OBJECTIVETo establish the mothod to dectect the microdialysis recovery of HCPT and to investigate the influencing factors, thus to supply experimental basis for in-vivo microdialysis of HCPT.

METHODThe in vitro recovery of HCPT was detected by concentration difference method (increment method and decrement method). The influence of flow rates, medium concentration and temperature on the HCPT recovery and the stability were studied.

RESULTThe recovery detected by increment method was the same as by decrement method. The recovery was independent of HCPT concentrations in the medium. The hydroxycamptothecine recovery had good stability and increased as the temperature rose.

CONCLUSIONMicrodialysis sampling can be used for the pharmacokinetic study of HCPT. Retrodialysis can be used for the determination of the HCPT in vivo recovery.

Camptothecin ; analogs & derivatives ; chemistry ; isolation & purification ; Drug Stability ; Microdialysis ; Temperature

OBJECTIVETo observe the clinical efficacy of cetuximab plus chemotherapy in the treatment of metastatic colorectal carcinoma.

METHODSClinicopathological data of 128 patients with metastatic colorectal cancer admitted in the Department of Oncology, Chinese PLA General Hospital from 2008 to June 2012 were analyzed retrospectively. Among them, 91 patients received cetuximab as the first-line therapy and 37 in the second-line or more-line therapy. The chemotherapy regimens included oxaliplatin-based therapy (FOLFOX/XELOX), irinotecan-based therapy (FOLFIRI/XELIRI) and fluorouracil-based therapy (Xeloda). The efficacy was evaluated according to RECIST 1.0 criteria. The remission rate, control rate and time to disease progression were compared among patients receiving cetuximab combined with different chemotherapy regimens in different periods.

RESULTSThe disease control rate of cetuximab applied in the first-line treatment was higher than that of the second-line or more-line [85.9% (61/71) vs. 59.3% (16/27), P=0.004]. The disease control rate of the group treated with cetuximab plus oxaliplatin-based chemotherapy was much higher compared to the other two groups [91.1% (41/45) vs. 68.1% (32/47), 4/6, P=0.021]. But there were no significant differences among three regimens in the terms of overall response rate (all P>0.05). The median time to progression of groups with cetuximab plus irinotecan, oxaliplatin or capecitabine was 7.8 months, 8.5 months and 5.2 months respectively. The median time to progression of cetuximab combined with chemotherapy in the first-line treatment and the second-line or more-line was 8.2 and 7.7 months respectively. However, the differences were not statistically significant (P>0.05).

CONCLUSIONSCetuximab in combination with oxaliplatin-based chemotherapy is recommended as the first-line application in the treatment of metastatic colorectal carcinoma patients, because it is helpful to improve the rate of disease control.

Antineoplastic Combined Chemotherapy Protocols ; Camptothecin ; analogs & derivatives ; Cetuximab ; Colorectal Neoplasms ; Deoxycytidine ; analogs & derivatives ; Fluorouracil ; analogs & derivatives ; Humans ; Leucovorin ; Neoplasm Metastasis ; Organoplatinum Compounds ; Retrospective Studies ; Treatment Outcome

AIMTo find new anticancer drug based on the structure of 10-hydroxy camptothecin.

METHODSSeven camptothecin derivatives (3 -9) were synthesized and the antitumor activities of these derivatives were evaluated.

RESULTSStructures of seven new compounds were determined by 1HNMR, IR, MS. Seven compounds showed inhibitory effects on Hela, BEL-7402, 7901 cell lines in vitro. Especially, compound 4 showed high bioactivities to all of the tumor cells in vitro, its anticancer activity against human cervical carcinoma Hela was much higher than that of 10-hydroxy camptothecin.

CONCLUSIONSome compounds are worth further studying.

Antineoplastic Agents ; chemical synthesis ; chemistry ; pharmacology ; Camptothecin ; analogs & derivatives ; chemical synthesis ; chemistry ; pharmacology ; Cell Line, Tumor ; Humans ; Molecular Structure

OBJECTIVETo develop HCPT liposome with small diameter and to study the tissue distribution of the HCPT liposome in rats.

METHODModified solvent-injection method was used to prepare HCPT liposome. The entrapment efficiency, morphology, size and zeta potential were also investigated. The transformation temperature and the ratio of cholesterol to phospholipids were determined by fluorescence spectrophotometry. HCPT liposome and HCPT injection (5 mg x kg(-1)) were injected by tail vein in mice, respectively. The tissue concentrations of HCPT were determined by LC-MS/MS.

RESULTUnder selected process conditions, the HCPT liposomes were spherical and integrated with the mean entrapment efficiency of (96.83 +/- 2.32)%, the size of (180.5 +/- 4.5) nm and the zeta potential of--(32.1 +/- 1.3) mV. It showed that the optimum proportion of cholesterol to phospholipids was 1.5: 10, the optimum transformation temperature was 32.5 degrees C; HCPT liposome at a dose of 5 mg x kg(-1) led to higher concentration and longer duration of action compared with HCPT injection on market.

