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At least 163 records · Page 9Linked to original sources
PubMed1999

Procarbazine, lomustine, and vincristine (PCV) chemotherapy for anaplastic astrocytoma: A retrospective review of radiation therapy oncology group protocols comparing survival with carmustine or PCV adjuvant chemotherapy.

PURPOSE: To determine any differences in outcome for patients with anaplastic astrocytoma (AA) treated with adjuvant carmustine (BCNU) versus procarbazine, lomustine, and vincristine (PCV) chemotherapy. MATERIALS AND METHODS: The Radiation Therapy Oncology Group (RTOG) database was reviewed for patients with newly diagnosed AA treated according to protocols that included either BCNU or PCV adjuvant chemotherapy. All patients were treated with radiation therapy. The outcome analysis included overall survival, taking into account patient age, extent of resection, Karnofsky performance status (KPS), and treatment group (BCNU v PCV). Stratified and nonstratified Cox proportional hazards models were used, as well as an analysis using matched cases between the groups. RESULTS: A total of 257 patients were treated with BCNU according to RTOG protocols 70-18, 83-02, and 90-06; 175 patients were treated with PCV according to RTOG protocol 94-04. All pretreatment characteristics except KPS were well balanced by treatment group; 61% of the BCNU group had a KPS of 90 to 100 compared with 73% of the PCV group (P =.0075). No statistically significant difference in survival was observed in any age group or by KPS or extent of surgery. The stratified analysis also showed no trends for improved survival by treatment group (P =. 40). The Cox model identified only age, KPS, and extent of surgery as important variables influencing survival, not treatment group. Matching cases between groups using age, KPS, and surgery resulted in 133 matched pairs. No difference in survival was observed (P =. 41). In a Cox model in which each matched pair is a strata, there was no difference between groups (P =.20). CONCLUSION: Using this retrospective analysis, there does not seem to be any survival benefit to PCV chemotherapy. Future phase III studies for patients with AA may need to consider whether BCNU or PCV is used in the control arm.

Adult↗
PubMed1999

Phase III clinical trial of the combination of cisplatin, dacarbazine, and carmustine with or without tamoxifen in patients with advanced malignant melanoma.

PURPOSE: A prospective randomized phase III clinical trial was conducted to assess whether the addition of tamoxifen (TAM) to the three-agent regimen of cisplatin (CDDP), dacarbazine (DTIC), and carmustine (BCNU) significantly increased the progression-free survival and overall survival of patients with advanced malignant melanoma. PATIENTS AND METHODS: Patients with advanced malignant melanoma were treated with CDDP + DTIC + BCNU (CDB) with or without TAM. The dose schedule was CDDP 25 mg/m(2) given intravenously (IV) for 30 to 45 minutes in 500 mL of dextrose and (1/2) normal saline (NS) on days 1 to 3 of a 3-week cycle; DTIC 220 mg/m(2) IV for 1 hour in 500 mL of dextrose and (1/2) NaCl on days 1 to 3 of a 3-week cycle; BCNU 150 mg/m(2) IV for 2 to 3 hours in 750 to 1,000 mL of dextrose and 5% water on day 1 of every odd 3-week cycle; and TAM 20 mg taken orally every morning. RESULTS: There were 184 eligible patients enrolled. These patients were observed until death or for a minimum of 1.3 years. At last contact, 12 were still alive. The median time to progression was 3.4 months on the CDB arm and 3.1 months on the CDB + TAM arm. The median survival time was 6.8 months with CDB and 6.9 months with CDB + TAM. Progression-free survival (P =.429) and overall survival (P =.545) were not found to differ by treatment. CONCLUSION: The addition of TAM to this three-agent regimen of CDB was not found to provide a meaningful clinical advantage in the treatment of patients with advanced malignant melanoma.

Adult↗
PubMed2000

Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma.

