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

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*

Extraskeletal Ewing's sarcoma has been recognized as being histologically indistinguishable from Ewing's sarcoma of bone. Histopathologically, Ewing's sarcoma consists of solid sheets of small round cells with vesicular nuclei and scant cytoplasm, and the cells are arranged in irregular masses separated by strands of fibrous tissue. Extraskeletal Ewing's sarcoma may arise virtually anywhere, but it is most common in the deep soft tissues of the extremities. We report here on a 27-year-old woman with cutaneous extraskeletal Ewing's sarcoma. She presented with a subcutaneous tumor of the right upper arm, and this was without osseous involvement. The patient underwent wide local excision and she received chemotherapy with vincristine, cyclophosphamide, etoposide and ifosfamide. There has been no evidence of recurrence or metastasis during 16 months of follow up.
Adult ; Arm ; Cyclophosphamide ; Cytoplasm ; Etoposide ; Extremities ; Female ; Follow-Up Studies ; Humans ; Ifosfamide ; Neoplasm Metastasis ; Recurrence ; Sarcoma, Ewing ; Skin ; Vincristine

Neuroblastoma is the most common intraabdominal malignant tumor of childhood, with 40% arising from the adrenal gland. Bilateral adrenal involvement from synchronous development or metastatic spread of tumor is rarely seen in children with neuroblastoma. The patient was born with a spontaneous vaginal delivery. Birth weight was 3,200 g. Fetal ultrasonography showed a left adrenal cystic mass. At two weeks of age, she was admitted due to a massive abdominal distension and tachypnea. Percutaneous ultrasonography guided biopsy of the left adrenal mass was performed. The result of the biopsy was neuroblastoma. Vincristine and cyclophosphamide were administerd intravenously and 450 cGy of irradiation was added. Left adrenalectomy was accomplished and postoperative course was uneventful. The patient received cancer chemotherapy with a combination of carboplatin, ifosfamide and VP-16 and is now being followed up for three months. We have experienced a case of congenital bilateral neuroblastoma and report the case with brief review of related literatures.
Adrenal Glands ; Adrenalectomy ; Biopsy ; Birth Weight ; Carboplatin ; Child ; Cyclophosphamide ; Drug Therapy ; Etoposide ; Humans ; Ifosfamide ; Neuroblastoma* ; Tachypnea ; Ultrasonography ; Ultrasonography, Prenatal ; Vincristine

PURPOSE: To establish the feasibility of high dose ifosfamide, carboplatin, and etoposide (ICE) chemotherapy followed by autologous stem cell transplantation (ASCT) in patients with high-risk or metastatic breast cancer. MATERIALS AND METHODS: High-risk breast cancer is defined as 10 or more involved axillary lymph nodes (n=3) or stage III (n=2). Patients with metastatic cancer have relapsed diseases after curative resection (n=10) or initially metastatic lesion (n=1). Colony stimulating factor with either cyclophosphamide or combination chemotherapy was administered to mobilize the stem cells. High dose chemotherapy consisted of ifosfamide 16 g/m2, carboplatin 1.8 g/m2, and etoposide 0.75 g/m2 (dose I) and later modified to ifosfamide 12 g/m2, carboplatin 1.35 g/m2, and etoposide 1.2 g/m2 (dose II). RESULTS: The median duration of grunulocyte nadir (<500/ microliter) was 11 (10~17) days and platelet transfusion dependency (<20,000/ microliter) was 11 (7~53) days in 14 patients who achieved engraftment. One out of 5 patients with high-risk breast cancer relapsed after high dose therapy. Two patients remain disease-free at 18th and 40th months. Two among the 4 patients treated with dose I died due to treatment-related complications. The responses of metastatic diseases to ICE chemotherapy were 1 continuing CR, 1 CR, 1 PR, 4 SD and 3 PD in 10 evaluable patients. CONCLUSION: High dose ICE chemotherapy, especially dose II and ASCT were feasible in high-risk or metastatic breast cancer.
Breast Neoplasms* ; Breast* ; Carboplatin* ; Colony-Stimulating Factors ; Cyclophosphamide ; Drug Therapy* ; Drug Therapy, Combination ; Etoposide* ; Humans ; Ice ; Ifosfamide* ; Lymph Nodes ; Platelet Transfusion ; Stem Cell Transplantation* ; Stem Cells*

OBJECTIVETo evaluateclinical features, treatment and outcomes of patients diagnosed with primary breast diffuse large B-cell lymphoma（DLBCL）.

