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PubMed2003

Sensitization of pancreatic tumor xenografts to carmustine and temozolomide by inactivation of their O6-Methylguanine-DNA methyltransferase with O6-benzylguanine or O6-benzyl-2'-deoxyguanosine.

Adenocarcinoma of the pancreas is refractory to chemotherapeutic agents, including BCNU and streptozotocin. We have previously shown that drugs, which adduct the O(6)- position of guanine, are ineffective against pancreatic tumor cell lines because of high expression of O(6)-methylguanine-DNA methyltransferase (MGMT). The effect of MGMT inactivation on the resistance of pancreatic tumors to carmustine (BCNU) and to temozolomide (TMZ) was examined in five human pancreatic tumor xenografts in athymic mice. Tumor-bearing mice were treated: (a) with a single i.p. injection of BCNU or TMZ at the maximum-tolerated doses of 75 and 340 mg/m(2), respectively; and (b) with O(6)-benzylguanine (BG) or O(6)-benzyl-2'-deoxyguanosine (dBG) in combination with BCNU or TMZ. Pretreatment with the MGMT inactivators BG or dBG reduced the maximum-tolerated doses of BCNU and TMZ to 35 and 170 mg/m(2), respectively. MIA PaCa-2, CFPAC-1, PANC-1, CAPAN-2, and BxPC-3 having MGMT levels of 890, 1680, 680, 900, and 330 fmol/mg protein, respectively, were unresponsive to BCNU. MIA PaCa-2 and CFPAC-1 were also unresponsive to TMZ, whereas CAPAN-2 responded with a tumor delay of 32 days. BG or dBG sensitized all tumors to both BCNU and TMZ. BG plus BCNU treatment of MIA PaCa-2, CFPAC-1, PANC-1, CAPAN-2, and BxPC-3 induced tumor delays of 18, 16, 12, 14, and 16 days, respectively. In comparison, dBG plus BCNU at doses that were equitoxic to BCNU plus BG yielded tumor delays of 30, 19, 16, 21, and 22 days, respectively. The pancreatic tumors tested displayed functional mismatch repair that, however, may not be always sufficiently restrictive to prevent mutations under alkylation stress. Treatments with either BCNU or TMZ resulted in some degree of mutation in recurring tumors with the exception of CAPAN-2, the only wt-p53 xenograft. dBG, a weak MGMT inactivator in vitro as compared with BG, was markedly more effective than the latter in enhancing the efficacy of BCNU against pancreatic tumor xenografts. Both BG and dBG also enhanced the efficacy of TMZ against pancreatic tumors, possibly because of the repression of MGMT, which cannot be achieved with TMZ treatments alone. These results suggest that pancreatic tumors, which are resistant to DNA alkylating agents, may be sensitized to such agents when pretreated with MGMT inactivators.

Alkylating Agents↗
PubMed2005

Combination chemotherapy with carmustine and cisplatin followed by procarbazine, lomustine, and vincristine for adult high-grade astrocytoma.

BACKGROUND: We have reported that carmustine (BCNU) and cisplatin administered before, during, and after radiotherapy did not improve the survival of patients with high-grade astrocytomas and were associated with more serious toxicities than radiotherapy plus BCNU. In an attempt to improve survival, we studied a combination regimen procarbazine, lomustine, and vincristine (PCV) after radiotherapy in addition to BCNU and cisplatin during radiotherapy. METHODS: From 1994 through 1998, 42 patients were enrolled in the study. Of these, 20 had glioblastoma multiforme and 22 had anaplastic astrocytoma. The patients had a median age of 48.5 years. All patients had subtotal or total resection, or biopsy as the initial procedure. Then, all patients were treated with BCNU and cisplatin concurrently during radiotherapy followed by PCV after radiotherapy. RESULTS: The median time to follow up for survivors was 13.8 months (range, 1.7-108.2 months). The median time to tumor progression was 7.2 months (range, 0-88.7 months) and median survival time was 13.3 months (range, 1.7-88.7 months). The only factor that had a conventionally significant effect on the overall survival was resectability. Patients who had received subtotal/total resection had a longer median survival compared with patients who had received biopsy only (18.0 vs. 9.5 months). This combined modality treatment program was associated with reversible grade 3 to 4 hematological toxicity in 10 patients, with grade 3 ototoxicity in one patient and grade 2 neurotoxicity in one patient. CONCLUSION: A combination of BCNU and cisplatin with cranial irradiation followed by PCV was moderately toxic and appeared to offer no obvious survival advantages compared with radiotherapy plus BCNU and cisplatin alone.

