BACKGROUND: Bendamustine is an attractive option for the management of both de novo and relapsed lymphomas. It is being increasingly used in the conditioning regimen for autologous stem cell transplantation (SCT) and can be an alternative to the traditionally-used carmustine. In this study, we aimed to determine the safety and efficacy of bendamustine in the conditioning regimen for autologous SCT in refractory/relapsed lymphomas. METHODS: We designed a descriptive study to evaluate bendamustine in combination with etoposide, cytarabine, and melphalan (BeEAM) in the conditioning regimen for autologous SCT. RESULTS: Fourteen patients (median age, 28 yr) with Hodgkin's lymphoma (HL) (N=8), non-Hodgkin's lymphomas (NHL) (N=5), or peripheral T-cell lymphoma, not otherwise specified (PTCL NOS) (N=1) were included in the study. A median number of 5.95×10⁶ CD34+ cells/kg were transfused. Median times to absolute neutrophil count and platelet engraftment were 17 days and 24 days, respectively. The 100-day transplantation mortality rate was 28% (4 patients). Eight patients (57.14%) had GII-III acute kidney injury, four patients (28.5%) had GIII-IV hyperbilirubinemia, and twelve patients (85%) had GII-III diarrhea. After 3 months, 37% (5 patients) and 21.4% (3 patients) demonstrated complete response and partial response, respectively. The median follow-up was 5.5 months (15 days–19 mo). At the final follow-up, 7 patients (50%) were alive and in CR. CONCLUSION: Our study showed that bendamustine is a potentially toxic agent in the conditioning regimen for autologous SCT, resulting in significant liver, kidney, and gastrointestinal toxicity. Further studies are required to assess its safety and efficacy at reduced doses.
Acute Kidney Injury ; Bendamustine Hydrochloride ; Blood Platelets ; Carmustine ; Cytarabine ; Diarrhea ; Etoposide ; Follow-Up Studies ; Hodgkin Disease ; Humans ; Hyperbilirubinemia ; Kidney ; Liver ; Lymphoma ; Lymphoma, Non-Hodgkin ; Lymphoma, T-Cell, Peripheral ; Melphalan ; Mortality ; Neutrophils ; Stem Cell Transplantation ; Stem Cells

BACKGROUNDOur previous study had cloned two glioma cell lines SWOZ1 and SWOZ2 isolated from parental glioma cell line SWO38. The 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) resistance of SWOZ1 was higher than that of SWOZ2. Since O6-methylguanine-DNA methyltransferase (MGMT) was thought to be closely related to BCNU resistance in glioma, this study aimed to explore the function of MGMT in glioma resistant to BCNU.

METHODSA BCNU resistant glioma cell line SWOZ2-BCNU was established. The expression of MGMT was detected in SWOZ1, SWOZ2 and SWOZ2-BCNU. Small interferencing RNA targeting MGMT was used to silence the expression of MGMT in resistant cell lines SWOZ1 and SWOZ2-BCNU. The cytotoxicity of BCNU to these cells was measured using the cell counting kit-8 assay. Statistical analysis was carried out by one-way analysis of variance in statistical package SPSS 13.0.

RESULTSThe resistance of SWOZ1 and SWOZ2-BCNU against BCNU was 4.9-fold and 5.3-fold higher than that of SWOZ2. The results of quantitative RT-PCR and Western blotting confirmed that MGMT was both significantly increased in SWOZ1 and SWOZ2-BCNU compared to SOWZ2. After transfection with small interferencing RNA targeting MGMT, a decreased level of MGMT mRNA expression in SWOZ1 and SWOZ2-BCNU for more than 75% compared to negative control was found and confirmed by Western blotting. As a result, the resistance against BCNU was reversed for about 50% both in the BCNU-resistant cell lines SWOZ1 and SWOZ2-BCNU.

CONCLUSIONSSilencing MGMT with specific small interferencing RNA can reverse the BCNU resistant phenotype in these glioma cell lines. MGMT may play an important role both in intrinsic and acquired BCNU-resistance in glioma.

