OBJECTIVETo explore the inhibitory effects of highly toxic organophosphorus compound and its substitute (methamidophos and acephate) on acetylcholinesterase (AChE) and their toxic mechanisms.

METHODSEllman method was used to measure AChE activity in vitro and vivo.

RESULTSAcephate and methamidophos could directly inhibit AChE activities in human erythrocyte membrane and rat brain synatosomal membrane in dose- and time-dependent manners in vitro, and this effect was irreversible. The IC50 of acephate and methamidophos affecting human erythrocyte membrane and rat synatosomal membrane were approximately 10(-4) mol/L and 10(-5) mol/L respectively and the Ki were 10(2) mol.L-1.min-1 and 10(3) mol.L-1.min-1 respectively. In vivo, after rats being administered with them for 5 d, the inhibitory rate of AChE activities in blood were increased to 68.24% and 54.80% respectively. When rats being administrated with acephate, there was 31.68% of inhibition on the brain stem, but no significant inhibition in other brain region was noticed, while methamidophos had a strong inhibitory effect on the activity of AChE in all brain regions, especially the cerebellum and brain-stem(71.51% and 61.85% respectively).

CONCLUSIONAcephate and methamidophos could directly inhibit the AChE activities in vitro, but the inhibition degree was different. In vivo, both could also inhibit AChE activities in blood. The difference in inhibition on brain regions may be one of the reason of various toxic effect of them.

Animals ; Cholinesterase Inhibitors ; toxicity ; Erythrocyte Membrane ; enzymology ; Humans ; Insecticides ; toxicity ; Organothiophosphorus Compounds ; toxicity ; Phosphoramides ; Rats ; Synaptosomes ; enzymology

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

Animals ; Binding Sites ; drug effects ; Brain ; metabolism ; Calcium ; metabolism ; Cerebral Cortex ; metabolism ; Cyclic AMP ; metabolism ; Hippocampus ; metabolism ; Insecticides ; toxicity ; Male ; Organothiophosphorus Compounds ; toxicity ; Phosphoramides ; Rats ; Rats, Sprague-Dawley

OBJECTIVE: To observe rule of medicine concentration of blood and the last concentration that through hemoperfusion after poisoned by acephate. METHODS: Utilizeng the patient annual bonus venous blood in hospital emergency room, the content of acephate in plasma was analyzed by gas chromatography. RESULTS: After hemoperfusion, the concentration of acephate showed a rapid drop and the characteristic that the concentration drops quicker if medicine concentration of blood before hemoperfusion is higher. CONCLUSION Hemoperfusion is able to rapidly reduce the concentration of acephate in blood, its speed is determined by initial concentration and the beginning time of hemoperfusion etc.
Acute Disease ; Adult ; Charcoal/therapeutic use* ; Chromatography, Gas ; Coma/therapy* ; Emergency Service, Hospital ; Female ; Hemoperfusion ; Humans ; Male ; Middle Aged ; Organothiophosphorus Compounds/poisoning* ; Phosphoramides ; Poisoning/therapy* ; Time Factors

OBJECTIVETo investigate the effect of lentivirus-mediated Bcl-2 gene transfection in protecting human primary ovarian granulosa cells against phosphoramide mustard (PM)-induced apoptosis.

METHODSGranulosa cells were isolated from the follicle fluid of women undergoing in vitro fertilization and embryo transfer. The lentiviral vectors carrying Bcl-2 gene (pGC-FU-Bcl-2) and enhanced green fluorescence protein (pGC-FU-EGFP) were constructed and packaged into high-titer lentiviruses. The resulting recombinant lentivirus carrying Bcl-2 and EGFP genes or the empty vector were used to infect the primary human ovarian granulosa cells, followed by addition of PM in the cell culture, with untreated granulosa cells as the control. The cell apoptosis was detected by Annexin V and Hochst 33258 staining, and the expression of Bcl-2 protein was assessed using Western blotting.

RESULTSThe control granulosa cells showed an apoptotic rate of (1.93±0.28)%. The cells infected with pGC-FU-Bcl-2 prior to PM exposure had a apoptotic rate of (6.99±10.55)%, significantly higher than that of the control cells, but significantly lower than that of the cells with PM exposure only and those infected with the empty vector before PM exposure (P<0.05). The expression of Bcl-2 was the highest in the cells infected with pGC-FU-Bcl-2 prior to PM exposure (P<0.05).

CONCLUSIONLentivirus-mediated Bcl-2 gene transfection can protect human ovarian granulosa cells against PM-induced apoptosis by upregulating Bcl-2 protein expression.

