjected to treatment with peroxides or under conditions normally used for typical acid and base hydrolysis. The drug was found to be stable under other stress conditions attempted such as photolytic and thermal. Successful separation and isolation of the drug from related impurities and degradation products formed under stress conditions was achieved on an Inertsil ODS-3V (250 mm × 4.6 mm, 5 μm) column using a phosphate buffer, acetonitrile, methanol and Nanopure water. The developed HPLC method was validated with respect to specificity, linearity, accuracy, precision, sensitivity, robustness and solution stability. The assay method was found to be linear in the range of 0.16 mg/mL to 0.24 mg/mL with a correlation coefficient of 0.999 and the linearity of the impurities was established from 0.02% (LOQ) to 0.3%. Recoveries of assay and impurities were found between 99.4% and 100.3%. The developed HPLC method can be used to determine the related substances and assay determinations of 10-HCTN and also to evaluate the quality and long term stability of production samples.展开更多
Chemotherapy outcomes for the treatment of glioma remains unsatisfactory due to the inefficient drug transport across the blood–brain barrier(BBB) and insufficient drug accumulation in the tumor region. Although many...Chemotherapy outcomes for the treatment of glioma remains unsatisfactory due to the inefficient drug transport across the blood–brain barrier(BBB) and insufficient drug accumulation in the tumor region. Although many approaches, including various nanosystems, have been developed to promote the distribution of chemotherapeutics in the brain tumor, the delivery efficiency and the possible damage to the normal brain function still greatly restrict the clinical application of the nanocarriers.Therefore, it is urgent and necessary to discover more safe and effective BBB penetration and gliomatargeting strategies. In the present study, menthol, one of the strongest BBB penetration enhancers screened from traditional Chinese medicine, was conjugated to casein, a natural food protein with brain targeting capability. Then the conjugate self-assembled into the nanoparticles to load anti-cancer drugs.The nanoparticles were characterized to have appropriate size, spheroid shape and high loading drug capacity. Tumor spheroid penetration experiments demonstrated that penetration ability of mentholmodified casein nanoparticles(M-CA-NP) into the tumor were much deeper than that of unmodified nanoparticles. In vivo imaging further verified that M-CA-NPs exhibited higher brain tumor distribution than unmodified nanoparticles. The median survival time of glioma-bearing mice treated with HCPT-MCA-NPs was significantly prolonged than those treated with free HCPT or HCPT-CA-NPs. HE staining ofthe organs indicated the safety of the nanoparticles. Therefore, the study combined the advantages of traditional Chinese medicine strategy with modern delivery technology for brain targeting, and provide a safe and effective approach for glioma therapy.展开更多
5-fluarouracil-based chemotherapy has become a standard regimen for the treatment of advanced colorectal cancer （ACRC）.^1 Defined as the second line therapy for ACRC with 5-fluarouracil （5-Fu） plus leucovorin （LV...5-fluarouracil-based chemotherapy has become a standard regimen for the treatment of advanced colorectal cancer （ACRC）.^1 Defined as the second line therapy for ACRC with 5-fluarouracil （5-Fu） plus leucovorin （LV） combined with oxaliplatin （OXA）, the response rate （RR）, progression-free survival （PFS） and overall survival （OS） were 21.2%, at 4.7 and 11.5 months, whereas RR, PFS and OS with 5-Fu plus LV combined with irinotecan （CPT-11） were 11.4%, at 3.2 and 12.2 months. There were no statistical difference between the two protocals.^2,3 Those results may well suggest that some of these patients were resistant to 5-Fu. Therefore it is necessary to find a more effective regimen without 5-Fu to treat recurrent ACRC patients that were initially treated with 5-Fu. Our previous study showed that OXA can enhance the function of hydroxycamptothecine （HCPT） in inducing the apoptosis of a human colorectal cell line in vivo.^4 So we chose OXA plus HCPT （OH） regimen to treat 28 patients with ACRC and compared RR, one-year survival rate, PFS, OS and main toxicities with a 5-Fu plus LV combined with OXA （OFL） regimen.展开更多
