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*

PURPOSE: We conducted a phase II study to determine the antitumor activity of BACOD/EISHAP alternating 9-drug chemotherapy in previously untreated patients with intermediate or high grade non-Hodgkin's lymphoma (NHL). MATERIALS AND METHODS: Intermediate or high grade non-Hodgkin's lymphoma patients were treated with BACOD/EISHAP (bleomycin, doxorubicin, cyclophosphamide, vincristine, dexame thasone/etoposide, ifosfamide, high dose cytarabine, cisplatin, dexamethasone) alternating com bination chemotherapy. Stage I and IIA lymphoma patients were excluded. BACOD/EISHAP alternating chemotherapy was given to the eligible patients every 3 weeks/4 weeks respectively. RESULTS: Between April, 1995 and December, 1997, among 25 eligible patients, 19 patients were evaluable for response. Six patients could not be evaluated for response because of follow-up loss within 2 cycles of chemotherapy. Complete response (CR) was achieved in 12 patients (63%) after BACOD/EISHAP alternating combination chemotherapy. With a follow-up period of 41 months (25~57 months), the disease free survival did not reach median (4~47 months) and 3-year disease free survival rate was 75%. Major toxicity was marrow suppression and the incidence of severe leukopenia (WBC<2,000/mm3) and thromobocytopenia (<25,000/mm3) were 15%, 5%, respectively. No treatment-related death was observed. For non-hematologic toxicities, nausea and vomiting were observed in 65% of patients, stomatitis in 25%, peripheral neuropathy in 20%. CONCLUSION: BACOD/EISHAP alternating chemotherapy was feasible with acceptable toxicities. The 63% complete response rate was comparable to other regimens but 75% 3year disease-free survival rate was encouraging. Further evaluation of this regimen is warranted.
Bone Marrow ; Cisplatin ; Cyclophosphamide ; Cytarabine ; Disease-Free Survival ; Doxorubicin ; Drug Therapy ; Drug Therapy, Combination* ; Follow-Up Studies ; Humans ; Ifosfamide ; Incidence ; Leukopenia ; Lymphoma ; Lymphoma, Non-Hodgkin* ; Nausea ; Peripheral Nervous System Diseases ; Stomatitis ; Vincristine ; Vomiting

A desmoplastic small-round-cell tumor (DSRCT) is a rare, aggressive neoplasm that develops mostly in the abdominal cavity in children and young adults. We present a case of a 19-year-old male with right upper quadrant discomfort for 3 months. On abdominal computerized tomography, multiple huge and demarcated masses were found in the liver, retroperitoneal lymph nodes, and peritoneal and retroperitoneal cavities. Fine needle aspiration biopsy of the hepatic mass was performed and DSRCT was diagnosed by hematoxylin and eosin staining and immunohistochemical analysis. He was treated initially with high-dose systemic chemotherapy (alternating schedules of cyclophosphamide, vincristine, doxorubicin, ifosfamide, and etoposide), underwent two debulking surgeries and pelvic irradiation between systemic chemotherapy schedules, and achieved complete remission after the 15 months of treatment duration. We report this case to emphasize the importance of aggressive local treatment modalities as well as high-dose systemic chemotherapy for treatment of DSRCT even with initially unresectable or extensively metastatic presentation.
Abdominal Cavity ; Appointments and Schedules ; Biopsy ; Biopsy, Fine-Needle ; Child ; Cyclophosphamide ; Desmoplastic Small Round Cell Tumor ; Doxorubicin ; Eosine Yellowish-(YS) ; Hematoxylin ; Humans ; Ifosfamide ; Liver ; Lymph Nodes ; Male ; Vincristine ; Young Adult