CONCLUSIONHCPT liposome prepared by solvent-injection method was characteristic of small mean diameter, high encapsulation efficiency and long circulation in vivo.

Animals ; Camptothecin ; administration & dosage ; analogs & derivatives ; pharmacokinetics ; Female ; Liposomes ; Particle Size ; Rats ; Rats, Sprague-Dawley ; Tissue Distribution

OBJECTIVETo investigate the effects of hydroxycamptothecin (HCPT) on proliferation and apoptosis of rat hepatic stellate cells (HSC).

METHODSRat HSC line (HSC-T6) and rat hepatocyte line (BRL-3A) were treated with different concentrations of HCPT (0, 0.008, 0.016, 0.031, 0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 32 mg/L respectively) for 24 h. Cell proliferation was assessed by MTT colorimetric assay, apoptosis was detected with PI staging followed by flow cytometry, and by DNA ladder assay. The morphological change of apoptosis was observed under transmission electron microscopy (TEM).

RESULTSMTT assay indicated that HCPT significantly inhibited the proliferation of HSC-T6 and BRL-3A in a dose-dependent manner. 24 h after the treatment with different concentrations of HCPT (0.25, 0.5, 1 mg/L), the apoptosis rate (13.46%+/-2.42%, 26.25%+/-5.65%, 47.05%+/-8.76%, respectively) in HSC-T6 was significantly higher than that in control cells (4.89%+/-1.80%, F = 34.24, P less than 0.01). 24 h after 0.5 mg/L HCPT treatment, cell shrinkage, nucleoli disappearance, chromatin condensation were found under TEM, and DNA ladder was demonstrated by agarose gel electrophoresis.

CONCLUSIONHCPT could significantly inhibit proliferation and induce apoptosis of HSC-T6 in a dose-dependent manner.

Animals ; Apoptosis ; drug effects ; Camptothecin ; analogs & derivatives ; pharmacology ; Cell Line ; Cell Proliferation ; drug effects ; Hepatic Stellate Cells ; drug effects ; Rats

OBJECTIVESTo investigate the differentially expressed mitochondrial proteins in hydroxycamptothecin (HCPT)-treated SMMC-7721 cells by using quantitative proteome.

METHODSSMMC-7721 cell apoptosis was induced by HCPT and the mitochondria were isolated with a mitochondria isolation kit. Mitochondrial proteins labeled with a cleavable isotope-coded affinity tag were identified and quantified using two-dimensional liquid chromatography/tandem mass spectrometry.

RESULTSHighly purified mitochondria were obtained. Seventy-four mitochondrial proteins, which were statistically significantly altered (P less than 0.05) in HCPT-treated cells, were identified and analyzed. A total of 42 proteins were significantly down-regulated, and 32 were up-regulated in the cells that responded to apoptosis. The functions of these proteins were likely involved in cell energy metabolism, nucleic acid translation and transcription, cytoskeleton, etc.

CONCLUSIONOur results about the information of differentially expressed mitochondrial proteins in HCPT-treated cells and the control cells will help to understand the mechanism by which HCPT induces cell apoptosis. The integrated techniques we used in this study will be helpful to the investigation of subcellular quantitative proteomics.

Apoptosis ; drug effects ; Camptothecin ; analogs & derivatives ; pharmacology ; Cell Line, Tumor ; Humans ; Mitochondria ; metabolism ; Mitochondrial Proteins ; metabolism ; Proteome ; metabolism

OBJECTIVETo investigate the differentially expressed mitochondrial proteins in hydroxycamptothecin (HCPT)-treated SMMC-7721 cells by comparative proteomic analysis.

METHODSApoptosis of SMMC-7721 cells were induced by using HCPT and their mitochondria were isolated with a mitochondria isolation kit for cultured cells. Three different solubility protein fractions were extracted with ReadyPrep Sequential Extraction Kit and were separated by two-dimensional gel electrophoresis (2-DE). PDQuest software was used to differentiate mitochondrial proteins between control cells and HCPT-treated cells. Matrix assisted laser desorption/ionization time of flying mass spectrometry (MALDI-TOF-MS) was used to identify some of the different proteins.

RESULTSHighly purified mitochondria and high resolution 2-DE patterns of the proteins were obtained. Forty-four mitochondrial protein spots from the HCPT-treated cells showed different expressions compared to those of the control cells. Twenty of the different protein spots were analyzed by MALDI-TOF-MS.

CONCLUSIONDifferently expressed mitochondrial proteins in HCPT-treated cells and control cells were obtained in this study. This will be of help to understand the mechanism by which HCPT induces cell apoptosis.

Antineoplastic Agents, Phytogenic ; pharmacology ; Camptothecin ; analogs & derivatives ; pharmacology ; Cell Line, Tumor ; Humans ; Membrane Potentials ; drug effects ; Mitochondrial Proteins ; metabolism ; Proteomics

OBJECTIVETo evaluate the efficacy and adverse effects of weekly irinotecan combined with capecitabine as a second-line chemotherapy for treatment of advanced gastric cancer.