Transcatheter arterial embolization with hydroxycamptothecine, cantharidin and cisplatin,thoroughly mixed with large doses of interferon and interleukin-2, was performed in 48 cases with unre-sectable intermediate or ...Transcatheter arterial embolization with hydroxycamptothecine, cantharidin and cisplatin,thoroughly mixed with large doses of interferon and interleukin-2, was performed in 48 cases with unre-sectable intermediate or advanced hepatocellular carcinoma. The results demonstrate a partial remissionrate of 54. 2%, significantly higher than that in embolization with chemotherapeutic agents alone (cis-platin, adriamycin and mitomycin, 32. 1%, P<O. 01) . Morever, the adverse reactions of hydroxycamp-tothecine and cantharidin, when applied systemically, including hematuria or urodynia were successfullyeliminated.展开更多
基金supported by Young Elite Scientists Sponsorship Program by China Association for Science and Technology(No.CACM-2023-QNRC1–02)Shandong Province Key R&D Program(Major Technological Innovation Project)(No.2021CXGC010501)+6 种基金National Natural Science Foundation of China(No.22107059)Natural Science Foundation of Shandong Province(No.ZR2021QH057)Program for Youth Innovation Technology in Colleges and Universities of Shandong Province of China(No.2021KJ035)Taishan Scholars Program(No.TSQN202211221)Shandong Science Fund for Excellent Young Scholars(No.ZR2022YQ66)Funded by Shandong Postdoctoral Science Foundation(No.SDCX-ZG-202400084)the National Administration of Traditional Chinese Medicine Young Qihuang Scholar Project。
文摘Drug resistance poses a significant challenge to effective long-term treatment across various medical fields.This study proposed a feasible strategy to enhance lysosomal alkalinization by transporting mitochondria-targeting quaternary ammonium salts into lysosomes,creating a deprotonated environment.This environment allows drugs to bypass protonation issues in lysosomes,thereby reversing drug resistance and improving therapeutic efficacy.As a proof of concept,a quaternary ammonium salt-based pH indicator was developed,berberrubine(BRB),enhancing the action of the anticancer drug hydroxycamptothecin(HCPT)in resistant cells.BRB-induced alkalinization increased lysosomal pH and deactivated lysosomal activity,enabling HCPT to bypass protonation constraints.This enhancement markedly improved the anticancer efficacy of HCPT in resistant cells,providing an innovative approach to address drug resistance and advancing therapeutic technologies.
文摘Camptothecine （CPT） and hydroxycamptothecin （HCPT）, two kinds of anti-cancer alkaloids, were extracted from Camptotheca acuminata leaves using homogenate extraction technology under different conditions such as the ratio of material to liquid, ethanol concentration, and homogenate time. The optimum technology parameters for homogenate extraction of CPT and HCPT from C acuminata leaves were determined as homogenate time at 8 rain, ethanol concentration at 55% and the ratio of material to liquid at 1：15 （g：mL）. By using the optimized parameters, we obtained 0.639‰ extraction rate for CPT and 0.437‰ for HCPT. The extraction yields of CPT and HCPT extracted by homogenating technology were higher than those by other extractive methods, such as ultrasonic, reflux, shaking in water bath. It is concluded that the homogenate extraction technology was an efficient method for extracting CPT and HCPT from C acuminata leaves, with characteristics of less extraction time and high yield.
基金This paper was supported by National Natural Science Foundation of China (No. 30070086).
文摘The determination method of 10-hydroxycamptothecin in Camptotheca acuminata fruits by high-performance liquid chromatogram (HPLC) was studied. The HPLC analysis was performed on a HIQ sil C18(4.6×250 mm) column with mobile phase of acetonitrilewater (3:7, V:V), flow rate 1 mLmin-1 and UV detective wavelength 266 nm. Extracting 10-hydroxycamptothecin by ultrasonic method from fruits of C. acuminata to prepare samples for analysis was systematically discussed. The optimal extraction condition was carried out by 60% alcohol solution at 60℃ for 50 minutes.