PURPOSE: The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT), which removes chloroethylation or methylation damage from the O(6) position of guanine. O(6)-benzylguanine (O(6)-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial of carmustine (BCNU) plus O(6)-BG to define the toxicity and maximum-tolerated dose (MTD) of BCNU in conjunction with the preadministration of O(6)-BG with recurrent or progressive malignant glioma. PATIENTS AND METHODS: Patients were treated with O(6)-BG at a dose of 100 mg/m(2) followed 1 hour later by BCNU. Cohorts of three to six patients were treated with escalating doses of BCNU, and patients were observed for at least 6 weeks before being considered assessable for toxicity. Plasma samples were collected and analyzed for O(6)-BG, 8-oxo-O(6)-BG, and 8-oxoguanine concentration. RESULTS: Twenty-three patients were treated (22 with glioblastoma multiforme and one with anaplastic astrocytoma). Four dose levels of BCNU (13.5, 27, 40, and 55 mg/m(2)) were evaluated, with the highest dose level being complicated by grade 3 or 4 thrombocytopenia and neutropenia. O(6)-BG rapidly disappeared from plasma (elimination half-life = 0. 54 +/- 0.14 hours) and was converted to a longer-lived metabolite, 8-oxo-O(6)-BG (elimination half-life = 5.6 +/- 2.7 hours) and further to 8-oxoguanine. There was no detectable O(6)-BG 5 hours after the start of the O(6)-BG infusion; however, 8-oxo-O(6)-BG and 8-oxoguanine concentrations were detected 25 hours after O(6)-BG infusion. The mean area under the concentration-time curve (AUC) of 8-oxo-O(6)-BG was 17.5 times greater than the mean AUC for O(6)-BG. CONCLUSION: These results indicate that the MTD of BCNU when given in combination with O(6)-BG at a dose of 100 mg/m(2) is 40 mg/m(2) administered at 6-week intervals. This study provides the foundation for a phase II trial of O(6)-BG plus BCNU in nitrosourea-resistant malignant glioma.

Adult↗
PubMed2002

Phase II trial of carmustine plus O(6)-benzylguanine for patients with nitrosourea-resistant recurrent or progressive malignant glioma.

PURPOSE: We conducted a phase II trial of carmustine (BCNU) plus the O(6)-alkylguanine-DNA alkyltransferase inhibitor O(6)-benzylguanine (O(6)-BG) to define the activity and toxicity of this regimen in the treatment of adults with progressive or recurrent malignant glioma resistant to nitrosoureas. PATIENTS AND METHODS: Patients were treated with O(6)-BG at an intravenous dose of 120 mg/m(2) followed 1 hour later by 40 mg/m(2) of BCNU, with cycles repeated at 6-week intervals. RESULTS: Eighteen patients were treated (15 with glioblastoma multiforme, two with anaplastic astrocytoma, and one with malignant glioma). None of the 18 patients demonstrated a partial or complete response. Two patients exhibited stable disease for 12 weeks before their tumors progressed. Three patients demonstrated stable disease for 6, 12, and 18 weeks before discontinuing therapy because of hematopoietic toxicity. Twelve patients experienced reversible > or = grade 3 hematopoietic toxicity. There was no difference in half-lives (0.56 +/- 0.21 hour v 0.54 +/- 0.20 hour) or area under the curve values (4.8 +/- 1.7 microg/mL/h v 5.0 +/- 1.3 microg/mL/h) of O(6)-BG for patients receiving phenytoin and those not treated with this drug. CONCLUSION: These results indicate that O(6)-BG plus BCNU at the dose schedule used in this trial is unsuccessful in producing tumor regression in patients with nitrosourea-resistant malignant glioma, although stable disease was seen in five patients for 6, 12, 12, 12, and 18 weeks. Future use of this approach will require strategies to minimize dose-limiting toxicity of BCNU such as regional delivery or hematopoietic stem-cell protection.

Adult↗
PubMed2003

Phase II trial of thalidomide and carmustine for patients with recurrent high-grade gliomas.