METHODSClinical data were analyzed for all patients diagnosed with primary breast DLBCL（n=21）. Kaplan-Meier method was used to estimate 5- year overall survival（OS）rate, and the difference was compared by Log- rank test.

RESULTSThe 21 cases of patients with primary breast DLBCL were all female with median age at diagnosis as 48 years （range 21-64 years）. 13 patients had International Prognostic Index（IPI）of 0, 6 IPI 1, and 2 IPI 2. The 5- year OS rates of CHOP/R- CHOP and R±DICE after R±EPOCH groups were 40.0% and 72.2% , respectively（P=0.035）. The central nervous system relapse rate of CHOP/R-CHOP and R±DICE after R± EPOCH groups were 16.7% and 6.7%（P=0.500）, respectively. The 5- year OS rates of patients with primary breast DLBCL staging Ⅱ E-Ⅲ E and Ⅰ E were 21.4% and 83.3% , respectively（P=0.025）.

CONCLUSIONPrimary breast DLBCL was rare. The patients of primary breast DLBCL with chemotherapy regimen of R±DICE after R±EPOCH might have a better prognosis and lower relapse rate of central nervous system; the primary breast DLBCL patients staging ⅡE-ⅢE might have a poor prognosis.

Antibodies, Monoclonal, Murine-Derived ; Antineoplastic Combined Chemotherapy Protocols ; Breast Neoplasms ; diagnosis ; drug therapy ; pathology ; China ; Cisplatin ; Cyclophosphamide ; Dexamethasone ; Doxorubicin ; Etoposide ; Female ; Humans ; Ifosfamide ; Lymphoma, Large B-Cell, Diffuse ; diagnosis ; drug therapy ; pathology ; Neoplasm Recurrence, Local ; Prednisone ; Prognosis ; Retrospective Studies ; Vincristine

PURPOSE: Neuroblastoma is the second common solid tumor in chidhood and has the worst prognosis in stage IV case. To improve the future survival rate in this disease the clinical and laboratory characteristics of patients, the characteristics and chemosensitivity test of cultured neuroblastoma cells and the outcome were compared. METHODS: The clinical characteristics including age, urinary catecholamines, serum ferritin, neuron specific enolase, pathology, stage, and patient's outcome were evaluated in four neuroblastoma patients diagnosed at the Department of Pediatrics, Kyungpook National Univesity Hospital. The neuroblastoma cells obtained from tumor or bone marrow cells were cultured and used for immunobead test using mononuclear antibody, biochemical analysis, N-myc oncogene copy, chromosome study and chemosensitivity test. Cyclophosphamide, cisplatin, doxorubicin, etoposide, ifosfamide and melphalan were used in chemosensitivity test. The statistical analyses were done by chi2-method. RESULTS: The age of patients were 6~31 (mean; 18) months. The adrenal gland was the primary site and the stage was IV in all cases. In laboratory data, serum ferritin level were 40~352 (204) ng/mL, neuron specific enolase 45~167 (107) ng/mL, urinary excretion of HVA 1.8~268 (73) mg/day, of VMA 0.2~345 (87) mg/day and the HVA/VMA ratio 0.8~67 (20). Cultured neuroblastoma cells and immunobeads attached around the cell were observed. The partial deletion of short arm or monosomy of chromosome 1, double minutes or homogenous stained region were found in three patients. N-myc oncogene copy was positive in one of two tested. Radical surgery was done in three patients and chemotherpy and radiotherpy by CCG-3881 or -3891 were given in four patients. The duration of survival in three died patients were 6~13 (mean; 10) months. One is survived in relapse-free state for 52 months. In chemosensitivity test, the neuroblastoma cell of survivor was highly sensitive in all drugs compared to the neuroblastoma cell of relapsed patients. CONCLUSION: Normal serum ferritin level or normal chromosome were correlated as a good prognostic factors in survivor compare in relapsed patients. In chemosensitivity test, the neuroblastoma cells of survivor were higher sensitive to all drugs compare to those of relapsed patients. The chemosensitivity test of this method were relatively simple and could be used in selection of anticancer drug and as a prognostic factor in neuroblastoma.
Adrenal Glands ; Arm ; Bone Marrow Cells ; Catecholamines ; Chromosomes, Human, Pair 1 ; Cisplatin ; Cyclophosphamide ; Doxorubicin ; Etoposide ; Ferritins ; Gyeongsangbuk-do ; Humans ; Ifosfamide ; Melphalan ; Monosomy ; Neuroblastoma* ; Oncogenes ; Pathology ; Pediatrics ; Phosphopyruvate Hydratase ; Prognosis ; Survival Rate ; Survivors