1.Effect of brentuximab vedotin combined with chlormethine hydrochloride on the treatment of 6 patients with relapsed and refractory Hodgkin lymphoma.
Zhigang CAO ; Zhihong WANG ; Junzhong SUN ; Chaojin PENG ; Shaomei FENG ; Xiaoyan ZHOU ; Qingming YANG
Chinese Journal of Hematology 2015;36(7):575-577
OBJECTIVETo observe the clinical efficacy and side effects of brentuximab vedotin (BV) plus chlormethine hydrochloride (CH) in patients with relapsed and refractory Hodgkin lymphoma (HL) after failure with BV alone.
METHODSFrom March, 2014 to December, 2014, 6 patients who failed with BV monotherapy were enrolled in this study. The chemotherapy regimen consisted of BV (1.2-1.8 mg/kg, iv. gtt, d1) and CH (6 mg/m2, iv. gtt, d1) was given for 3 weeks as one course, and all patients received about 3-8 courses of chemotherapy, with an median of 4 courses. Clinical efficacy and adverse events were assessed and observed by radiographic examination and serological detection.
RESULTSAmong 6 patients, the overall response rate was 100% with 2 complete remission and 4 partial remission. The main adverse events were grade I (2 patients) and IV (2 patients) bone marrow depression, grade II (2 patients)gastrointestinal reaction, grade I (1 patient) increase of transaminase and myocardial enzyme and grade I (1 patient) mouth ulcers.
CONCLUSIONThe combination of BV and CH in the treatment of relapsed and refractory HL after failure with BV alone was high effective and the toxicities were well tolerable.
Antineoplastic Agents, Alkylating ; therapeutic use ; Hodgkin Disease ; drug therapy ; Humans ; Immunoconjugates ; therapeutic use ; Mechlorethamine ; therapeutic use
2.Advances in the research of pharmacogenomics of cyclophosphamide.
Ling-Yan CHEN ; Xue-Ding WANG ; Min HUANG
Acta Pharmaceutica Sinica 2014;49(7):971-976
Cyclophosphamide (CPA) is the most common alkylating antineoplastic agent, as well as a strong immunosuppressant that is frequently applied to autoimmune diseases and organ transplantation. It is metabolized by cytochrome P450 oxidases (CYPs) to its active metabolite which played a critical role in therapy. CPA has serious and even fatal side effects, and its efficacy and adverse reactions are significantly varied among individuals. In this review, the association of the genetic polymorphisms in the metabolic enzymes and transporters involved in the disposition of CPA with the efficacy and adverse effects of CPA were summarized, thereby providing fundamental reference for further pharmacogenomic study of CPA.
Antineoplastic Agents, Alkylating
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pharmacology
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Cyclophosphamide
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pharmacology
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Humans
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NADPH-Ferrihemoprotein Reductase
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metabolism
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Pharmacogenetics
3.Progress in the studies on antitumor natural product ecteinascidin-743.
Ye WANG ; Zhan-zhu LIU ; Shi-zhi CHEN ; Xiao-tian LIANG
Acta Academiae Medicinae Sinicae 2004;26(4):474-478
The alkaloid ecteinascidin-743, isolated from the marine tunicate Ecteinascidia turbinata, binds to DNA and induces cytotoxic effects in several tumors. The drug is being codeveloped by Pharma Mar and Ortho Biotech. In May 2001 and October 2003, it was granted orphan drug status by the European Commission for soft tissue sarcoma and ovarian cancer, respectively. This paper reviews its research progress, including chemical synthesis, in vitro studies and mechanism of action, antitumor activity in vivo, toxicity, pharmacokinetics, and clinical studies.
Animals
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Antineoplastic Agents, Alkylating
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pharmacokinetics
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pharmacology
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toxicity
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Dioxoles
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pharmacokinetics
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pharmacology
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toxicity
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Humans
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Isoquinolines
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pharmacokinetics
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pharmacology
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toxicity
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Tetrahydroisoquinolines
6.Does Early Postsurgical Temozolomide Plus Concomitant Radiochemotherapy Regimen Have Any Benefit in Newly-diagnosed Glioblastoma Patients? A Multi-center, Randomized, Parallel, Open-label, Phase II Clinical Trial.
Ying MAO ; Yu YAO ; Li-Wei ZHANG ; Yi-Cheng LU ; Zhong-Ping CHEN ; Jian-Min ZHANG ; Song-Tao QI ; Chao YOU ; Ren-Zhi WANG ; Shu-Yuan YANG ; Xiang ZHANG ; Ji-Sheng WANG ; Ju-Xiang CHEN ; Qun-Ying YANG ; Hong SHEN ; Zhi-Yong LI ; Xiang WANG ; Wen-Bin MA ; Xue-Jun YANG ; Hai-Ning ZHEN ; Liang-Fu ZHOU
Chinese Medical Journal 2015;128(20):2751-2758
BACKGROUNDThe radiochemotherapy regimen concomitantly employing temozolomide (TMZ) chemotherapy and radiotherapy (RT) 4 weeks after surgery, followed by 6 cycles of TMZ is a common treatment for glioblastoma (GBM). However, its median overall survival (OS) is only 14.6 months. This study was to explore the effectiveness and safety of early TMZ chemotherapy between surgery and chemoradiotherapy plus the standard concomitant radiochemotherapy regimen.
