Effectiveness of two-stage treatment of multiple myeloma with melphalan and with melphalan in combination with cyclophosphamide, carmustine, vincristine and prednisone.
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Adult↗
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Results for “Carmustine”
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Third-line chemotherapy with mitomycin, vinblastine, and carmustine (BCNU) in refractory breast carcinoma: a pilot study.
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Adenocarcinoma↗
Stability of carmustine for topical application.
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Administration, Topical↗
Combination carmustine (BCNU) and dianhydrogalactitol in the treatment of primary brain tumors recurring after irradiation.
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Adult↗
Responsiveness of Carmustine (BCNU) treated mice to induction and inhibition of mixed function oxygenases.
The responsiveness of BCNU treated mice to phenobarbital (Pb) induction of hepatic microsomal mixed function oxygenase (MFO) activity was studied. BCNU (30 mg/kg ip) produced significant (P less than 0.05) decreases in cytochrome P-450, total ethylmorphine metabolism (TEM) and ethylmorphine N-demethylase (EMN) by 21 days after treatment. The specific activities of TEM and EMN were decreased more than was P-450 content. Benzpyrene hydroxylase (BPH) was increased and 7-ethoxycoumarin 0-deethylase (ECD) was unaffected at this time. Pb induction beginning on day 17 after BCNU treatment resulted in a greater inductive response in the BCNU treated mice than in controls. The specific activities of all MFO enzymes studied were more markedly affected than were the raw activities suggesting activation. However, the responsiveness of the MFOs to the actions of inhibitory was not markedly influenced by BCNU pretreatment.
Animals↗
Rapidly progressive, fatal pulmonary fibrosis induced by carmustine.
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Astrocytoma↗
Cure of hepatoma in rat with the nitrosourea carmustine (BCNU).
Two experiments were performed with a chemically induced hepatoma in the rat. In the first, tumors were inoculated subcutaneously into both flanks. After 10 days, when all rats had tumors, treatment was given intravenously on two successive days with 10 mg carmustine/kg body weight/day. All control rats displayed growing tumors and had to be killed 12 days after treatment. Treated rats initially lost weight with a slight increase in tumor size. After 3 weeks all tumors disappeared and the rats grew normally. After 4 months the rats were killed and had no tumors. In a second experiment, tumors were inoculated under the liver capsule. Treatment was given via the hepatic artery. Control rats had large tumors after 2 weeks and had to be killed. All treated rats were without tumors at sacrifice. One of them developed a liver cyst and was killed after 3 months, the others after 4 months.
Animals↗
Escalating dose of mitoxantrone with high-dose cyclophosphamide, carmustine, and etoposide in refractory lymphoma patients undergoing autologous bone marrow transplantation.
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Adult↗
Buthionine sulfoximine induction of gamma-L-glutamyl-L-cysteine synthetase gene expression, kinetics of glutathione depletion and resynthesis, and modulation of carmustine-induced DNA-DNA cross-linking and cytotoxicity in human glioma cells.
Glutathione (GSH) depletion by buthioninine sulfoximine (BSO) is being explored clinically as a means of enhancing the efficacy of cancer chemotherapy. We investigated the kinetics of GSH depletion and altered gamma-L-glutamyl-L-cysteine synthetase (gamma-GC-S) gene expression in two human malignant glioma cell lines, HBT5 and HBT28, and examined how these relate to GSH resynthesis and changes in DNA interstrand cross-link induction and cytotoxicity of 1,3-bis(2-chloroethyl)-nitrosourea (BCNU). GSH content was 54 and 126 nmol/mg/protein in HBT 5 and HBT 28, respectively, and after a 24-hr exposure to 100 microM BSO was decreased by 95% in HBT 5 and 91% in HBT 28. Basal gamma-GC-S enzyme activity in HBT 28 was twice that in HBT 5, and steady state gamma-GC-S gene transcripts were 2.6-fold higher in HBT 28 than in HBT 5, with no apparent amplification or rearrangement of the gene in either cell line. BSO exposure (100 microM) for 24 hr increased gamma-GC-S gene transcripts by 1.7-fold in HBT 5 and 2.8-fold in HBT 28. After BSO removal, the rate of GSH resynthesis in HBT 28 was twice that in HBT 5. Continuous BSO exposure increased the level of BCNU-induced DNA interstrand cross-links, and cytotoxicity was significantly higher in cells exposed continuously to BSO than in cells with only a 24-hr BSO preexposure. This increase was, however, greater in HBT 28 than in HBT 5. These findings indicate significant heterogeneity in the effects of BSO on gamma-GC-S gene expression and in the ability of BSO to sensitize tumors and cell lines to BCNU. The data also suggest that by preventing GSH resynthesis, a greater level of cytotoxicity is achieved with continuous BSO exposure than with BSO preexposure alone.