基金the Natural Science Foundation of Committee of Science and Technology of Shanghai Municipality(№964119035)
文摘AIM To study the effects of arsenic trioxide andHCPT on different degrees of differentiated gastriccancer cells（SGC-7901,MKN-45,MKN-28）withrespect to both cytotoxicity and induction ofapoptosis in vitro.METHODS The cytotoxicity of As<sub>2</sub>O<sub>3</sub> and HCPTon gastric cancer cells was determined by MTTassay.Morphologic changes of apoptosis ofgastric cancer cells were observed by lightmicroscopy and transmission electron microscopy.Apoptosis and cell cycle changes of gastric cancercells induced by HCPT and As<sub>2</sub>O<sub>3</sub> were investigatedby TUNEL method and flow cytometry.RESULTS As<sub>2</sub>O<sub>3</sub> and HCPT had remarkablecytotoxic effects on different degrees ofdifferentiated gastric cancer cells.The IC<sub>50</sub>ofAs<sub>2</sub>O<sub>3</sub> on well differentiated gastric cancer cellMKN-28,moderately differentiated gastric cancercell SGC-7901,and poorly differentiated gastriccancer cell MKN-28 were 8.91 μmol/L,10.57μmol/L,and 11.65 μmol/L,respectively.The IC<sub>50</sub>of HCPT on MKN-28,SGC-7901,and MKN-45 were9.35 mg/L,10.21 mg/L,and 12.63 mg/Lrespectively after 48 h treatment.After 12 h ofexposure to both drugs,gastric cancer cellsexhibited morphologic features of apoptosis,including cell shrinkage,nuclear condensation, and formation of apoptotic bodies.A typicalsubdiploid peak before G<sub>0</sub>/G<sub>1</sub> phase was observedby flow cytometry.The apoptotic rates of SGC-7901,MKN-45,and MKN-28 were 13.84%,22.52%,and 9.68%,respectively after 48 hexposure to 10 μmol/L As<sub>2</sub>O<sub>3</sub>.The apoptotic ratesof SGC-7901,MKN-45,and MKN-28 were 21.88%,12.35%,and 30.26%,respectively after 48 hexposure to 10 mg/L HCPT.The apoptotic indicewere 7%-15% as assessed by TUNEL method.The effect of As<sub>2</sub>O<sub>3</sub> on SGC-7901 showedremarkable cell cycle specificity,which inducedcell death in G<sub>1</sub> phase,and blocked G<sub>2</sub>/M phase.HCPT also showed a remarkable cell cyclespecificity,by inducing cell death and apoptosis inG<sub>1</sub> phase and arrest of proliferation at S phase.CONCLUSION As<sub>2</sub>O<sub>3</sub> and HCPT exhibitsignificant cytotoxicity on gastric cancer cells byinduction of apoptosis.As<sub>2</sub>O<sub>3</sub> and HCPT mighthave a promising prospect in the treatment ofgastric cancer,which needs to be further studied.
文摘The improved 3 step preparation of a key antitumor agent, 7 ethyl 10 hydroxycamptothecin(SN 38), which consists of ethylation, oxidation and photo chemical rearrangement, is described. The proposed reaction mechanism is also discussed.