METHODSA randomized, parallel group, open-label study of 99 newly diagnosed GBM patients was conducted at 10 independent Chinese neurosurgical departments from June 2008 to June 2012. Patients were treated with concomitant radiochemotherapy regimen plus early postsurgical temozolomide (early TMZ group) or standard concomitant radiochemotherapy regimen (control group). Overall response was assessed based on objective tumor assessments, administration of corticosteroid and neurological status test. Hematological, biochemical, laboratory, adverse event (AE), and neurological condition were measured for 24 months of follow-up. The primary efficacy endpoint of this study was overall survival (OS). The secondary endpoint was progression free survival (PFS).
RESULTSThe median OS time in the early TMZ group was 17.6 months, compared with 13.2 months in the control group (log-rank test P = 0.021). In addition, the OS rate in the early TMZ group was higher at 6, 12, and 18 months than in the control group, respectively (P < 0.05). The median PFS time was 8.7 months in the early TMZ group and 10.4 months in the control group (log-rank test P = 0.695). AEs occurred in 29 (55.8%) and 31(73.8%) patients respectively in early and control groups, including nausea (15.4% vs. 33.3%), vomiting (7.7% vs. 28.6%), fever (7.7% vs. 11.9%), and headache (3.8% vs. 23.8%). Only 30.8% and 33.3% were drug-related, respectively.
CONCLUSIONSAddition of TMZ chemotherapy in the early break of the standard concomitant radiochemotherapy regimen was well tolerated and significantly improved the OS of the GBM patients, compared with standard concomitant radiochemotherapy regimen. However, a larger randomized trial is warranted to verify these results.
Adult ; Aged ; Antineoplastic Agents, Alkylating ; therapeutic use ; Chemoradiotherapy ; methods ; Dacarbazine ; analogs & derivatives ; therapeutic use ; Glioblastoma ; drug therapy ; radiotherapy ; Humans ; Middle Aged ; Treatment Outcome ; Young Adult
7.Orthogonal experiments for optimizing the formulation and preparation conditions of temozolomide solid lipid nanoparticles.
Mingjin DOU ; Guihua HUANG ; Yanwei XI ; Na ZHANG
Journal of Biomedical Engineering 2008;25(5):1141-1145
TMZ-SLN were prepared by emulsification-low temperature solidification method with stearic acid. The formulation and the preparation conditions were optimized by orthogonal experiments using entrapment efficiency as the evaluation index. The morphology was detected by transmission electron microscope. The Zeta potentials and the particle size distribution were evaluated by Laser Doppler Anemometry. The entrapment efficiencies and the drug release characteristics in vitro were assessed. The result showed that TMZ-SLN were concinnous and spherical in shape. The mean diameter (d(av) ) was 65.0 +/- 6.2 nm and the Zeta potential was -37.2 mV. The average entrapment efficiency was 58.9% +/- 1.21 %. The drug release behavior in vitro conformed to Higuchi Equation. The formation of a new material phase was testified by analysis of differential scanning calorimetry.
Antineoplastic Agents, Alkylating
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administration & dosage
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chemistry
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Dacarbazine
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administration & dosage
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analogs & derivatives
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chemistry
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Drug Carriers
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chemistry
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Lipids
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chemistry
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Nanoparticles
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chemistry
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Particle Size
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Stearic Acids
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chemistry
8.Identification of glufosfamide metabolites in rats.
Yu-Ming SUN ; Xiao-Yan CHEN ; Da-Fang ZHONG
Acta Pharmaceutica Sinica 2006;41(6):513-517
AIMTo elucidate the metabolic pathway of glufosfamide in rats.
METHODSIn this study, a liquid chromatography-tandem mass spectrometric method was developed and applied to characterize the metabolites of glufosfamide in rat urine, after an i.v. administration of 50 mg x kg(-1). The analysis was performed under two ionization modes in two different chromatographic systems, separately. To make sure that the compounds detected in rat urine were metabolites or degradation products, the stability of glufosfamide, isophosphoramide mustard (M1), and the degradation products of M1 in urine were investigated.
RESULTSIn positive ionization mode, besides glufosfamide, two metabolites, isophosphoramide mustard and monoaziridinyl derivative of isophosphoramide mustard, were detected. In negative ionization mode, only glufosfamide itself was detected, while derivatives of isophosphoramide mustard have no response in such condition.
CONCLUSIONGlufosfamide was mainly unchanged excreted in urine, and two metabolites were detected as isophosphoramide mustard and monoaziridinyl derivative of isophosphoramide mustard.
