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PubMed1997

Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study.

OBJECTIVE: To find out the effect of carmustine (bischloroethyl-nitrosourea) combined with a biodegradable polymer in the treatment of malignant (Grades III and IV) gliomas, applied locally, at the time of the primary operation. METHODS: Prospective, randomized double-blind study of an active treatment group versus a placebo group. Conducted at the Departments of Neurosurgery of the University Hospitals of Helsinki, Tampere, and Turku in Finland and Trondheim in Norway. The study consisted of 32 patients (16 in each treatment group) enrolled between March 23, 1992, and March 19, 1993. The study was planned to include 100 patients but had to be terminated prematurely, because the drug that was being used had become unobtainable. The main outcome measures included the survival times of patients after the operations and the application of an active drug or placebo. RESULTS: The median time from surgery to death was 58.1 weeks for the active treatment group versus 39.9 weeks for the placebo group (P = 0.012). For 27 patients with Grade IV tumors, the corresponding times were 39.9 weeks for the placebo group and 53.3 weeks for the active treatment group (P = 0.008). At the end of the study, six patients were still alive, five of whom belonged to the active treatment group. CONCLUSION: Carmustine applied locally in a biodegradable polymer at the time of primary operation, seems to have a favorable effect on the life span of patients with high-grade gliomas.

Adult↗
PubMed1994

Phase I trial of dacarbazine with cyclophosphamide, carmustine, etoposide, and autologous stem-cell transplantation in patients with lymphoma and multiple myeloma.

PURPOSE: We investigated the feasibility of escalating doses of dacarbazine (DTIC) in combination with high-dose cyclophosphamide, carmustine, and etoposide (CBV) given with autologous stem-cell transplantation in 33 patients with relapsed or refractory lymphoma or multiple myeloma. PATIENTS AND METHODS: Eligible patients were treated in this phase I study with cyclophosphamide (7.2 g/m2), carmustine (BCNU) (600 mg/m2), etoposide (2.4 g/m2), and escalating doses of DTIC (3,000 to 6,591 mg/m2) administered either as a 2- (in 23 patients) or a 6- (in 10 patients) hour infusion to determine the maximum-tolerated dose (MTD) of DTIC and the toxicity profile of this combination. RESULTS: The MTD of DTIC infused over 2 hours and given with the CBV regimen was 3,900 mg/m2, with the dose-limiting toxicity being hypotension. Seven patients experienced transient acute hypocalcemia in association with the DTIC infusion. Prolonging the DTIC infusion to 6 hours or administration of supplemental calcium did not allow further dose escalation of DTIC to occur. Other non-hematologic toxicities observed with this regimen have been reported with CBV alone. Of 25 patients assessable for tumor response at first evaluation posttransplant, 13 (52%) were in complete remission (CR), four (16%) were in partial remission (PR), five (20%) had stable disease (SD), and three (12%) had progressive disease (PROG). Of 31 patients assessable for relapse-free survival, 22 are alive with 13 in CR, one in PR, two with SD, and six with PROG at a median follow-up duration of 313 days (range, 35 to 749+). Treatment-related mortality occurred in six patients (18%). CONCLUSION: The feasibility of combining DTIC in high doses with the CBV regimen has been demonstrated. Dose-limiting hypotension is transient and reversible when DTIC is administered at 3,900 mg/m2 with CBV. Future trials to evaluate the effect of the addition of DTIC to the CBV regimen on response rate and relapse-free survival are encouraged.

Adolescent↗
PubMed1999

Prospective randomized trial of melphalan and prednisone versus vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of primary systemic amyloidosis.

PURPOSE: Primary systemic amyloidosis is an immunoglobulin deposition disorder in which insoluble light chains cause organ dysfunction and death. The established conventional therapy is treatment with melphalan and prednisone. We investigated whether treatment with multiple alkylating agents improved the response rate or survival time, compared with melphalan and prednisone therapy. PATIENTS AND METHODS: We treated 101 patients with biopsy-proven primary amyloidosis. The patients were randomly assigned to receive melphalan and prednisone (52 patients) or vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (49 patients). Patients were stratified according to the presence of cardiac involvement, time from diagnosis to randomization, serum beta2-microglobulin level, and whether peripheral neuropathy was the major manifestation of the disease. RESULTS: The median duration of survival after randomization was 29 months, with no differences in survival time between the two groups. There were 29 patients who fulfilled the response criteria: 15 in the vincristine, carmustine, melphalan, cyclophosphamide, and prednisone arm and 14 in the melphalan and prednisone arm. CONCLUSION: Therapy with multiple alkylating agents did not result in a higher response rate or longer survival time, compared with standard melphalan and prednisone treatment in patients with primary systemic amyloidosis.