Blotting, Western ; Carmustine ; pharmacology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Drug Resistance, Neoplasm ; drug effects ; genetics ; Glioma ; genetics ; metabolism ; Humans ; O(6)-Methylguanine-DNA Methyltransferase ; genetics ; metabolism ; RNA, Small Interfering ; Reverse Transcriptase Polymerase Chain Reaction ; Sincalide ; metabolism

This study investigated the effect of TNP-470 in combination with carmustine (BCNU) on the growth of subcutaneously implanted human glioblastoma xenografts in nude mice. Human glioblastoma U-251 cells (1×10(7)) were injected into 24 nude mice subcutaneously. The tumor-bearing mice were randomly divided into 4 groups on the seventh day following tumor implantation: TNP-470 group, in which TNP-470 was given 30 mg/kg subcutaneously every other day 7 times; BCNU group, in which 20 mg/kg BCNU were injected into peritoneal cavity per 4 days 3 times; TNP-470 plus BCNU group, in which TNP-470 and BCNU were coadministered in the same manner as in the TNP-470 group and the BCNU group; control group, in which the mice were given 0.2 mL of the mixture including 3% ethanol, 5% acacia and 0.9% saline subcutaneously every other day 7 times. The tumor size and weights were measured. The tumor microvessel density (MVD) was determined by immunostaining by using goat-anti-mouse polyclonal antibody CD105. The results showed that on the 21th day following treatment, the volume of xenografts in the TNP-470 plus BCNU group was (108.93±17.63)mm(3), markedly lower than that in the TNP-470 group [(576.10±114.29)mm(3)] and the BCNU group [(473.01±48.04)mm(3)] (both P<0.01). And the xenograft volume in these 3 treatment groups was even much lower than that in the control group [(1512.61±470.25) mm(3)] (all P<0.01). There was no significant difference in the volume of xenografts between the TNP-470 group and the BCNU group (P>0.05). The inhibition rate of the tumor growth in the TNP-470 plus BCNU group was (92.80±11.37)%, notably higher than that in the TNP-470 group [(61.91±6.29)%] and the BCNU group [(68.73±9.65)%] (both P<0.01) on the 21th day following treatment. There was no significant difference in the inhibition rate of tumor growth between the TNP-470 group and the BCNU group (P>0.05). The MVD of xenografts in the TNP-470 plus BCNU group was decreased significantly as compared with that in the TNP-470 group or the BCNU group (both P<0.05). The MVD of xenografts in the 3 treatment groups was markedly reduced as compared with that in the control group (all P<0.05). No significant changes in weights were observed before and after the treatment in each group (all P>0.05). It was concluded that the combination of TNP-470 and BCNU can significantly inhibit the growth of human glioblastoma xenografts in nude mice without evident side effects.
Angiogenesis Inhibitors ; administration & dosage ; Animals ; Antibiotics, Antineoplastic ; administration & dosage ; Antineoplastic Agents, Alkylating ; administration & dosage ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Brain Neoplasms ; drug therapy ; Carmustine ; administration & dosage ; Cell Line, Tumor ; Cyclohexanes ; administration & dosage ; Female ; Glioblastoma ; drug therapy ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Sesquiterpenes ; administration & dosage ; Xenograft Model Antitumor Assays

BACKGROUND: Mycosis fungoides (MF) is the most frequent form of cutaneous lymphoma. Early stage MF is known to be responsible to the various topical and systemic therapies. However, there have been few clinical reviews of the treatment modalities of the early stoge MF in Korea. OBJECTIVE: The aim of this study is to investigate the therapeutic response of early MF to different treatment modalities. METHODS: The medical records, clinical photographs, and biopsied tissues, of fifty three cases of early MF were reviewed. RESULTS: The mean age at diagnosis of early MF was 43.0 years old (varied between 9 and 81 years old). Twenty three (43.4%) were male and thirty (56.6%) were female. Topical carmustine (bis-chloroethyl-nitrosourea, BCNU) was the most commonly used treatment modality in the early MF (34.0%). Patients treated by BCNU in stage IA (<10% skin involved) showed a response rate of 85.7%. Early MF recorred in only one patient after 93 months. However BCNU was not effective for the patients in stage IB (> or =10% skin involved). Even Psoralen plus UVA (PUVA) therapy, which was most efficient in stage IB, revealed a high relapse rate after one year. CONCLUSION: BCNU has been most commonly used for the treatment of early MF during the past 10 years in the authors' hospital. It showed a comparatively high response rate, and the relapse rate of BCNU was lower than for other therapies in stage IA. However many treatments became ineffective when MF progressed to stage IB. Therefore the authors confirm that early diagnosis and proper therapy are most important for the treatment of early MF.
Carmustine ; Diagnosis ; Early Diagnosis ; Female ; Ficusin ; Humans ; Korea ; Lymphoma ; Male ; Medical Records ; Mycosis Fungoides* ; Recurrence ; Skin