Antineoplastic Agents, Alkylating↗
High-dose carmustine, etoposide and melphalan ('BEM') with autologous stem cell transplantation: a dose-toxicity study.
We have investigated the toxicity of dose-escalation of BCNU, etoposide and melphalan ('BEM') chemotherapy with autologous stem cell transplantation in patients with haematological malignancies. Seventy-two patients with haematological malignancies were treated with BCNU (600 mg/m2, 450 mg/m2 or 300 mg/m2), etoposide 2 g/m2 and melphalan 140 mg/m2 followed by autologous bone marrow transplantation (ABMT), n = 51, or autologous peripheral blood progenitor cell transplantation (APBPCT), n = 21. Liver and pulmonary function was monitored pretransplant and at regular intervals post-transplant. Mucositis was graded daily during in-patient stay. There was a significantly higher incidence of symptomatic pulmonary toxicity in the patients who received BCNU at 600 mg/m2 than in the other two groups, and there was a significant increase in the incidence of asymptomatic decrease in carbon monoxide (KCO) in the patients who received BCNU 450 mg/m2. There was no significant difference between the three groups in the incidence and severity of mucositis or in the incidence of transiently abnormal liver function. We conclude that etoposide at 2 g/m2 can be used without unacceptable mucositis. BCNU at 600 mg/m2 is associated with an unacceptably high incidence of lung toxicity, but at 450 mg/m2 there is minimal symptomatic lung toxicity.
Adolescent↗
Poly(ADP-ribose) polymerase-independent potentiation of nitrosourea cytotoxicity by 3-aminobenzamide in human malignant glioma cells.
Poly(ADP-ribose) polymerase is a zinc-finger DNA-binding protein that detects specifically DNA strand breaks generated by genotoxic agents and is thought to be involved in DNA repair. Here, we examined the effects of 3-aminobenzamide, a poly(ADP-ribose) polymerase inhibitor, on the chemosensitivity of human malignant glioma cells. 3-Aminobenzamide selectively potentiated the cytotoxicity of the nitrosoureas, nimustine, carmustine and lomustine in 10 of 12 human malignant glioma cell lines. In contrast, 3-aminobenzamide did not modulate the cytotoxic effects of doxorubicine, teniposide, vincristine, camptothecin or cytarabine. The nitrosoureas did not induce poly(ADP-ribose) polymerase activity in the glioma cells. Ectopic expression of truncated poly(ADP-ribose) polymerase containing the poly(ADP-ribose) polymerase DNA-binding domain, which acts as a dominant-negative mutant, in LN-18 or LN-229 cells did not alter the 3-aminobenzamide effect on nitrosourea-mediated cytotoxicity. Thus, 3-aminobenzamide may target another nicotinamide adenine dinucleotide (NAD)-requiring enzyme, but not poly(ADP-ribose) polymerase, when enhancing nitrosourea cytotoxicity in human malignant glioma cells. Carmustine cytotoxicity was associated with a G2/M arrest. Coexposure to carmustine and 3-aminobenzamide overcame this G2/M arrest in T98G cells, which are sensitized to carmustine by 3-aminobenzamide, but not in U251MG cells, which are refractory to 3-aminobenzamide-mediated sensitization to carmustine. Thus, 3-aminobenzamide-mediated sensitization to carmustine cytotoxicity may result from interference with the stable G2/M arrest response to carmustine in human glioma cells.
Benzamides↗
[A prospective multi-centre study of the response of metastatic gastrointestinal tumours (author's transl)].
In a prospective, multi-centre, randomized study of 109 patients with metastatic gastro-intestinal adenocarcinomas the response rate, survival time and side-effects of two drug combinations, carmustin +5-fluorouracil and carmustin + ftorafur, were compared (same carmustin dosage in both groups). Response to the treatment was 32.7% in those receiving carmustin +5-fluorouracil, 26.3% in those on carmustin + ftorafur. This difference occurred among the 42 patients with gastric adenocarcinoma (33.3% compared with 25%), as well as in 11 with pancreatic adenocarcinoma, and in 56 with colorectal adenocarcinoma (32.1% and 28.6%). Median survival time for 5-fluorouracil + carmustin was 330 days, double that for ftorafur + carmustin (163 days). Bone-marrow toxicity (leukopenia, thrombopenia) was below 10% for both drug combinations. Alopecia occurred in only a few patients. Gastro-intestinal toxicity was common (20% and 18.5%, respectively), but there was no difference between the two groups. The somewhat lower effectiveness of ftorafur compared with 5-fluorouracil was probably due to the deliberately smaller dosage of the former.
Adenocarcinoma↗
Metabolism of a cholesterol-rich microemulsion (LDE) in patients with multiple myeloma and a preliminary clinical study of LDE as a drug vehicle for the treatment of the disease.