Adolescent↗
PubMed1991

High-dose cyclophosphamide, carmustine, and etoposide followed by autologous peripheral stem cell transplantation for patients with relapsed Hodgkin's disease.

Between February 1986 and March 1990, 56 patients with relapsed Hodgkin's disease treated with high-dose cyclophosphamide, carmustine, and etoposide (CBV) received an autologous peripheral stem cell transplantation (PSCT) rather than an autologous bone marrow transplantation (ABMT) because each patient had a marrow abnormality, either hypocellularity or tumor involvement. At least 6.5 x 10(8) [corrected] mononuclear cells/kg patient weight were collected from the peripheral blood of each patient, cyropreserved, and returned intravenously following CBV administration. Three patients had an early death 2, 22, and 25 days after PSCT. The actuarial event-free survival for these 56 patients at 3 years was 37% and was at least as good as that reported for relapsed Hodgkin's disease patients treated with CBV and ABMT. The 30 patients who had no marrow metastases at the time of PSC harvesting had an actuarial event-free survival of 47%, while those 26 patients with marrow metastases had a significantly different actuarial event-free survival of 27% (P = .02). CBV and PSCT for patients with relapsed Hodgkin's diseases who have marrow hypocellularity in traditional harvest sites or histopathologic evidence of BM metastases can result in long-term event-free survival.

Adult↗
PubMed1991

Treatment of advanced refractory lymphomas with a combination of carmustine, bleomycin, teniposide, dexamethasone, and cisplatin (the BBVDD regimen). An ECOG pilot study.

Forty-four patients with relapsed, refractory malignant lymphomas (12 Hodgkin's disease, 32 non-Hodgkin's lymphoma) were treated with a combination of carmustine, bleomycin, teniposide, dexamethasone, and cisplatin (BBVDD regimen). Patients had failed at least one, and frequently two, chemotherapy regimens before admission to the study. Of the patients with Hodgkin's disease, 2 (17%) achieved complete response (CR), and 3 (25%) attained a partial response (PR) for an overall response rate (CR + PR) of 42%. Among the patients with non-Hodgkin's lymphoma there were 6 CR (19%) and 12 PR (37%), for an overall response rate of 56%. Median durations of response ranged from 2.5 months for nodular non-Hodgkin's lymphoma in PR to 28.5 + months for Hodgkin's disease in CR. In these heavily pretreated patients, the incidence of toxic effects was grade 3 (48%), grade 4 (23%), grade 5 (2%). The one death (grade 5 toxicity) was attributed to pulmonary impairment due to bleomycin. BBVDD is a moderately effective regimen for the palliation of patients with refractory lymphomas and merits further study.

Ambulatory Care↗
PubMedDate not supplied

[Treatment of supratentorial glioma with intracarotid cisplatin and intravenous carmustine].

We report the results of intracarotid (IC) cisplatinum and intravenous carmustine (BCNU) in 26 patients with supratentorial malignant glioma and recurrent low grade glioma. A response rate of 53.84% (95% confidence interval 33.3%-73.4%) was found. The median survival for the whole group was 11 months (range 3-70), with 35% of patients surviving for 2 years. At the present time, 5 patients are still alive, with a median follow up of 68 months (range 56-70). Neurological toxicity has been low and transient, being attributable to the technical degree of care in catheter positioning, cisplatin dosage and the technique of drug administration into the carotid artery.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

Etoposide, carmustine, bleomycin, and methotrexate with leucovorin rescue as re-treatment for unfavorable non-Hodgkin's lymphoma.

Fifteen patients with unfavorable, non-Hodgkin's lymphoma refractory to front-line chemotherapy were treated with etoposide, carmustine, bleomycin, and methotrexate with leucovorin rescue. Four patients achieved complete response and two achieved partial response. The durations of the complete responses were 4, 12, 24, and 32 months, respectively. Three of the four complete responses occurred in five patients who failed to respond to initial combination chemotherapy. The major toxic effects were severe myelosuppression in eight of 52 courses and pulmonary fibrosis in two patients. This regimen is useful in inducing durable remissions in patients with refractory, unfavorable, non-Hodgkin's lymphomas.

Adult↗
PubMed1989

Cholestatic effect of carmustine in rats.