Adult↗
PubMed1993

Carmustine toxicity presenting as a lobar infiltrate.

Carmustine is a chemotherapeutic agent frequently employed in the treatment of malignant brain tumors. The side effect of pulmonary fibrosis occurs in 20 to 30 percent of patients receiving this drug. Herein we report a case of presumed carmustine-induced pulmonary fibrosis occurring with an unusual lobar distribution.

Adult↗
PubMed2000

Dexamethasone, carmustine, etoposide, cytarabine, and melphalan (dexa-BEAM) followed by high-dose chemotherapy and stem cell rescue--a highly effective regimen for patients with refractory or relapsed indolent lymphoma.

We performed a phase II study to determine the efficacy of maximal cytoreductive therapy with up to five cycles of Dexa-BEAM (dexamethasone, carmustine [BCNU], etoposide, cytarabine, and melphalan) followed by high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) for patients with advanced relapsed or refractory indolent lymphoma. Thirty-two patients with primary refractory or relapsed indolent lymphoma were treated with the Dexa-BEAM regimen. Thirteen patients had primary refractory disease, 4 patients partial remission, and 15 patients first or subsequent relapse. Patients achieving PR or CR received HDCT with ASCT. The conditioning regimen used was BEAM (carmustine [BCNU], etoposide, cytarabine, and melphalan). Twenty-two patients responded to Dexa-BEAM resulting in a response rate of 78%. Maximum response was observed after 3.2 (range 2-5) courses. One patient with progressive disease died in septic shock during neutropenia. Nineteen patients with partial or complete remission after Dexa-BEAM received HDCT. Hematopoietic stem cells (HSC) were collected after two cycles of Dexa-BEAM. The median number of CD34+ HSC reinfused was 3.1 x 10(6)/kg (range 1.6-8.2 x 10(6)/kg). There was no transplantation-related death. All patients receiving HDCT achieved complete remission. Overall survival (OS) and freedom from treatment failure (FFTF) for all patients are estimated to be 68% and 65% at two years, respectively. With a mean follow-up of 20 months (range 8-42 months), 16/19 patients receiving HDCT are in continuous complete remission. The Dexa-BEAM regimen is effective in overcoming drug resistance in patients with indolent lymphoma who failed to respond to conventional treatment or who relapsed. The CR rate of 100% of those patients receiving HDCT and ASCT after maximal cytoreductive treatment with Dexa-BEAM suggests the use of HDCT at the time of maximal response.

Adult↗
PubMed1990

Carmustine augments the effects of tert-butyl hydroperoxide on calcium signaling in cultured pulmonary artery endothelial cells.

The effects of oxidant stress and inhibition of glutathione reductase on the bradykinin-stimulated changes in cytosolic free Ca2+ concentration ([Ca2+]i) of calf pulmonary artery endothelial cells were determined using the intracellular fluorescent probe, fura-2. Changes in [Ca2+]i upon stimulation with bradykinin were measured after incubation of cells with the chemical oxidant tert-butyl hydroperoxide (0.4 mM) for various times. After 60 min, bradykinin-stimulated Ca2+ influx was significantly decreased. With more prolonged incubations with the peroxide, bradykinin had little effect on cytosolic calcium concentration. Preincubation of cells with the glutathione reductase inhibitor, carmustine, led to elevated basal [Ca2+]i, yet the cells remained responsive to bradykinin. However, incubation of carmustine-treated cells with tert-butyl hydroperoxide for 30 min dramatically reduced both bradykinin-stimulated release of Ca2+ from internal stores and influx of Ca2+ from the extracellular space. These results suggest that inhibition of glutathione reductase alters cytosolic Ca2+ homeostasis and enhances the effects of oxidative stress on signal transduction in vascular endothelial cells.

Animals↗
PubMed1987

High-dose carmustine with autologous bone marrow transplantation for the adjuvant treatment of high-grade gliomas of the central nervous system.