METHODSTwenty-one patients with advanced gastric cancer who had failed first-line therapy received irinotecan on days 1 and 8 plus capecitabine on days 1-14 for a 21-day cycle. Each patient was treated for at least two cycles and evaluated 4 weeks later for the responses.

RESULTSOf the 21 patients, none showed complete remission (CR), 5 (23.8%) showed partial remission (PR), 6 (28.6%) showed stable disease (SD) and 10 (47.6%) showed progressive disease (PD). The overall response rate was 23.8%, and 11 patients (52.4%) benefited (CR+PR+SD) from the clinical therapy, with a mean time to tumor progression of 3.61±0.97 months. The main adverse effects of this regimen included myelosuppression, nausea, vomiting and diarrhea.

CONCLUSIONThe regimen of weekly irinotecan plus capecitabine has a definite effect for treatment of advanced gastric cancer with tolerable toxicity.

Adenocarcinoma ; drug therapy ; pathology ; Adult ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Camptothecin ; administration & dosage ; analogs & derivatives ; Capecitabine ; Deoxycytidine ; administration & dosage ; analogs & derivatives ; Female ; Fluorouracil ; administration & dosage ; analogs & derivatives ; Humans ; Male ; Middle Aged ; Stomach Neoplasms ; drug therapy ; pathology ; Treatment Outcome

OBJECTIVETo evaluate efficacy, safety, and feasibility of maintenance therapy with capecitabine after fluoropyrimidines/oxaliplatin or fluoropyrimidines/irinotecan chemotherapy in patients with incurable colorectal cancer.

METHODSSeventy-three hospitalized patients with incurable colorectal cancer who received fluoropyrimidines/oxaliplatin or fluoropyrimidines/irinotecan as the first-line chemotherapy between May 2009 and December 2012 in our department were retrospectively analyzed. When the maximum percentage tumor size reduction was achieved, 42 patients received a maintenance therapy with capecitabine at 1000 mg/m(2) in two daily doses on days 1-14, and the other 31 patients without further chemotherapy or the maintenance therapy were followed up. The treatment was repeated every 3 weeks as a cycle until disease progression or intolerable toxicity. The efficacy and safety were evaluated by Kaplan-Meier analysis and Χ(2) analysis.

RESULTSThe 42 patients receiving capecitabine maintenance therapy achieved a median progression free survival (PFS) of 11.6 months (95%CI 7.8-15.4), significantly longer than the PFS of 7.4 months (95% CI 4.9-11.8) in the 31 patients without the maintenance therapy (P<0.01). The response rate (RR) after combined chemotherapy in the two groups were similar (42.8% vs 38.7%). Χ(2) analysis indicated significant reductions in the adverse reactions (P<0.05) in both groups after therapy without significant differences between the two groups (P>0.05) except for hand-foot syndrome.

CONCLUSIONIn patients with incurable colorectal cancer, capecitabine maintenance therapy following combined chemotherapy can achieve a prolonged PFS with a good safety and tolerance and retains the possibility of further intense therapy in the event of disease progression.

Antineoplastic Combined Chemotherapy Protocols ; Camptothecin ; analogs & derivatives ; Capecitabine ; Colorectal Neoplasms ; drug therapy ; Deoxycytidine ; analogs & derivatives ; Disease Progression ; Disease-Free Survival ; Fluorouracil ; analogs & derivatives ; Humans ; Kaplan-Meier Estimate ; Organoplatinum Compounds ; Retrospective Studies

Preoperative concurrent chemoradiotherapy based on 5-fluorouracil (5-FU) is an standard treatment mode for patients with locally advanced rectal cancer (LARC). Currently, more and more interests has now focused on new chemotherapeutic drugs, such as capecitabine, oxaliplatin, irinotecan, bevacizumab, and cetuximab in this treatment mode. Many prospective phase I-III clinical trials have been developed to explore these new drugs efficacy in the neoadjuvant chemoradiation (nCRT) for patients with LARC. Some results are very encouraging, yet others are undesirable. Capecitabine has been widely recognized in the nCRT for patients with LARC, and has the tendency to replace 5-FU. However, there are some controversies for oxaliplatin, irinotecan, and biologically targeted drugs in the nCRT mode because of their limited clinical benefits. It is potentially the development direction to study the mutual interaction mechanism among concurrent drugs or radiation and biologically targeted drugs, find new predicatively responsive targets, and screen the appropriate patient in the treatment of neoCRT for patients with LARC in the future.
Antineoplastic Agents ; therapeutic use ; Camptothecin ; analogs & derivatives ; therapeutic use ; Capecitabine ; Chemotherapy, Adjuvant ; Deoxycytidine ; analogs & derivatives ; therapeutic use ; Fluorouracil ; analogs & derivatives ; therapeutic use ; Humans ; Organoplatinum Compounds ; therapeutic use ; Rectal Neoplasms ; drug therapy ; surgery