A single i.p. dose of 20 mg/kg of carmustine [1,3-bis-(2-chloroethyl)-1-nitrosourea; BCNU] caused intrahepatic cholestasis in rats within 48 hr of administration. Cholestasis was characterized by a selective reduction of the bile salt independent fraction of bile flow. Increased plasma K+ and decreased plasma Na+ concentrations, consistent with this effect, were observed. Because bile: plasma osmolality and biliary bile salt concentrations were elevated, increased permeability to bile salts and other osmotically active solutes between bile and plasma is unlikely. Bile salt excretion was normal despite the reduced bile flow because biliary bile salt concentration was increased. In contrast, the treated rats were unable to concentrate bromosulfophthalein in bile before, during and after the onset of cholestasis. Because no reduction in hepatic perfusion was observed in vivo in BCNU-treated rats, reduced xenobiotic organic anion excretion may be a selective effect of the drug. The cholestatic effects of BCNU appear to be different from either alpha-naphthylisothiocyanate or estrogenic steroids.

Animals↗
PubMed1985

Arterial drug infusion with extracorporeal removal. II. Internal carotid carmustine in the rhesus monkey.

During cancer chemotherapy by intra-arterial drug administration, systemic toxicity often limits the tolerable dose. We evaluated the pharmacokinetic advantage obtained by infusing carmustine (BCNU) into the internal carotid artery during BCNU removal from the blood from the perfused region by hemoperfusion. A hemoperfusion column (XR-010, Extracorporeal Medical Specialties) was shown to remove BCNU quantitatively from sheep blood flowing at 300 ml/minute when the drug was infused at 13 mg/minute for 30 minutes. Under general anesthesia, adult rhesus monkeys underwent catheterization of the internal carotid artery and placement of a catheter in the ipsilateral jugular vein at its junction with the sigmoid sinus. BCNU (10 mg/kg) was infused over 20 minutes while blood was pumped from the jugular vein through a small column and back into the inferior vena cava. The procedure reduced systemic exposure by 46%-84% compared with iv infusion of the same dose. Brain-to-systemic exposure ratios ranged from 18:1 to 87:1, depending on the pump flow rate and method of calculation. Hematopoietic toxicity was prevented. It is suggested that tumor exposure to BCNU comparable to that associated with very high tumor cell kill in vitro may be feasible with little or no systemic toxicity.

Animals↗
PubMed1986

Randomized comparisons of radiotherapy and carmustine versus procarbazine versus dacarbazine for the treatment of malignant gliomas following surgery: a Southwest Oncology Group Study.

Between 1977 and 1981, the Southwest Oncology Group entered 278 patients on a randomized study (SWOG 7703) to compare the effect of three different chemotherapeutic agents given in combination with radiotherapy (6000 rads over 7 weeks) following surgery for malignant gliomas. The chemotherapy regimens were: carmustine (BCNU)--80 mg/m2 iv daily X 3 every 6 weeks; procarbazine (PCB)--100 mg/m2 orally; or dacarbazine (DTIC)--175 mg/m2 iv daily X 5 every 4 weeks. Patients were stratified according to age, and degree of resection, with no differences identified between groups. The response rates (complete plus partial) for BCNU and DTIC were significantly better than for PCB [BCNU, 39%; PCB, 13%; and DTIC, 38% (P less than 0.01)]. The response duration and survival were somewhat better in patients treated with BCNU and DTIC, but compared to patients treated with PCB, the difference was not statistically significant. Median survival times were: BCNU, 45 weeks; PCB, 31 weeks; and DTIC, 49 weeks (P greater than 0.3). There were six toxic deaths with BCNU and four with PCB, most of which were due to infection associated with leukopenia. The high toxicity and minimal benefit of chemotherapy added to radiotherapy compared to historical results with radiotherapy alone suggest that combined treatment may not be indicated for some patients.

Brain Neoplasms↗
PubMed1986

Phase II study of combined carmustine, 5-fluorouracil, hydroxyurea, and 6-mercaptopurine (BFHM) for the treatment of malignant gliomas.