The long-term survival of patients with high-grade gliomas of the CNS is poor despite the use of radiation therapy and chemotherapy. In an attempt to improve the survival of such patients, we administered adjuvant chemotherapy as high-dose carmustine with autologous bone marrow transplantation. Eighteen patients, 15 with glioblastoma multiforme and three with anaplastic astrocytoma, were treated shortly after completion of standard radiation therapy. One course of carmustine was administered at a total dose of 900-1050 mg/m2 iv over 3 days followed in 3 days by the reinfusion of the previously cryopreserved bone marrow. Acute toxicity was mild, but eight patients had severe pulmonary or CNS toxicity of which four episodes of pulmonary toxicity were fatal. For all patients treated, the median survival was 17.5 months from diagnosis and the estimated probability of surviving greater than 27 months was 22% (95% confidence limits of 14%-32%). Presently, there are four long-term survivors, two with progressive tumor, one suffering from severe encephalomyelopathy, and one alive and well. Although, in this series, we have observed long-term survivors, the overall estimated probability of survival is not substantially different from conventional treatment. In addition, the 22% incidence of fatal pulmonary toxicity suggests that this treatment will not measurably add to the treatment of CNS gliomas.

Adult↗
PubMed1983

Treatment of five subcutaneous human glioma tumor lines in athymic mice with carmustine, procarbazine, and mithramycin.

Five human glioma tumor lines were transplanted subcutaneously in athymic nude mice. Three of the lines (D-54 MG, U-118 MG, and U-251 MG) were derived from permanent human glioma cell lines, while the other two lines (N-456 and N-519) were established as direct xenografts in mice. Growth rates varied among the lines, but all were treated at a common average tumor volume of 200-300 mm3. Three drugs of known clinical activity against human anaplastic glial tumors were tested in this system. Procarbazine (PCB) produced significant responses in all five tumor lines, carmustine produced significant growth delays in two, and mithramycin produced a slight growth delay in only one. A carmustine-PCB combination produced a greater therapeutic effect than either agent alone against D-54 MG, but the combination was no more effective than PCB alone against U-118 MG. These results parallel clinical experience and indicate that this is a useful model for testing agents of potential activity in brain tumor therapy.

Animals↗
PubMedDate not supplied

Vindesine, carmustine, doxorubicin, and prednisone (EBAP) in recurrent lymphomas: a Southwest Oncology Group study.

Seventy-eight patients with Hodgkin's disease and non-Hodgkin's lymphoma who had failed prior chemotherapy or radiation therapy were treated with a combination of vindesine, carmustine, doxorubicin, and prednisone (EBAP). Outpatient therapy was administered at 21-day intervals. Complete and partial responses were seen in 32 patients (41%). The response rate was higher for Hodgkin's disease (59%) than for non-Hodgkin's lymphoma (31%). The median duration of response was 31 weeks in both groups, with a median survival of all patients of 35 weeks (responders, 122 weeks; nonresponders, 16 weeks). Myelotoxicity was greater using EBAP than in the earlier reported program with vincristine, carmustine, doxorubicin, and prednisone, and in the absence of higher response rates does not support the use of vindesine over vincristine in combination programs using nitrosoureas, anthracyclines, and prednisone.

Adolescent↗
PubMed1982

Potentiation of carmustine-cranial irradiation-induced myelosuppression by cimetidine.

In nine patients with glioblastomas, the histamine H2-receptor antagonist cimetidine was found to augment the myelosuppressive activities of carmustine and cranial irradiation. The nadir in neutrophil cell counts in this group averaged 650 +/- 220/microL. In a comparable series of 31 patients who did not receive cimetidine, the lowest neutrophil cell count averaged 2,160 +/0 240/microL. Further, marked suppression of these cells in the patients receiving cimetidine extended through day 42 of the treatment cycle. By contrast, the patients treated with carmustine and cranial irradiation alone did not experience significant neutropenia. This suggests that cimetidine may enhance the myelosuppressive effects of cytotoxic therapy.

Adult↗
PubMed1994

Carmustine, Ara C, cyclophosphamide and etoposide with autologous bone marrow transplantation in relapsed or refractory lymphoma: a dose-finding study.

The purpose of this study was to define the dose-limiting non-hematologic toxicity of carmustine, Ara C, cyclophosphamide and etoposide (BACE). Between October 1986 and March 1990, 37 patients with relapsed or refractory lymphoma received escalating doses of combination chemotherapy followed by autologous bone marrow transplant (ABMT). Twenty patients with Hodgkin's disease (HD) and 17 patients with intermediate or high grade non-Hodgkin's lymphoma (NHL) initially received conventional-dose therapy with either a 7 week course of modified MACOP-B or a single dose of cyclophosphamide (CY) at 2 g/m2 depending on prior therapy and response. Regardless of response, patients then received escalating doses of BACE, toxicity permitting. Ten patients obtained complete responses (CR) and 12 patients were partial responders (PR), CR+PR (75%) with modified MACOP-B and 7 (64%) patients obtained PR with CY. The maximum-tolerated dose (MTD) for BACE was determined to be carmustine 700 mg/m2, Ara C 1500 mg/m2, CY 150 mg/kg and etoposide 1500 mg/m2. When Ara C was escalated from 1500 mg/m2 to 3000 mg/m2 holding the other drugs at the prior doses, the next two patients died secondary to diffuse alveolar damage. Overall and event-free survivals are identical with 14 of 37 patients (38%) alive with a median follow-up of 61 months (range 38-79 months). Ten patients were treated at the MTD, none of whom died a toxic death and 3 (30%) are alive with a median follow-up of 42 months (range 38-52 months). We defined the MTD and BACE showing pulmonary toxicity to be the dose-limiting non-hematologic toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2000