PURPOSE: Previously we have shown that cholesterol-rich microemulsions that bind to LDL receptors have the ability to concentrate in acute myeloid leukemia cells and in ovarian and breast carcinomas. Thus, LDE may be used as a vehicle for drugs directed against neoplastic cells. Indeed, we subsequently showed that when carmustine is associated with LDE the toxicity of the drug is significantly reduced in patients with advanced cancers. The aim of the present study was to verify whether LDE may be taken up by multiple myeloma cells and whether patients with multiple myeloma respond to treatment with LDE associated with carmustine. METHODS: A total of 131 consecutive volunteer patients with recently diagnosed multiple myeloma classified as clinical stage IIIA had their plasma lipid profile determined. LDE plasma kinetics were performed in 14 of them. Cell uptake of LDE and the cytotoxicity of carmustine associated with the emulsion were evaluated in a multiple myeloma cell line. A pharmacokinetic study of LDE-carmustine was performed in three patients. Finally, an exploratory clinical study of LDE-carmustine (carmustine dose 180 mg/m(2) body surface every 4 weeks) was performed in seven untreated multiple myeloma patients. RESULTS: LDL cholesterol was lower in the 131 multiple myeloma patients than in healthy controls and the fractional clearance rate (FCR, in units per minute) in the 14 multiple myeloma patients was twice that in 14 paired healthy control subjects. Moreover, entry of LDE into multiple myeloma cells was shown to be mediated by LDL receptors. Taken together, these findings indicate that LDE may target multiple myeloma. The exploratory clinical study showed that gammaglobulin decreased by 10-70% (mean 36%) after three cycles and by 25-75% (mean 44%) after six cycles. Furthermore, there was amelioration of symptoms in all patients. Cholesterol concentrations increased after treatment, suggesting that the treatment resulted in at least partial destruction of neoplastic cells with receptor upregulation. Side effects of the treatment were negligible. CONCLUSIONS: Because it targets multiple myeloma and, when associated with an antineoplastic agent, produces therapeutic responses in patients with fewer side effects, LDE has the potential for use as a drug vehicle in the treatment of the disease.
Adult↗
Comparison of ftorafur with 5-fluorouracil in combination chemotherapy of advanced gastrointestinal carcinoma.
The aim of the study was to compare the combination 5-FU-carmustine with ftorafur-carmustine in the treatment of advanced gastrointestinal cancer. To this end, a prospective, multicenter, randomized trial was initiated. Part I of this trial showed that similar response rates can be obtained with 5-FU-carmustine and ftorafur-carmustine in 109 patients (32.7% versus 26.3%). However, median survival was better in patients treated with 5-FU-carmustine (307 days versus 163 days). Part II of the trial revealed that neither a higher dosage of ftorafur (2 g/m2/day X 5 days) nor the addition of vincristine to both regimens changed the previously obtained results significantly. Again, median survival was found to be better in patients treated with 5-FU combination chemotherapy (304 days versus 144 days). Both the 5-FU and the ftorafur combination were tolerated reasonably well. The results suggest that combination chemotherapy including 5-FU is superior to ftorafur at the applied dosages in terms of survival.
Adult↗
Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group.
Chemotherapy for brain tumours has been limited because of difficulty in achieving adequate exposure to the tumour without systemic toxicity. We have developed a method for local sustained release of chemotherapeutic agents by their incorporation into biodegradable polymers. Implantation of the drug-impregnated polymer at the tumour site allows prolonged local exposure with minimal systemic exposure. We conducted a randomised, placebo-controlled, prospective study to evaluate the effectiveness of biodegradable polymers impregnated with carmustine to treat recurrent malignant gliomas. In 27 medical centres, 222 patients with recurrent malignant brain tumours requiring re-operation were randomly assigned to receive surgically implanted biodegradable polymer discs with or without 3.85% carmustine. Randomisation balanced the treatment groups for all of the prognostic factors examined. Median survival of the 110 patients who received carmustine polymers was 31 weeks compared with 23 weeks for the 112 patients who received only placebo polymers (hazard ratio = 0.67, p = 0.006, after accounting for the effects of prognostic factors). Among patients with glioblastoma, 6-month survival in those treated with carmustine-polymer discs was 50% greater than in those treated with placebo (mortality = 32 of 72 [44%] vs 47 of 73 [64%], p = 0.02). There were no clinically important adverse reactions related to the carmustine polymer, either in the brain or systemically. Interstitial chemotherapy delivered with polymers directly to brain tumours at the time of surgery seems to be a safe and effective treatment for recurrent malignant gliomas.
Biodegradation, Environmental↗
Stability and compatibility of antitumor agents in glass and plastic containers.