OBJECTIVE: Nitric oxide(NO) is implicated in a wide range of biological processes in tumors and is produced in glioma. To investigate the role of NO and its interaction with the tumoricidal effects of anticancer drugs, we study the antitumor activities of NO donors, with or without anticancer drugs, in human glioma cell lines. METHODS: U87MG and U373MG cells were treated with the NO donors sodium nitroprusside(SNP) and S-nitroso-N-acetylpenicillamine(SNAP), alone or in combination with the anticancer drugs 1, 3-bis(2-chloroethyl)-1-nitrosourea(BCNU) and cisplatin. Cell viability, cell proliferation, DNA fragmentation, nitrite level, and the expression of Bcl-2 and Bax were determined. RESULTS: NO was markedly increased after treatment with SNP or SNAP; however, the addition of the anticancer drugs did not significantly affect NO production. NO donors or anticancer drugs reduced glioma cell viability and, in combination, acted synergistically to further decrease cell viability in a dose- and time-dependent manner. Cell proliferation was inhibited and apoptosis were enhanced by combined treatment. Bax expression was increased by combined treatment, whereas Bcl-2 expression was reduced. The antitumor cytotoxicity of NO donors and anticancer drugs differed according to cell type. CONCLUSION: BCNU or cisplatin can inhibit cell viability and proliferation of glioma cells and can induce apoptosis. These effects are further enhanced by the addition of a NO donor which modulates the antitumor cytotoxicity of chemotherapy depending on cell type. Further biological, chemical, and toxicological studies of NO are required to clarify its mechanism of action in glioma.
Apoptosis ; Biological Processes ; Carmustine ; Cell Line ; Cell Proliferation ; Cell Survival ; Cisplatin ; DNA Fragmentation ; Drug Therapy ; Glioma* ; Humans ; Nitric Oxide Donors* ; Nitric Oxide* ; Sodium ; Tissue Donors

The treatment outcomes with conventional second-line chemotherapy or radiotherapy aregenerally very poor for patients with relapsed primary CNS lymphoma (PCNSL). We treated three relapsed PCNSL patients with high-dose cytarabine plus etoposide (CYVE) chemotherapy, and this was followed by autologous stem cell transplantation (ASCT). The salvage CYVE chemotherapy consisted of cytarabine 2g/m2/d on days 2 to 5 in a 3-hour infusion and 50mg/m2/d on days 1 to 5 in a 12-hourinfusion, and etoposide 200mg/m2/d on days 2 to 5 in a 2-hour infusion. After two cycles of CYVE chemotherapy, two patients achieved a complete response (CR), and one patient achieved a partial response (PR). All three patients experienced febrile neutropenia and grade 4 thrombocytopenia with the CYVE chemotherapy. However, the hematologic toxicities were well managed without any complications. The conditioning regimen for ASCT consisted of BCNU 300mg/m2 on day -7, etoposide 100mg/m2 on days -6 to -3, cytarabine 100mg/m2 on days -6 to -3, and cyclophosphamide 35mg/kg on days -6 to -3 (BEAC). After ASCT, the patient who initially showed a PR with CYVE chemotherapy then achieved a CR. At the time of this report, one patient remained alive in CR for 41 months after CYVE chemotherapy. The remaining two patients experienced relapse 5 months and 4 months after ASCT, respectively, and they ultimately died of disease progression 18 months and 8 months after ASCT, respectively. In our cases, the CYVE chemotherapy+ASCT was well tolerated, and this induced the complete disappearance of the tumor, and one patient showed prolonged disease-free survival. CYVE chemotherapy+ASCT could be a treatment option for relapsed PCNSL.
Anemia, Hemolytic, Autoimmune ; Carmustine ; Cyclophosphamide ; Cytarabine* ; Disease Progression ; Disease-Free Survival ; Drug Therapy ; Etoposide* ; Febrile Neutropenia ; Humans ; Lymphoma* ; Radiotherapy ; Recurrence ; Stem Cell Transplantation* ; Stem Cells* ; Thrombocytopenia ; Waldenstrom Macroglobulinemia

OBJECTIVETo explore high effective and low toxic chemotherapeutic regimens in the treatment of non-small-cell lung cancer (NSCLC).

METHODSA total of 126 patients with advanced NSCLC (Stage III, IV) were randomly divided into two groups: high dose impulsion chemotherapy group (HDIC group) and low dose density chemotherapy group (LDDC group) with 54 patients in HDIC group who received paclitaxel 135-175 mg/m2 on day 1, DDP 80-100 mg/m2 on day 1 and BCNU 125 mg given for brain metastasis on days 1-3 in a 4-6 weeks cycle. Seventy-two patients in LDDC group were given paclitaxel 60-80 mg/m2 on day 1, DDP 40-80 mg/m2 on day 1 repeated weekly and BCNU 125 mg given for brain metastasis with an interval of 2 weeks, in a 4-6 weeks cycle. Antiemetic agent and fluid were administered routinely in HDIC group whereas LDDC group was given antiemetic agent only.