The Neuro-oncology Service of the University of California Brain Tumor Research Center conducted a nonrandomized phase II study to evaluate, in patients with recurrent malignant glioma, the benefit of a four-drug combination (BFHM) consisting of carmustine (1,3-bis (2-chloroethyl)-1-nitrosourea), 5-fluorouracil, hydroxyurea, and 6-mercaptopurine. There were 29 evaluable glioblastoma multiforme patients and 45 nonglioblastoma anaplastic glioma patients available for analysis. Tumor progression was analyzed as the primary study endpoint. Of the glioblastoma patients, 16 of 29 (55%) responded or stabilized on therapy; of the other anaplastic gliomas, 32 of 45 (71%) responded or stabilized. For patients who stabilized or responded to treatment, BFHM achieved a median time to tumor progression of 46 weeks with a 25th percentile time to tumor progression of 68 weeks for anaplastic gliomas and a median time to tumor progression of 23 weeks with a 25th percentile time to tumor progression of 36 weeks for glioblastoma multiforme patients. A Cox multivariate analysis demonstrated that age and Karnofsky score were important prognostic variables for these patients.

Adolescent↗
PubMed1988

Cell-cycle, phase-specific cell killing by carmustine in sensitive and resistant cells.

Cell-cycle, phase-specific cell kill caused by carmustine (BCNU) was measured in 4 cell lines with different sensitivities to the drug. Cells were treated with BCNU for 1 hour after which enriched subpopulations in various phases of the cell cycle were obtained by centrifugal elutriation and were assayed for cell survival. Levels of activity of guanine O6-alkyltransferase were measured for each line; intracellular levels of this repair protein have been correlated with cellular resistance to chloroethylnitrosoureas. Only BTRC-19, a clone of the 9L line, had significant levels of alkyltransferase activity and exhibited a relatively flat age-response curve to BCNU. Alkyltransferase activity was not detected in the other 3 cell lines, all of which displayed a similar age response in which G1- and G2/M-phase cells were relatively sensitive to BCNU compared with the response of S-phase cells. We conclude that alkyltransferase activity may overwhelm other determinants that cause cell-cycle phase specificity to BCNU.

Animals↗
PubMedDate not supplied

Lack of enhanced antitumor efficacy for L-buthionine sulfoximine in combination with carmustine, cyclophosphamide, doxorubicin or melphalan in mice.

A series of studies was performed in tumor bearing mice to evaluate the impact of glutathione (GSH) depletion by L-buthionine sulfoximine (L-BSO). L-BSO doses of 50 or 500 mg/kg were used alone or with one of 4 sulfhydryl-dependent anticancer agents (SHDAA). When L-BSO was administered to tumor-bearing mice, Colon 38 cells were significantly depleted of GSH content, but this did not occur with P388 cells or MOPC-315 cells in vivo. GSH levels in these ascites tumors declined significantly without L-BSO treatment as the tumor rapidly grew in the IP space. SHDAAs, including doxorubicin (DOX), cyclophosphamide (CTX), carmustine (BCNU) and melphalan (L-PAM) were then combined with L-BSO in mice bearing P388, MOPC-315 or colon 38 tumors. There was no consistent enhancement of antitumor efficacy using a treatment interval of 24 hrs (L-BSO given first). In contrast, there was some evidence of significantly enhanced SHDAA toxicity with L-BSO. Further studies should evaluate different dosing intervals to take advantage of the slower rate of GSH replenishment observed in normal tissues compared to solid tumor cells (Colon 38) in vivo. In addition, significant reductions for any SHDAA combined with L-BSO are indicated in any such trial.

Animals↗
PubMed1986

Randomized comparison of 5-FU alone or combined with carmustine, doxorubicin, and mitomycin (BAFMi) in the treatment of advanced gastric cancer: a phase III trial of the Italian Clinical Research Oncology Group (GOIRC).

Eighty-two evaluable patients with advanced gastric carcinoma were randomized to receive either 5-FU alone or the combination of carmustine, doxorubicin, 5-FU, and mitomycin (BAFMi). Objective remissions were seen in 15% of the patients who received 5-FU alone and in 22% of the patients on the BAFMi regimen. The difference was not statistically significant. The median duration of objective remission (31 vs 40 weeks) was longer using BAFMi combination, and the median duration of survival, calculated in the 85 randomized patients, was slightly longer using 5-FU (28 vs 24 weeks). The differences were not statistically significant. It is concluded that there is no therapeutic advantage in using the BAFMi combination over 5-FU alone.

Adult↗
PubMed1986

Modified chemotherapy with carmustine, cytarabine, cyclophosphamide, and 6-thioguanine (BACT) and autologous bone marrow transplantation in 24 poor-risk patients with acute lymphoblastic leukemia.