文摘Objective： Although 5-fluarouracil-based chemotherapy has become a standard regimen for treatment of advanced colorectal cancer, the efficacy, as second line therapy, is not high. It is necessary to find a new regimen as a substitute for these patients. The study was to evaluate the short-time effects and toxicity of combination of HCPT plus L-OHP regimen in treatment of advanced colorectal cancer. Methods： Forty-seven patients with pathological evidence of advanced colorectal cancer were enrolled and were treated with HCPT plus L-OHP regimen for 86 cycles. All patients were treated with L-OHP 130 mg/m^2 day 1 and HCPT 6 mg/m^2day 1-4, the chemotherapy was repeated every 3 weeks as a cycle. The Short-time efficats and side effects were evaluated after 2 cycles for each patient. Results： 38 cases can be evaluated to short-time effects and achieved the overall response rate （CR＋PR） was 36.8%. KPS improved in 20 cases （52.6%）. In the total 86 cycles, the leucopenia occurred in 59 cycles （68.6%）,18 cycles （30.5%） in grade Ⅲ and Ⅳ and the diarrhea occurred in 48 cycles （55.8%）, 18 cycles （37.5%） in grade Ⅲ and Ⅳ. Conclusion： A satisfied response rate was obtained in advanced colorectal cancer patients treated by HCPT plus L-OHP regimen, especially who were the failure of first-line chemotherapy with 5-FU. The limited-dose toxicity was leucopenia and diarrhea.
文摘OBJECTIVE To estimate effects, survival rate after the short-time efficacy, side the treatment of combining chemotherapy of oxaliplatin or 5-fluorouracil/leucovorin with hydroxycamptothecine （HCPT） for the patients with advanced colorectal cancer. METHODS From January 2002 to November 2005, 59 patients with advanced colorectal cancer confirmed by pathology were enrolled into this study in the department of medical oncology, in the Sixth People＇s Hospital of Shanghai Jiaotong University, Shanghai. Patients＇ characteristics in two groups were similarly confirmed by statistic. All 37 patients in OH group received oxalip21atin （130 mg/m^2 d1） plus hydroxycamptothecine （6 mg/m d1-4）, and all 22 patients in the HLF group received hydroxycamptothecine （6 mg/m^2 d1-4） plus leucovorin （300 mg d1-5） and 5-fluorouracil （0.375 g/m^2 d1-5）. The regimens in both groups were 21-day cycle that was repeated three weeks. The side effects were evaluated. The efficacy was estimated after two cycles of chemotherapy for each patient. RESULTS The efficacy of the treatment in the OH group with 37 patients and in the HLF group with 22 patients was estimated. The overall response rate （CR ＋ PR） was 32.4% in the OH group and 22.7% in the HLF group. There was no complete response （CR） and there was no statistical significantly difference （%2= 0.876, P = 0.704） in two groups. The 1-year survival rate was 30.98% in the OH group and 15.02% in the HLF group, and it had no significant difference between the two groups. The median PSF and OS were 5.83 months and 11.17 months in the OH group vs. 7.40 months and 10.48 months in the HLF group, and it had no significant differences between the two groups （P 〉 0.05）. The major side effects of grade III and IV in the two groups were myelosuppression and gastrointestinal reactions. The statistically significant difference in side effects appeared in leukopenia （χ^2= 17.173, P = 0.001）, nausea/vomiting （χ^2= 6.426, P = 0.039）, diarrhea （χ^2= 16.245, P = 0.000） and peripheral neuropathy. CONCLUSION The efficacy was almost equal between the OH and the HLF groups, and the two regimens can be used as the second-line treatments for the patients with colorectal cancer. Leucopenia, nausea, diarrhea and peripheral neuropathy appeared more in OH group, and anemia and thrombocytopenia were almost equal between the OH and the HLF groups.
基金supported by National Key Tech-nology R & D Program (grant no. 2006BAD18B04).
文摘Camptothecine(CPT) and hydroxycamptothecin(HCPT), two kinds of anti-cancer alkaloids, were extracted from Camptotheca acuminata leaves using homogenate extraction technology under different conditions such as the ratio of material to liquid, ethanol concentration, and homogenate time.The optimum technology parameters for homogenate extraction of CPT and HCPT from C.acuminata leaves were determined as homogenate time at 8 min, ethanol concentration at 55% and the ratio of material to liquid at 1:15(g:mL).By using the optimized parameters, we obtained 0.639‰ extraction rate for CPT and 0.437‰ for HCPT.The extraction yields of CPT and HCPT extracted by homogenating technology were higher than those by other extractive methods, such as ultrasonic, reflux, shaking in water bath.It is concluded that the homogenate extraction technology was an efficient method for extracting CPT and HCPT from C.acuminata leaves, with characteristics of less extraction time and high yield.