PURPOSE: The use of thalidomide as an antiangiogenic agent has met with only limited success in the treatment of malignant gliomas. On the basis of preclinical data demonstrating synergistic antitumor activity when antiangiogenic agents are combined with cytotoxic agents, we explored the clinical activity of the combination of thalidomide and carmustine (BCNU) in patients with recurrent high-grade gliomas. PATIENTS AND METHODS: Patients with a histologic diagnosis of high-grade glioma and radiographic evidence of tumor progression after standard surgery, radiation, and chemotherapy were eligible for the study. Patients received BCNU 200 mg/m2 on day 1 of every 6-week cycle, and 800 mg/d of thalidomide that was escalated to a maximal dose of 1,200 mg/d as tolerated. RESULTS: A total of 40 patients (38 with glioblastomas, two with anaplastic gliomas) were accrued to the study. The combination of thalidomide and BCNU was well tolerated; mild myelosuppression and mild to moderate sedation were the most common side effects. The median progression-free survival (100 days) and the objective radiographic response rate (24%) for patients with glioblastoma compared favorably with data from historical controls. CONCLUSION: This is one of the first clinical trials to evaluate the strategy of combining a putative antiangiogenic agent with a cytotoxic agent in patients with primary brain tumors. Our data demonstrate that thalidomide in combination with BCNU is well tolerated and has antitumor activity in patients with recurrent high-grade gliomas. Although the combination seems to be more active than either agent alone, such conclusions await confirmatory trials.

Adult↗
PubMed2003

Dose escalation of carmustine in surgically implanted polymers in patients with recurrent malignant glioma: a New Approaches to Brain Tumor Therapy CNS Consortium trial.

PURPOSE: This New Approaches to Brain Tumor Therapy CNS Consortium study sought to determine the maximum-tolerated dose (MTD) of carmustine (BCNU) that can be implanted in biodegradable polymers following resection of recurrent high-grade gliomas and the systemic BCNU exposure with increasing doses of interstitial BCNU. PATIENTS AND METHODS: Forty-four adults underwent tumor debulking and polymer placement. Six patients per dose level were studied using polymers with 6.5%, 10%, 14.5%, 20%, and 28% BCNU by weight. Toxicities were assessed 1 month after implantation by a safety monitoring committee to determine whether subsequent escalations should occur. Nine additional patients were studied at the MTD to confirm safety. BCNU blood levels were obtained before and after polymer implantation. RESULTS: No dose-limiting toxicities were identified at the 6.5%, 10%, or 14.5% dose levels, although difficulties with wound healing, seizures, and brain edema were noted. At the 20% dose, these effects seemed more prominent, and six additional patients were treated at this dose and tolerated treatment well. Three of four patients receiving the 28% polymers developed severe brain edema and seizures, and accrual to this cohort was stopped. Nine additional patients received 20% polymer, confirming this as the MTD. Maximum BCNU plasma concentrations with the 20% loaded polymers were 27 ng/mL. Overall median survival was 251 days. CONCLUSION: The MTD of BCNU delivered in polymer to the surgical cavity is 20%. This polymer provides five times more BCNU than standard commercially available BCNU polymers and results in minimal systemic BCNU exposure. Additional studies are needed to establish the efficacy of high-dose BCNU polymers.

Absorbable Implants↗
PubMed2004

Second-line chemotherapy with irinotecan plus carmustine in glioblastoma recurrent or progressive after first-line temozolomide chemotherapy: a phase II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO).

PURPOSE: Glioblastoma multiforme (GBM), the most frequent brain tumor in adults, is not considered chemosensitive. Nevertheless, there is widespread use of first-line chemotherapy, often with temozolomide, as a therapeutic option in patients with progressive disease after surgery and radiotherapy. However, at the time of second recurrence and/or progression, active and noncross-resistant chemotherapy regimens are required. The aim of the present multicenter phase II trial, therefore, was to ascertain the efficacy of second-line carmustine (BCNU) and irinotecan chemotherapy. PATIENTS AND METHODS: Patients with histologically confirmed GBM, recurring or progressing after surgery, standard radiotherapy and a first-line temozolomide-based chemotherapy, were considered eligible. The primary end-point was progression-free survival at 6 months (PFS-6), and secondary end-points included response rate, toxicity, and survival. All patients were on enzyme-inducing antiepileptic prophylaxis. Chemotherapy consisted of BCNU (100 mg/m2 on day 1) plus irinotecan (175 mg/m2/weekly for 4 weeks), every 6 weeks, for a maximum of eight cycles. In the absence of grade 2 toxicity, the irinotecan dose was increased to 200 mg/m2. RESULTS: A total of 42 patients (median age, 53.4 years; median Karnofsky performance status, 80; range, 60 to 90) were included in the study. PFS-6 was 30.3% (95% CI, 18.5% to 49.7%). Median time to progression was 17 weeks (95% CI, 11.9 to 23.9). Nine partial responses (21.4%; 95% CI, 9% to 34%) were obtained. Toxicity was manageable. CONCLUSION: The BCNU plus irinotecan regimen seems active and non-cross-resistant in patients with GBM with recurrence after temozolomide-based chemotherapy.