Adult ; Apoptosis ; drug effects ; Female ; Genes, bcl-2 ; Genetic Vectors ; Granulosa Cells ; drug effects ; Humans ; Lentivirus ; genetics ; Phosphoramide Mustards ; Transfection

Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain chemotherapeutic drugs. Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. To date, five distinct classes of bioreactive prodrugs have been developed to target hypoxic cells in solid tumors. These hypoxia-activated prodrugs, including nitro compounds, N-oxides, quinones, and metal complexes, generally share a common mechanism of activation whereby they are reduced by intracellular oxidoreductases in an oxygen-sensitive manner to form cytotoxins. Several examples including PR-104, TH-302, and EO9 are currently undergoing phase II and phase III clinical evaluation. In this review, we discuss the nature of tumor hypoxia as a therapeutic target, focusing on the development of bioreductive prodrugs. We also describe the current knowledge of how each prodrug class is activated and detail the clinical progress of leading examples.
Anthraquinones ; chemistry ; pharmacology ; Antineoplastic Agents ; chemistry ; pharmacology ; Aziridines ; chemistry ; pharmacology ; Cell Hypoxia ; drug effects ; Humans ; Indolequinones ; chemistry ; pharmacology ; Molecular Structure ; NAD(P)H Dehydrogenase (Quinone) ; chemistry ; pharmacology ; Neoplasms ; drug therapy ; pathology ; Nitrogen Mustard Compounds ; chemistry ; pharmacology ; Nitroimidazoles ; chemistry ; pharmacology ; Phosphoramide Mustards ; chemistry ; pharmacology ; Prodrugs ; chemistry ; pharmacology ; Triazines ; chemistry ; pharmacology

No abstract available.
Ifosfamide*

No abstract available.
Ifosfamide*

PURPOSE: The benefit of consolidation high-dose chemotherapy (HDC) for high-risk primary breast cancer is controversial. We evaluated the efficacy and safety of consolidation HDC with cyclophosphamide, thiotepa and carboplatin (CTCb) followed by autologous stem-cell transplantation (ASCT) in resected breast cancer patients with 10 or more positive lymph nodes. MATERIALS AND METHODS: Between December 1994 and April 2000, 22 patients were enrolled. All patients received 2 to 6 cycles of adjuvant chemotherapy after surgery for breast cancer. The HDC regimen consisted of cyclophosphamide 1, 500 mg/m2/day, thiotepa 125 mg/m2/day and carboplatin 200 mg/m2/day intravenous for 4 consecutive days. RESULTS: With a median follow-up of 58 months, 11 patients recurred and died. The median disease-free survival (DFS) and median overall survival (OS) were 49 and 69 months, respectively. The 5-year DFS and OS rates were 50% and 58%, respectively. The 12 patients with 10 to 18 involved nodes had better 5-year DFS (67%) and OS (75%) than 10 patients with more than 18 involved nodes (30% and 38%, respectively). The most common grade 3 or 4 nonhematologic toxicity was diarrhea, which occurred in 5 patients (23%). No treatment-related death was observed. CONCLUSION: Consolidation HDC with CTCb followed by ASCT for resected breast cancer with more than 10 positive nodes had an acceptable toxicity but does not show promising survival.
Breast Neoplasms* ; Breast* ; Carboplatin* ; Chemotherapy, Adjuvant ; Cyclophosphamide* ; Diarrhea ; Disease-Free Survival ; Drug Therapy* ; Follow-Up Studies* ; Humans ; Lymph Nodes* ; Peripheral Blood Stem Cell Transplantation ; Thiotepa*

OBJECTIVES: Recently high dose chemotherapy with autologous peripheral blood stem cell transplantation (APBSCT) has been investigated with the hope of maximizing tumor response and increasing survival. The purpose of this study is to evaluate the effect, feasibility, and toxicity of high-dose cyclophosphamide, thiotepa, and carboplatin (CTCb) with APBSCT in patients with metastatic or high risk primary breast cancer. METHODS: Four cases of high-risk primary breast cancer (with more than 10 involved axillary nodes) and three cases of metastatic disease in complete or partial response were enrolled. Peripheral blood stem cells were mobilized by G-CSF plus chemotherapy, and median number of collected mononuclear cells was 5.44 X 108/kg(range, 1.95-7.08 X 108/kg). High-dose chemotherapy of cyclophosphamide (1,500mg/m2/day), thiotepa (125mg/m2/day) and carboplatin (200mg/m2/day) was administered for 4 days and peripheral blood stem cells were reinfused to the patients 72 hours after the completion of chemotherapy. RESULTS: The median days of recovery for neutrophil (over 500/mm3) and for platelet (over 50,000/mm3) were 10 (range, 8 to 33) and 30 (range, 10 to 40). One patient suffered from seizure attack and grade 3 hepatotoxicity during high dose chemotherapy, There were no treatment-related death. Four patients with high-risk primary breast cancer remained disease-free at 2, 8, 12 and 19 months post-transplant. In one patient with bone metastasis, complete response was induced following APBSCT. All three patients with metastatic disease remained progression-free at 8, 18 and 19 months post-transplant. CONCLUSION: High-dose chemotherapy and autologous peripheral blood stem cell transplantation was feasible and would be a potentially effective treatment modality in high risk and metastatic breast cancer.
Blood Platelets ; Breast Neoplasms* ; Breast* ; Carboplatin* ; Cyclophosphamide* ; Drug Therapy* ; Granulocyte Colony-Stimulating Factor ; Hope ; Humans ; Neoplasm Metastasis ; Neutrophils ; Peripheral Blood Stem Cell Transplantation* ; Seizures ; Stem Cells ; Thiotepa*