基金the Natural Science Foundation of Jiangsu Province,China(No.BK2007168)
文摘A novel camptothecin analogue, 9-methyl-10-hydroxycamptothecin （4）, was unexpectedly synthesized from 10-hydroxycamptothecin in two steps. The key step included an efficient Mannich-type reaction. The overall yield was 47.2%. An ether analogue of 4, 9-methyl-10-benzylaminomethoxycamptothecin （5）, was also prepared. These new camptothecin analogues were evaluated for in vitro cytotoxicity against four human cancer cell lines, and exhibited more potent antitumor activities than contrals camptothecin and topotecan against several cancer cells.
文摘Hydroxycamptothecin is a potent antineoplastic agent that has shown efficacy against multiple tumor lines in vitro. This is the first study to investigate the release, distribution, and efficacy of hydroxycamptothecin which was incorporated into the biodegradable polymer Polylactic Acid (PLA), and implant into brain directly. In vitro release curve generated showed that a large initial release occurred over the first three days and was followed by a steady, but considerably slower rate of release over the next 25 days. After implanting the discs into 40 male SD rats, the animals were followed up to 28 days, where the concentration in brain tissue was far higher than that in peripheral blood at the each of the eight time-points evaluated, and it was also within the therapeutic range for C6 cells tested in vitro. The in vivoefficacy of the discs was evaluated with rats inoculated intracranially with C6 glioma and treated with hydroxycamptothecin polymer compared to intravenous as well as intratumoral injections;the median survival is 21.1, 13.9, 14.9 days, respectively. Given these data, we conclude that the biodegradable polymer PLA releases hydroxycamptothecin, producing tumoricidal levels in brain tissues and prolonging survival in a rat glioma model.
基金Supported by the Foundation of Shandong Province Educa-tion Bureau (J06060)
文摘The binding reaction between 10-hydroxycamptothecin （10-HCPT） and human serum albumins （HSA） is studied by means of fluorescence spectroscopy, UV-Vis absorption spectrum, IH NMR spectrum, and molecular simulation. The results indicate that the binding reaction of 10-HCPT and HSA is a single static quenching process, and the binding equilibrium constant for 10-HCPT binding with HSA is estimated K0-4.93×10^4 L · mol-I at 25 ℃ with the molar ratio of I ： 1. The distance （r） and energy transfer efficiency（E） between donor （HSA） and acceptor （10-HCPT） are obtained as follows, r=3.51 nm; E-0.27. The enthalpy change （△Hφ） and entropy change （△Sφ） are calcu- lated at different temperatures, and the hydrophobic force and shidipole force are the functions in the reaction. The results show that 10-HCPT binds within the subdomain II A of HSA by the hydrophobic force, and the 10-OH and 20-OH of 10-HCPT bind with both residue Leu-238 of HSA and Ala 291 of HSA by hydrogen bonds.
文摘The present method gives a detailed description for the development and validation of a simple stability indicating reverse phase liquid chromatographic method for 10-hydroxycamptothecin(10-HCTN) in the presence of its impurities namely Imp A and Imp B along with degradation products generated from forced degradation studies. The drug was subjected to stress conditions of hydrolysis (acid, base and neutral), oxidative, photolytic and thermal stress degradation. Degradation was observed when subjected to treatment with peroxides or under conditions normally used for typical acid and base hydrolysis. The drug was found to be stable under other stress conditions attempted such as photolytic and thermal. Successful separation and isolation of the drug from related impurities and degradation products formed under stress conditions was achieved on an Inertsil ODS-3V (250 mm × 4.6 mm, 5 μm) column using a phosphate buffer, acetonitrile, methanol and Nanopure water. The developed HPLC method was validated with respect to specificity, linearity, accuracy, precision, sensitivity, robustness and solution stability. The assay method was found to be linear in the range of 0.16 mg/mL to 0.24 mg/mL with a correlation coefficient of 0.999 and the linearity of the impurities was established from 0.02% (LOQ) to 0.3%. Recoveries of assay and impurities were found between 99.4% and 100.3%. The developed HPLC method can be used to determine the related substances and assay determinations of 10-HCTN and also to evaluate the quality and long term stability of production samples.