Adult↗
PubMed1999

Inhibition of carboxyethylphosphoramide mustard formation from 4-hydroxycyclophosphamide by carmustine.

It has been reported that the toxicity of carmustine (BCNU)/cyclophosphamide (CY)/etoposide regimen (when BCNU is split into 4 doses) is less than that of BCNU/CY/cisplatin regimen (when the same amount of BCNU is administered as a single dose). We hypothesized that this might in part be due to the inhibition of aldehyde dehydrogenase 1 (ALDH1) by BCNU or its degradation product, 2-chloroethyl isocyanate, which is likely to be more pronounced at the higher BCNU dose. The effects of BCNU and 2-chloroethyl isocyanate on the formation of carboxyethylphosphoramide mustard (CEPM) from 4-hydroxycyclophosphamide (HCY) was evaluated in human liver cytosol incubations. We found that CEPM formation from HCY was inhibited strongly by BCNU and weakly by 2-chloroethyl isocyanate. The mechanism of inhibition of ALDH1 activity by BCNU was elucidated using indole-3-acetaldehyde (IAL) as the probe substrate in ALDH1 prepared from human erythrocytes. BCNU was a competitive inhibitor of ALDH1 activity with a K(i) of 1.95 microM. The inhibition was independent of preincubation time and reversible by dialysis. The calculated %inhibition of ALDH1 activity by acrolein and BCNU in patients receiving BCNU in 4 split doses with CY was 81%, and it increased to 92% in single dose BCNU regimen. Thus, the calculation indicates that residual operating ALDH1 activity is halved in the presence of single-dose BCNU compared to split-dose BCNU. The inhibition of ALDH1 may contribute to the observed lower incidence of toxicity when BCNU was split into 4 doses compared with single dose and coadministered with CY although dose-dependent effects of BCNU on glutathione and glutathione reductase are also likely to contribute.

Acrolein↗
PubMed1994

Severe diffuse interstitial pneumonitis induced by carmustine (BCNU).

We report a fatal case of acute interstitial pneumonitis in a patient treated with carmustine (BCNU) for a brain tumor. Bronchoalveolar lavage (BAL) revealed lymphocyte alveolitis with a low CD4/CD8 ratio (0.36), consistent with an immunoallergic phenomenon, rather than the most often evoked toxic hypothesis.

Acute Disease↗
PubMed1995

Empiric prednisone therapy for pulmonary toxic reaction after high-dose chemotherapy containing carmustine (BCNU).