RESULTSOf 157 courses in HDIC group, an average of 2.9 courses per patient, CR 3, PR 23, SD 17 and PD 11 were observed. The effective remission rate was 48.1%, the median effective remission period was 4.5 months and the 1-year survival rate was 46.3%. Of 184 courses in LDDC group, an average of 2.6 courses per patient, CR 9, PR 30, SD 24 and PD 9 were observed. The effective remission rate was 54.2%, the median effective remission period was 6 months and the 1-year survival rate was 56.9%. The effective remission rate and the 1-year survival rate were higher in HDIC group than those in LDDC group, but there was no statistical difference between the two groups (P > 0.05). Severe toxicity was higher in HDIC group than in LDDC group. Two patients in HDIC group died of treatment-related complications (3.7%). Quality of life was better in LDDC group (70.8%) than in HDIC group (51.9%).

CONCLUSIONWhen comparing with high dose impulsion, low dose density regimen of paclitaxel plus cisplatin is more effective and better tolerated with improvement of quality of patients' life in the treatment of NSCLC due to its low dose and short interval duration.

Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols ; adverse effects ; therapeutic use ; Brain Neoplasms ; secondary ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; secondary ; Carmustine ; administration & dosage ; Cisplatin ; administration & dosage ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Female ; Humans ; Leukopenia ; chemically induced ; Lung Neoplasms ; drug therapy ; pathology ; Male ; Middle Aged ; Paclitaxel ; administration & dosage ; Quality of Life ; Remission Induction ; Survival Rate ; Thrombocytopenia ; chemically induced

Treatment-related myelodysplastic syndrome (t-MDS) and acute myelogenous leukemia (t-AML) are now well established as complications of cytotoxic chemotherapy. We experienced a 28-yr-old female patient who developed t-MDS/t-AML with characteristic chromosomal abnormalities including 11q23 chromosomal rearrangement following high-dose chemotherapy with autologous stem cell transplantation (ASCT) for non-Hodgkin's lymphoma. The patient was admitted with bulky abdominal masses of B cell lineage non-Hodgkin's lymphoma. After 2 cycles of systemic chemotherapy of the Vanderbilt regimen, the patient underwent ASCT with high dose chemotherapy of the BEAC regimen. She also received radiation of 48 Gy for the residual periportal lymphadenopathy. The initial cytogenetic analysis of the infused mononuclear cells revealed a normal karyotype. Twenty two months after the ASCT, pancytopenia was noted and her bone marrow aspirate showed dysplastic hemopoiesis with myeloblasts up to 12% of nonerythroid nucleated cells. The patient was diagnosed as t-MDS (refractory anemia with an excess of blasts). Cytogenetic analysis showed complex chromosomal abnormalities including 11q23 rearrangement, which is frequently found in topoisomerase II inhibitor-related hematologic malignancies. Four months later, it was noted that the t-MDS had evolved into an overt t-AML. Cytogenetic analysis showed an evolving pattern with more complex abnormalities. The patient was treated with combination che-motherapy, but her leukemic cells were resistant to the therapy.
Adult ; Antineoplastic Agents, Phytogenic/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/*adverse effects ; B-Lymphocytes/cytology ; Bone Marrow Cells/pathology ; Carmustine/*adverse effects ; Chromosome Aberrations ; Chromosomes, Human, Pair 11 ; Combined Modality Therapy/adverse effects ; Cyclophosphamide/*adverse effects ; Cytarabine/*adverse effects ; Etoposide/*adverse effects ; Female ; Gene Rearrangement ; Hematopoietic Stem Cell Transplantation/*adverse effects ; Humans ; Leukemia, Myeloid, Acute/*etiology/genetics ; Lymphoma, Non-Hodgkin/*therapy ; Myelodysplastic Syndromes/*etiology/genetics ; Neoplasms, Second Primary/*etiology ; Pelvis ; Pregnancy ; Pregnancy Complications, Neoplastic/*therapy ; Transplantation, Autologous