The stability of methotrexate, fluorouracil, cytarabine, dactinomycin, doxorubicin, bleomycin sulfate, mitomycin, mithramycin, vincristine sulfate, vinblastine sulfate, cyclophosphamide, dacarbazine, carmustine, and leucovorin calcium in underfilled plastic and glass administration containers was determined. Drugs were reconstituted according to manufacturers' instructions and added to 5% dextrose injection 50 ml in both polyvinyl chloride bags and glass partial-fill bottles. In addition, mitomycin was added to 0.9% sodium chloride injection 50 ml in both polyvinyl chloride bags and glass partial-fill bottles. All admixtures were stored at room temperature, not protected from light. Stability was determined over 24 hours (48 hours for doxorubicin and fluorouracil) by high-pressure liquid chromatography, except for cyclophosphamide (analyzed by mass spectrometry) and carmustine (analyzed by spectrophotometry). Methotrexate, leucovorin calcium, cytarabine, dactinomycin, mithramycin, vinblastine sulfate, cyclophosphamide, and dacarbazine were equally stable (10% or less change in concentration over 24 hours) in glass and plastic containers. Doxorubicin and fluorouracil were more stable in plastic containers than glass containers. The T90 value for doxorubicin in glass was 40 hours; there was no apparent decrease in plastic even after 48 hours. The T90 value for fluorouracil in glass was seven hours and in plastic, 43 hours. Vincristine sulfate, bleomycin sulfate, and carmustine were more stable in glass than plastic. The T90 value for vincristine sulfate in plastic was 10 hours. The T90 value for bleomycin sulfate in plastic was 0.7 hour. The T90 value for carmustine in plastic was 0.6 hour. Mitomycin dissolved in 0.9% sodium chloride injection was more stable in plastic. Mitomycin dissolved in 5% dextrose injection was not stable. Carmustine and bleomycin sulfate should be administered only in glass containers. Continuous infusions of doxorubicin and fluorouracil are more completely delivered from plastic containers. Mitomycin should not be dissolved in 5% dextrose injection.
Antineoplastic Agents↗
Temozolomide in combination with other cytotoxic agents.
Temozolomide (Temodar in the United States, Temodal globally; Schering Corporation, Kenilworth, NJ) has several characteristics that make it appealing for combination therapies: broad-spectrum antitumor activity, the ability to cross the blood-brain barrier, a good safety profile with nonoverlapping toxicities, an oral formulation, and the ability to overcome resistance to nitrosoureas. Preclinical and phase I trials have shown the additive or synergistic activity of temozolomide combined with carmustine against solid tumors, including malignant glioma, and the sequence-dependent effects of the combination. Toxicity is lower and the maximum tolerated dose is higher when carmustine is given before temozolomide. Studies also have examined the combination of temozolomide with the topoisomerase I inhibitor irinotecan (CPT-11), an alkaloid derivative of camptothecin that has shown activity against malignant glioma. Temozolomide followed by CPT-11 was more effective than either agent alone. A major issue facing investigators now is determining which of the several schedules of temozolomide and CPT-11 are optimal. Completed and ongoing studies of temozolomide in combination with carmustine, including polifeprosan carmustine implant (Gliadel wafers; Aventis Pharmaceuticals, Parsippany, NJ), and CPT-11 are described.
Antineoplastic Combined Chemotherapy Protocols↗
Intravenous cereport (RMP-7) enhances delivery of hydrophilic chemotherapeutics and increases survival in rats with metastatic tumors in the brain.
PURPOSE: The following experiments determined whether intravenous infusions of Cereport enhance delivery of chemotherapeutics and prolong survival in rats with metastatic tumors in the brain. METHODS: Autoradiography and scintillation were used to examine uptake of the lipophilic (paclitaxel and carmustine) and the hydrophilic (carboplatin) chemotherapeutic agents, as well as the large hydrophilic marker, 70 kDa dextran. Cereport was also tested in combination with the chemotherapeutic drugs carboplatin, vinorelbine, gemcitabine and carmustine to determine if Cereport could enhance the survival benefit beyond that provided by chemotherapy alone. RESULTS: Cereport enhanced the uptake of carboplatin and dextran, but not paclitaxel or carmustine. The pattern of Cereport's uptake effect with carboplatin revealed that Cereport selectively increased the proportion of highly permeable regions. Survival was significantly enhanced when Cereport was combined with either carboplatin, vinorelbine, or gemcitabine, but not carmustine, compared to each chemotherapeutic agent alone. CONCLUSIONS: These data provide the first evidence that Cereport, or any receptor-mediated approach intended to enhance the permeability of the blood-brain tumor barrier, can increase the delivery hydrophilic drugs to metastatic tumors in the brain, increasing survival in tumor-bearing rats.
Animals↗