STUDY OBJECTIVE: To determine pretreatment factors that predict for pulmonary toxic reactions after high-dose chemotherapy containing carmustine (BCNU) and to determine the utility of prednisone in preventing pulmonary toxic reactions. DESIGN: Retrospective review. SETTING: Tertiary care referral center. PATIENTS: Forty-five patients with relapsed or refractory lymphoma and 27 patients with breast cancer with normal cardiopulmonary function were treated with one of two high-dose combination chemotherapeutic regimens containing the same dose of BCNU. MEASUREMENTS: Recorded pretreatment patient characteristics included previous chemotherapy or radiation therapy, history of pulmonary metastases, history of chronic obstructive pulmonary disease, and history of smoking. Spirometry and single-breath carbon monoxide diffusing capacity (DCO) were obtained before and after high-dose chemotherapy. INTERVENTIONS: Patients were treated with prednisone for a 5% or more drop in postchemotherapy DCO whether or not symptoms were present. RESULTS: Fifty-nine patients were evaluable. No pretreatment characteristic predicted for declines in pulmonary function postchemotherapy. The FEV1/FVC ratio did not change significantly after high-dose chemotherapy, but the DCO decreased 12.1% (p < 0.001). Of the 59 evaluable patients, 30 were treated with prednisone for declines in postchemotherapy DCO. Sixteen (53%) of these 30 patients were asymptomatic. The DCO increased 10.3% in patients treated with prednisone compared with a decrease of 2.3% in patients not treated (p = 0.017). There was no statistically significant difference in FEV1/FVC in patients treated with prednisone compared with those not treated. Regression analysis of pretreatment characteristics, type of high-dose chemotherapy received, and treatment with prednisone identified only treatment with prednisone as a significant variable in predicting an increase in DCO (p = 0.03; regression coefficient = +11.5%, SE = +/- 5.2%) after high-dose chemotherapy containing BCNU. CONCLUSIONS: High-dose BCNU-containing chemotherapeutic regimens cause decreases in DCO that are often asymptomatic and likely represent subclinical pulmonary toxic reactions. Pretreatment clinical parameters cannot predict which patients will manifest pulmonary toxic reactions after high-dose chemotherapy. Empiric treatment with prednisone will reverse chemotherapy-induced decreases in DCO. Earlier institution of glucocorticoids for evidence of pulmonary dysfunction is recommended.

Adult↗
PubMed1995

Late carmustine lung fibrosis. Age at treatment may influence severity and survival.

Previously, we have reported in 1990 that 35% of carmustine treated patients (6 of 17) who survived childhood brain tumors died of pulmonary fibrosis between 2 and 13 years after treatment. In addition, 8 patients studied in 1989 (13 to 17 years post treatment), had physiologic and biopsy or radiologic evidence of pulmonary fibrosis. We now report 3 more years of follow-up on these patients. Between 1989 and 1992, two more patients have died of pulmonary fibrosis, giving an overall mortality of 47%. Of the eight patients who died of pulmonary fibrosis, the median age at treatment was 2.5 years, whereas the nine long-term survivors had a median age at treatment of 10 years. All five patients treated below the age of 5 years have died of lung fibrosis. Analysis by the standard survival curve method indicated that patients treated at an age less than 6 years were more likely to die than those treated at an age older than 7 years (p = 0.03). Of the nine survivors, seven were observed over 3 more years. There was a gradual decline in mean forced vital capacity from 55% predicted (range, 44 to 81) to 51% predicted (range, 41 to 72) and total lung capacity fell from 65% predicted (range, 51 to 89) to 57% predicted (range, 47 to 77).

Adolescent↗
PubMed1981

Topical administration of the antineoplastic carmustine: tolerance of normal rabbit eyes.

We evaluated the tolerance of ocular tissues to topical application of the anticancer agent 1,3 bis(2-chloroethyl)-1-nitrosourea (carmustine, BCNU) in eight normal rabbit eyes. Early changes in the anterior ocular structures, including moderate to severe chemosis, lid swelling, and superficial punctate keratitis with epithelial defect and corneal edema, occurred within the first 36 hours. These changes subsided gradually following administration of Cortisporin ointment (polymyxin B-bacitracin-neomycin-hydrocortisone) in the eyes that received 1.0 mg of BCNU per day. In one of the two eyes given the 3.0-mg dose, corneal clouding with interstitial vascularization was still present 40 days after drug administration, despite Cortisporin treatment.

Animals↗
PubMed2001

Incidence of post transplant myelodysplasia/acute leukemia in non-Hodgkin's lymphoma patients compared with Hodgkin's disease patients undergoing autologous transplantation following cyclophosphamide, carmustine, and etoposide (CBV).