Animals ; Antineoplastic Agents, Alkylating ; metabolism ; urine ; Gas Chromatography-Mass Spectrometry ; Glucose ; analogs & derivatives ; Ifosfamide ; analogs & derivatives ; Injections, Intravenous ; Male ; Phosphoramide Mustards ; metabolism ; urine ; Rats ; Rats, Wistar
9.Effects of triptolide on proliferation and apoptosis of Jurkat cell line in acute T lymphocytic leukemia.
Gen-Hong YAO ; Jian-Feng LUAN ; Dong YE ; Jing-Mei YAN ; Qian-Hong LEI ; Pei-Yuan ZHU ; Jie JIN
Journal of Experimental Hematology 2008;16(3):506-509
The aim of this study was to investigate the anti-proliferation and pro-apoptosis of triptolide on Jurkat cell line in acute T lymphocytic leukemia. The Jurkat cells were treated with various concentrations of triptolide (0, 1, 2, 4, 8, 16 microg/L) for 12 hours. The inhibitory ratio was measured by Cell Counting Kit-8 assay. The effects of triptolide on apoptosis of Jurkat cells were determined by DNA fragmentation (DNA ladder), Hoechst 33258, PI and Annexin V-FITC/PI double staining. The results demonstrated that triptolide inhibited the proliferation of Jurket cells. The 50% inhibitory concentration (IC(50)) was 4.0 microg/L. Chromatin condensation in the cells treated with triptolide could be seen by light microscopy. DNA electrophoresis showed evidence of nuclear fragmentation (DNA ladder). The hypoploid (sub-G(1)) population was increased after treatment with triptolide. The translocation of phosphatidylserine at the outer surface of the cell plasma membrane could be induced by triptolide. After treatment with triptolide for 12 hours, the rates of apoptotic cells were significantly increased. Moreover, these pro-apoptosis effects were in time-dependent manner. It is concluded that triptolide can inhibit the proliferation and induce the apoptosis of Jurkat cells. This study provides experimental basis for clinical use of triptolide in leukemia therapy.
Antineoplastic Agents, Alkylating
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pharmacology
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Apoptosis
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drug effects
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Cell Proliferation
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drug effects
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Diterpenes
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pharmacology
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Epoxy Compounds
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pharmacology
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Humans
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Jurkat Cells
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Phenanthrenes
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pharmacology
10.Mechanism of thalidomide to enhance cytotoxicity of temozolomide in U251-MG glioma cells in vitro.
Song GAO ; Xue-jun YANG ; Wen-gao ZHANG ; Yan-wei JI ; Qiang PAN
Chinese Medical Journal 2009;122(11):1260-1266
BACKGROUNDGlioma is the most common primary brain tumor with poor prognosis. Temozolomide has been used with thalidomide to treat gliomas. We investigated the synergistic mechanism of these two drugs in vitro.
METHODSHuman malignant glioma cells U251-MG were cultured and assigned to four groups with different treatments for 3 days: temozolomide group (100 micromol/L), thalidomide group (100 microg/L), temozolomide (100 micromol/L) plus thalidomide group (100 microg/L) and control group. MTT assay was applied to evaluate the cell viability. Cell cycle was analyzed by flow cytometry. The ultra-structural features of autophagosomes were observed with electron microscope. Acridine orange and monodansylcadaverine were adopted to label autophagosomes and flow cytometry was applied for quantification of autophagosomes. The expression of autophagy-associated protein was detected by Western blotting.
RESULTSProliferation of tumor cell was obviously suppressed by temozolomide with thalidomide treatment than by either drug used alone (P = 0.000 for each day). The combination treatment induced cell cycle arrest at G0/G1 phase. Typical autophagic ultra-structural character was found after the combined treatment. Thalidomide promoted the autophagy induced by temozolomide. The autophagy-associated proteins-microtubule associated protein 1 light chain 3 (MAP1LC3) and Beclin1 were more significantly up-regulated by the combined treatment than temozolomide used alone (MAP1LC3, P = 0.000; Beclin1, P = 0.004). The expression level of phosphatase and tensin homolog deleted on chromosome ten (PTEN), which promoted autophagy by suppressing PI3K/Akt/mTOR signaling pathway, was elevated by thalidomide (thalidomide group: P = 0.000; combined group: P = 0.002).
CONCLUSIONSThalidomide enhances the cytotoxicity of temozolomide by promoting the autophagy induced by temozolomide. Contributing to the up-regulation of PTEN by thalidomide, the expression of autophagy associated protein-MAP1LC3 and Beclin1 was enhanced, which leads to a reinforced autophagy in the combined treatment of temozolomide and thalidomide in vitro.
Antineoplastic Agents, Alkylating ; pharmacology ; Autophagy ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Dacarbazine ; analogs & derivatives ; pharmacology ; Glioma ; pathology ; Humans ; Thalidomide ; pharmacology