基金financial support from the National Natural Science Foundation of China(No.81573616,81690263 and81773911,China)the Development Project of Shanghai Peak Disciplines-Integrated Medicine(No.20150407,China)
文摘Chemotherapy outcomes for the treatment of glioma remains unsatisfactory due to the inefficient drug transport across the blood–brain barrier(BBB) and insufficient drug accumulation in the tumor region. Although many approaches, including various nanosystems, have been developed to promote the distribution of chemotherapeutics in the brain tumor, the delivery efficiency and the possible damage to the normal brain function still greatly restrict the clinical application of the nanocarriers.Therefore, it is urgent and necessary to discover more safe and effective BBB penetration and gliomatargeting strategies. In the present study, menthol, one of the strongest BBB penetration enhancers screened from traditional Chinese medicine, was conjugated to casein, a natural food protein with brain targeting capability. Then the conjugate self-assembled into the nanoparticles to load anti-cancer drugs.The nanoparticles were characterized to have appropriate size, spheroid shape and high loading drug capacity. Tumor spheroid penetration experiments demonstrated that penetration ability of mentholmodified casein nanoparticles(M-CA-NP) into the tumor were much deeper than that of unmodified nanoparticles. In vivo imaging further verified that M-CA-NPs exhibited higher brain tumor distribution than unmodified nanoparticles. The median survival time of glioma-bearing mice treated with HCPT-MCA-NPs was significantly prolonged than those treated with free HCPT or HCPT-CA-NPs. HE staining ofthe organs indicated the safety of the nanoparticles. Therefore, the study combined the advantages of traditional Chinese medicine strategy with modern delivery technology for brain targeting, and provide a safe and effective approach for glioma therapy.
文摘5-fluarouracil-based chemotherapy has become a standard regimen for the treatment of advanced colorectal cancer （ACRC）.^1 Defined as the second line therapy for ACRC with 5-fluarouracil （5-Fu） plus leucovorin （LV） combined with oxaliplatin （OXA）, the response rate （RR）, progression-free survival （PFS） and overall survival （OS） were 21.2%, at 4.7 and 11.5 months, whereas RR, PFS and OS with 5-Fu plus LV combined with irinotecan （CPT-11） were 11.4%, at 3.2 and 12.2 months. There were no statistical difference between the two protocals.^2,3 Those results may well suggest that some of these patients were resistant to 5-Fu. Therefore it is necessary to find a more effective regimen without 5-Fu to treat recurrent ACRC patients that were initially treated with 5-Fu. Our previous study showed that OXA can enhance the function of hydroxycamptothecine （HCPT） in inducing the apoptosis of a human colorectal cell line in vivo.^4 So we chose OXA plus HCPT （OH） regimen to treat 28 patients with ACRC and compared RR, one-year survival rate, PFS, OS and main toxicities with a 5-Fu plus LV combined with OXA （OFL） regimen.
文摘Transcatheter arterial embolization with hydroxycamptothecine, cantharidin and cisplatin,thoroughly mixed with large doses of interferon and interleukin-2, was performed in 48 cases with unre-sectable intermediate or advanced hepatocellular carcinoma. The results demonstrate a partial remissionrate of 54. 2%, significantly higher than that in embolization with chemotherapeutic agents alone (cis-platin, adriamycin and mitomycin, 32. 1%, P<O. 01) . Morever, the adverse reactions of hydroxycamp-tothecine and cantharidin, when applied systemically, including hematuria or urodynia were successfullyeliminated.