Secondary malignancies, particularly myelodysplasia (MDS), are serious events following high dose therapy with autologous stem cell support. We observed a higher frequency of secondary malignancies in patients with Hodgkin's disease (HD) than in patients with non-Hodgkin's lymphoma (NHL) undergoing high dose therapy with the same non-TBI conditioning regimen. Three hundred patients with Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) were treated with cyclophosphamide, carmustine and etoposide and autologous stem cell support from 1986 through 1994. Median follow up of survivors is 3.9 years. Five-year survival is 51% for HD and 48% for NHL. Eleven patients developed second malignancies (9/150 treated for HD vs. 2/150 treated for NHL) a median of 2.4 years from transplantation and 5.2 years from initial diagnosis. Six patients had myelodysplasia or acute leukemia (MDS/AML) and 5 had lymphomas or solid tumors. Actuarial risk of MDS/AML at five years for patients transplanted for non-Hodgkin's lymphoma is 3% (95% CI 0.6-9.6%). HD patients had significantly different pretreatment characteristics than patients with NHL. A Cox model showed that greater number of prior relapses and prior radiation therapy were significant risk factors for the development of MDS/AML. These data suggest that CBV is associated with a lower risk of secondary MDS/AML than TBI containing regimens and that much of the risk is associated with the pre-transplantation therapy. The use of autotransplantation early in the course of therapy for relapsed lymphoma might prevent some cases of MDS/AML.

Acute Disease↗
PubMed1999

Protracted results of dose-intensive therapy using cyclophosphamide, carmustine, and continuous infusion etoposide with autologous stem cell support in patients with relapse or refractory Hodgkin's disease: a phase II study from the North American Marrow Transplant Group.

To determine the long-term results of high-dose chemotherapy and stem cell support in relapsed or primary refractory Hodgkin disease patients. One hundred and thirty-one patients with relapsed or primary refractory Hodgkin's disease were treated with a dose-intensive therapy protocol consisting of etoposide (2400 mg/m2 continuous intravenous infusion) cyclophosphamide (7200 mg/m2 intravenously), and carmustine (300-600 mg/m2 intravenously) CBVi. All patients had previously failed conventional chemoradiotherapy. Severe toxicities were related to infectious, hepatic, and pulmonary complications. Fatal, regimen-related toxicity was 19%; liver and lung dysfunction, as well as infection, were the most frequent problems. Ninety-one (69%) of the patients achieved a complete response (CR) (95% CI = 59% to 75%) after CBVi and autologous stem cell infusion. With a median follow-up of 5.1 years (range 3.0 to 9.5 years), overall and event-free survival are 44% (95% CI = 33% to 47%) and 38% (95% CI = 28% to 46%) respectively. While univariate analysis did not reveal a statistically significant variable to predict a better response, responsiveness to therapy demonstrated a trend. We conclude that CBVi is an effective therapy for relapsed or refractory Hodgkin's disease, producing long-term, durable remissions.

Adolescent↗
PubMed1986

High-dose cyclophosphamide, carmustine, and etoposide and autologous bone marrow transplantation for relapsed Hodgkin's disease.

Thirty patients with relapsed Hodgkin's disease were treated with high-dose cyclophosphamide, carmustine, and etoposide (CBV) and autologous bone marrow transplantation. The median age of the patients was 28 years, and 18 were male. More than half had extranodal sites of relapse and constitutional symptoms. Most had been heavily pretreated with multiple salvage chemotherapy regimens and radiotherapy. At the time of transplantation, 23 patients were having progressive disease despite salvage chemotherapy. High-dose CBV chemotherapy induced complete responses in 15 patients and partial responses in 10 patients. Eleven patients are still in complete remission, 1 of whom has had an unmaintained remission for more than 44 months. Toxicity was moderate; all patients had severe myelosuppression requiring supportive therapy, and 1 patient failed to reconstitute her bone marrow. High-dose CBV chemotherapy and autologous bone marrow rescue proved to be effective as salvage therapy for a select group of heavily pretreated patients with relapsed Hodgkin's disease.

Adolescent↗
PubMed2000

Serial CT and MR imaging of carmustine wafers.