PURPOSE: Autografts with peripheral blood stem cells (PBSCT) have become an accepted alternative to bone marrow transplantation for restoring hematopoiesis after marrow ablative therapy. METHODS: Questionnaires are given to all the transplantation centers in Korea. Eleven centers reported 63 cases and retrospective analysis of these cases were done. RESULTS: Sixty-three children with acute myelogenous leukemia (AML) underwent PBSCT following cytoreductive chemotherapy at 11 transplant centers of the Korean Society of Pediatric Hematology-Oncology from January, 1996 through June, 2000. The patients consisted of 40 males and 23 females with a median age at PBSCT of 10 year (range 1~16). Peripheral blood stem cell (PBSC) were collected by a median of 5 apheresis per patient. Various kinds of multi-drug therapy as cytoreductive regimen were used, and the 'BCVAC' regimen consisting of BCNU, cyclophosphamide, VP-16 and cytarabine was used in 35 patients. The median number of infused mononuclear cell (MNC) and CD34 cells was 8.14 (0.3~26.6) 108/kg and 4.90 (0.12~46.9) 106/kg, respectively. Hematological recovery was evaluated in all patients. The median number of days required to achieve an absolute neutrophil count (ANC) of > 500/mm3, > 1,000/mm3 and platelet count of > 50 103/mm3 was 12 (8~48), 12 (9~84) and 35 (10~370), respectively. Sixteen patients relapsed 1 month to 18 months (median 2 months) after PBSCT, 1 patient progressed to secondary MDS 15 months after PBSCT and 1 patient died at d+39 due to CMV infection. So currently 45 patients are surviving disease free at 2 to 50 months (median 23 months). CONCLUSION: Even though the follow-up period was short and the number of patient was small the autologous PBSCT might be an alternative therapy in childhood AML.
Autografts ; Blood Component Removal ; Bone Marrow ; Bone Marrow Transplantation ; Carmustine ; Child ; Cyclophosphamide ; Cytarabine ; Drug Therapy ; Etoposide ; Female ; Follow-Up Studies ; Hematopoiesis ; Hematopoietic Stem Cell Transplantation* ; Hematopoietic Stem Cells* ; Humans ; Korea* ; Leukemia, Myeloid, Acute* ; Male ; Neutrophils ; Platelet Count ; Surveys and Questionnaires ; Retrospective Studies ; Stem Cells

BACKGROUND: High-dose chemotherapy is increasingly employed in many refractory malignant diseases. This therapy has been reported to increase response rate and survival benefits but it is also associated with higher treatment-related morbidity and mortality. We evaluated clinical characteristics and course of the pulmonary toxicity following high-dose chemotherapy with peripheral blood stem cell transplantation. METHODS: Ninety-seven patients who had received high-dose chemotherapy with peripheral blood stem cell transplantation were evaluated. Five patients who developed lung lesions which were not related to infection nor primary malignant disease underwent transbronchial lung biopsy. The patients' clinical characteristics, treatments, and prognosis were reviewed retrospectively. RESULTS: Five patients(5.1%) developed idiopathic pneumonia syndrome. The high dose chemotherapy regimens employed were cyclophosphamide, BCNU, and cisplatin in 3 cases, one case of BCNU, etoposide, Ara-C, cyclophosphamide combination, and a regimen consisting of BCNU, etoposide, Ara-C, and melphalan. The total dose of BCNU used was 300-400 mg/m2 and that of cyclophosphsmide was 6,000 mg/m2. All of 5 patients received radiation therapy before this treatment. After an average duration of 14 weeks (4-26 weeks) of high-dose chemotherapy, patients developed cough, dyspnea and fever. The chest X-rays showed bilateral diffuse infiltration in 3 cases and the focal infiltration in the other 2 cases. All the patients received corticosteroid therapy as a treatment for the lung lesions. Two of them progressed to acute respiratory distress syndrome and died. Three patients recovered without residual lung lesion but one of them died of dilated cardiomyopathy. CONCLUSION: High-dose chemotherapy with peripheral blood stem cell transplantation especially which containing BCNU regimen may develop idiopathic pneumonia syndrome related to pulmonary toxicity and corticosteroid therapy may be beneficial in some cases.
Biopsy ; Cardiomyopathy, Dilated ; Carmustine ; Cisplatin ; Cough ; Cyclophosphamide ; Cytarabine ; Drug Therapy* ; Drug-Related Side Effects and Adverse Reactions ; Dyspnea ; Etoposide ; Fever ; Humans ; Lung ; Melphalan ; Mortality ; Peripheral Blood Stem Cell Transplantation* ; Pneumonia ; Prognosis ; Respiratory Distress Syndrome, Adult ; Retrospective Studies ; Thorax