Comparative effects of (SBE)7m-beta-CD and HP-beta-CD on the stability of two anti-neoplastic agents, melphalan and carmustine.

The purpose of this study was to evaluate and compare the potential use of two parenterally safe beta-cyclodextrins derivatives, (SBE)7m-beta-CD and HP-beta-CD, as solubilizers and stabilizers for melphalan and carmustine, two very unstable antineoplastic agents. Phase solubility and chemical stability of the compounds in the presence of the cyclodextrins were studied. UV, fluorescence, and several NMR techniques were used to probe the potential causes for the differences observed. The phase solubility method was found to provide only qualitative data on the binding of melphalan to the cyclodextrins since rapid degradation and the presence of products of degradation complicated the interpretation of the results. Qualitatively, however, the solubilizing potential was similar for the two cyclodextrins. The chemical stability studies indicate that both of the drugs had similar binding constants for both cyclodextrins; however, the intrinsic reactivities in the complexes were significantly lower with (SBE)7m-beta-CD than for HP-beta-CD. The main cause for this distinct difference appeared to correlate with differences in the site of binding and the polarity of the binding site.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1991

High-dose carmustine and autologous bone marrow reinfusion in the treatment of refractory or relapsed small cell lung carcinoma.

Fourteen patients with small cell carcinoma of the lung in relapse or with disease refractory to chemotherapy were treated with carmustine (BCNU) at doses of 600 to 1000 mg/m2 intravenously followed by autologous bone marrow transplantation. All patients previously were treated with cyclophosphamide, doxorubicin, vincristine, and etoposide. Seven of the 14 patients responded to the high-dose BCNU (50% response with 95% confidence limits ranging from 23% to 77%). Three patients had a complete response, and four had a partial response. Regrowth of tumor occurred within 60 days of treatment in the responding patients. Death occurred in six patients before the recovery of the platelet count to 50,000 cells/microliters. Although the response rate was high, the toxicity was excessive. In the dosage range of 600 to 1000 mg/m2 in heavily pretreated patients, BCNU is not recommended, but additional investigation may be warranted in patients with central nervous system metastases who previously were treated with radiation therapy.

Adult↗
PubMed2001

A phase III study of radiation therapy plus carmustine with or without recombinant interferon-alpha in the treatment of patients with newly diagnosed high-grade glioma.

BACKGROUND: The current study was conducted to determine whether the addition of interferon-alpha (IFN-alpha) to treatment with radiation therapy and carmustine (BCNU) improves time to disease progression or overall survival in patients with high-grade glioma. METHODS: Patients with anaplastic astrocytoma, anaplastic oligoastrocytoma, glioblastoma multiforme, or gliosarcoma received radiation therapy plus BCNU as initial therapy. Subsequently, patients without tumor progression at the completion of radiation therapy were stratified by age, extent of surgery, tumor grade and histology, Eastern Cooperative Oncology Group performance status, and treating institution, and then were randomly assigned to receive either BCNU alone (200 mg/m(2) on Day 1) or BCNU (150 mg/m(2) on Day 3) plus IFN--alpha (12 million U/m(2) on Days 1-3, Weeks 1, 3, and 5) every 7 weeks for a maximum of 6 cycles. RESULTS: Of the 383 patients enrolled in the study, 275 eligible patients were randomized. There was no significant difference with regard to time to disease progression or overall survival between the two groups. Patients receiving IFN-alpha experienced more fever, chills, myalgias, and neurocortical symptoms including somnolence, confusion, and exacerbation of neurologic deficits. Cox multivariate regression models confirmed known favorable prognostic variables including younger age, Grade 3 tumor (according to World Health Organization criteria), and greater extent of surgery. Cox and classification and regression tree analysis models also demonstrated that a normal baseline Folstein mini-mental status examination (MMSE) score was associated with better prognosis. CONCLUSIONS: IFN-alpha does not appear to improve time to disease progression or overall survival in patients with high-grade glioma and appears to add significantly to toxicity. The baseline MMSE score may serve as an independent prognostic factor and warrants further investigation.