BACKGROUND AND PURPOSE: A new option in the treatment of recurrent malignant glioma is surgical placement of chemotherapy-laden biodegradable wafers. We describe the CT and MR appearance of chemotherapy wafers in patients after surgery for recurrent malignant glioma METHODS: Eighteen patients had carmustine (BCNU) wafers implanted during reoperation for malignant glioma; three patients had empty, placebo wafers placed. The 21 patients had a total of 22 CT and 57 MR imaging studies. Repeat CT studies were conducted for up to 6 months, the MR studies for up to 1 year. Examinations were evaluated for attenuation on CT scans, signal abnormalities on MR images, and changing appearance during the follow-up period. Enhancement characteristics were also assessed. RESULTS: On CT scans, 13 of 16 acute (<7 days) cases showed linear high-attenuation wafers, with three showing low attenuation. On MR images, all T1 and T2 studies performed in the acute stage showed decreased signal of the wafers. Eight of 15 studies showed a transient increase in T1 only at about 2 months. Wafers decreased in conspicuity on both CT and MR studies after 2 months. The wafers did not enhance. One postoperative tumor showed a transient increase in edema and increased enhancement at 5 weeks. The presence or absence of BCNU within the wafers did not change their appearance. CONCLUSION: BCNU wafers have a characteristic appearance: in the first 7 days after implantation they are linear, usually of increased attenuation on CT scans, and always show decreased signal on MR images; they do not enhance, and become less conspicuous after 2 months.

Antineoplastic Agents, Alkylating↗
PubMed2000

Identification of transforming growth factor-beta1-binding protein overexpression in carmustine-resistant glioma cells by MRNA differential display.

BACKGROUND: The authors previously demonstrated the presence of cells in primary human malignant gliomas that intrinsically are resistant to carmustine (BCNU). Numerous studies have identified mechanisms of therapy resistance in these cells; however, the authors' work and that of others suggest that additional mechanisms of resistance exist. METHODS: The authors identified a glioma cell line that lacks detectable methylguanine methyltransferase expression and does not alter its expression of glutathione-S-transferase-pi in response to BCNU chemotherapy. This cell line was used in mRNA differential display experiments to identify genes involved in what to the authors' knowledge were previously undescribed mechanisms of resistance. RESULTS: The overexpression of the gene encoding the transforming growth factor latency binding protein was demonstrated in glioma cells selected for resistance to BCNU, compared with their parental unselected cells. CONCLUSIONS: Transforming growth factor-beta1 has pleiotropic functions in transformed and normal cells. Although activation of TGF-beta1 does not appear to be a causative factor in BCNU resistance in the current study, it may be involved in the growth of these resistant cells.

Aged↗
PubMed2000

O6-benzylguanine potentiates the antitumor effect of locally delivered carmustine against an intracranial rat glioma.

Local delivery of carmustine (BCNU) via biodegradable polymers prolongs survival against experimental brain tumors and in human clinical trials. O6-benzylguanine (O6-BG), a potent inhibitor of the DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT), has been shown to reduce nitrosourea resistance and, thus, enhance the efficacy of systemic BCNU therapy in a variety of tumor models. In this report, we demonstrate that O6-BG can potentiate the activity of BCNU delivered intracranially via polymers in rats challenged with a lethal brain tumor. Fischer 344 rats received a lethal intracranial challenge of 100,000 F98 glioma cells (F98 cells have significant AGT activity, 328 fmol/mg protein). Five days later, animals receiving an i.p. injection of O6-BG (50 mg/kg) 2 h prior to BCNU polymer (3.8% BCNU by weight) implantation had significantly improved survival (n = 7; median survival, 34 days) over animals receiving either O6-BG alone (n = 7; median survival, 22 days; P = 0.0002) or BCNU polymer alone (n = 8; median survival, 25 days; P = 0.0001). Median survival for the control group (n = 8) was 23.5 days. Moreover, there was no physical, behavioral, or pathological evidence of treatment-related toxicity. These findings suggest that O6-BG can potentiate the effects of interstitially delivered BCNU and, for tumors expressing significant AGT, may be necessary for the BCNU to provide a meaningful therapeutic benefit. Given the clinical use of BCNU polymers against malignant gliomas, concurrent treatment with O6-BG may provide an important addition to our therapeutic armamentarium.

Animals↗