Twenty-four poor-risk patients with acute lymphoblastic leukemia received a modified regimen of carmustine, cytarabine, cyclophosphamide, and 6-thioguanine (BACT) followed by autologous bone marrow transplantation (ABMT). Nineteen patients were in second or subsequent complete remission (CR) when treated with this regimen; 3 died early, 2 died of pneumonia in CR, 11 relapsed within 3 months (median), and 3 remain in CR with no maintenance therapy 14-24 months after ABMT. Of the 5 patients with measurable disease who were treated, 3 had CR and 1 remains in CR without maintenance therapy more than 28 months after ABMT. The toxicity of this regimen was acceptable, but late pulmonary toxic effects remain a major concern. These results are poor in terms of efficacy, and new effective methods of eradicating acute lymphoblastic leukemia in patients with poor prognosis should be investigated.

Adolescent↗
PubMed1986

Pulmonary toxicity of carmustine in patients treated for malignant glioma.

Carmustine (BCNU) was employed as the only chemotherapeutic agent in a Radiation Therapy Oncology Group multimodality study comparing misonidazole-radiosensitized radiation therapy to conventional radiation therapy in 318 patients with malignant glioma. In 289 patients evaluable for BCNU pulmonary toxicity, there were no clinical manifestations of toxicity in patients receiving less than 902-mg/m2 total BCNU dose. Ten of 107 patients receiving more than this dose developed detectable pulmonary toxicity. Results of a multivariate regression analysis of risk factors, which corrects for survival time bias, suggested increased risk of pulmonary toxicity when total dose exceeds 1400 mg/m2. The risk of pulmonary toxicity was not increased by the administration of misonidazole and does not appear to be related to age.

Adult↗
PubMed1986

Pharmacokinetics and immediate effects of high-dose carmustine in man.

The pharmacokinetics and acute toxicity of carmustine (BCNU) have been studied in ten patients receiving high-dose combination chemotherapy with cyclophosphamide, cisplatin, and BCNU as treatment for advanced neoplasms. Patients received from 300 to 750 BCNU mg/m2 of body surface area as a 2-hour infusion. The immediate effects of this schedule of BCNU included tachycardia, hypotension, flushing, confusion, nausea, and vomiting. Hypotension was a prominent feature of high-dose BCNU administration. The pharmacokinetics of high-dose BCNU were studied via serial blood samples obtained during and following BCNU infusion. Concentrations of BCNU in total plasma and ultrafiltrable (bioavailable) plasma were determined by high-pressure liquid chromatography with UV detection. Average pharmacokinetic parameters for bioavailable plasma BCNU, calculated on the basis of a one-compartment model, include an elimination constant of 0.031 min-1 and a volume of distribution of 5.1 L/kg. Average clearance of total plasma BCNU is 77.6 ml/kg/min. When corrected to a constant dose of 1 g/m2, the average peak concentration at the end of the infusion was 7.8 microM and the area under the curve was 538 microM X min. Plasma BCNU was largely (77%) protein bound. The distribution, clearance, and protein binding of high-dose BCNU were similar to those reported for standard-dose BCNU.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1985

Polychemotherapy with carmustine, cyclophosphamide plus adriamycin in the treatment of advanced ovarian cancer.

The Authors describe their experience with a combination therapy with carmustine (BCNU), cyclophosphamide (CTX) plus adriamycin (ADM) in the treatment of advanced ovarian cancer. The complete remission was obtained in 33.3% of subjects, the partial remission in 37.5%. Almost all patients suffered nausea, vomiting and alopecia. Myelosuppression was acceptable. No heart damage was observed. This pharmacological association can be considered an effective medical treatment in the management of ovarian carcinomas in advanced stages.

Adenocarcinoma↗
PubMed1978

Pancreatic cancer treated with carmustine, fluorouracil, and spironolactone: a randomized study.

A prospective randomized trial between two drug regimens in 38 patients with advanced pancreatic carcinoma was performed. The two-drug regimen consisted of carmustine and fluorouracil. The survival rate and response to these two drugs was compared to a three-drug regimen consisting of these same two drugs plus spironolactone. Objective partial responses were rare in both groups, being 3/18 in the two-drug group and 2/20 in the three-drug group. Life table analysis in previously untreated patients from time of treatment shows longer survival for the three-drug group, but this difference was not statistically significant.

Adult↗