Adult↗
PubMed2005

Combined chemotherapy with carmustine, doxorubicin, etoposide, vincristine, and cyclophosphamide plus mitoxantrone, cytarabine and methotrexate with citrovorum factor for the treatment of aggressive non-Hodgkin lymphoma: a long-term follow-up study.

BACKGROUND: The standard treatment for patients with aggressive non-Hodgkin lymphoma (NHL) is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Since 1989, the authors have used a new chemotherapy regimen with combined carmustine, doxorubicin, etoposide, vincristine, and cyclophosphamide plus mitoxantrone, cytarabine and methotrexate with citrovorum factor called BAVEC-MiMA. The objective of the current study was to explore, after a long follow-up period, the impact of this third-generation regimen for the treatment of aggressive NHL. METHODS: One hundred and one consecutive patients (median age, 41 years) with either B-cell (n=94 patients) or non-B-cell (n=7 patients), aggressive lymphoma were diagnosed and treated between 1989 and 1999 with the BAVEC-MiMA regimen. RESULTS: The complete response rate was 74%, and the overall response rate was 89%. Eleven patients with refractory disease died rapidly after a median period of 5 months. The major toxicity was Grade 4 neutropenia (according to World Health Organization criteria), which was observed in 15 patients (15%). There were four toxicity-related deaths. The overall survival rate was 63% at 9 years. In multivariate analysis, factors that were associated with advantage in overall survival were response to induction therapy, bulky disease, and high score on the International Prognostic Index (IPI). The disease-free survival rate was 77% at 9 years. In multivariate analysis, the IPI was the most important variable for the definition of disease-free survival. CONCLUSIONS: The BAVEC-MiMA regimen was feasible on an outpatient basis, it was tolerated well, and it showed a low toxicity-related mortality. The long follow-up in patients with NHL, which is a rapidly fatal disease, led the authors to observe that, with this regimen, a cure was obtained in > 50% of patients who had low-risk or low-to-intermediate-risk, aggressive NHL.

Adolescent↗
PubMed2006

Similar response rates and superior early progression-free survival with gemcitabine, dexamethasone, and cisplatin salvage therapy compared with carmustine, etoposide, cytarabine, and melphalan salvage therapy prior to autologous stem cell transplantation for recurrent or refractory Hodgkin lymphoma.

BACKGROUND: The objective of this study was to compare the response rates, ability to mobilize autologous hematopoietic (peripheral blood) stem cells (PBSCs), and progression-free survival (PFS) after second-line chemotherapy with either gemcitabine, dexamethasone, and cisplatin (GDP) or carmustine, etoposide, cytarabine, and melphalan (mini-BEAM) followed by high-dose therapy and hematopoietic stem cell transplantation (ASCT) for patients with recurrent or refractory Hodgkin lymphoma. METHODS: The outcomes of 68 consecutive patients who were referred for salvage therapy (34 patients received mini-BEAM, and 34 patients received GDP) were compared retrospectively. Patients received mini-BEAM as inpatient treatment every 3-4 weeks, whereas GDP was administered on an outpatient basis every 3 weeks. Responding patients proceeded to stem cell mobilization, followed by high dose etoposide and melphalan, and ASCT. Patients who had disease bulk at recurrence that measured > 5 cm received involved-field radiation post-ASCT. RESULTS: The response rate to GDP prior to ASCT (complete responses, unconfirmed complete responses, and partial responses) was 62% (95% confidence interval [95% CI], 45-78%) compared with 68% (95% CI, 52-83%) for mini-BEAM (P = 0.61). After mobilizing chemotherapy, the proportion of patients for whom the target PBSC number of > or = 5 x 10(6) CD34-positive cells/kg was obtained was 97% after GDP and 57% after MB (P = 0.0003). More patients completed collection with a single apheresis procedure after GDP than after mini-BEAM (73% vs. 36%; P = 0.004), and fewer patients in the GDP group required bone marrow harvesting to proceed to ASCT. After a median follow-up of 1.8 years after ASCT, PFS was significantly better for patients who received GDP compared with patients who received mini-BEAM (74% vs. 35% at 1.5 yrs, respectively; P = 0.005). Overall survival at 1.5 years was 91% after GDP and 82% after mini-BEAM (P = 0.23). CONCLUSIONS: Although this was a retrospective analysis, response to GDP and early PFS after ASCT compared favorably with mini-BEAM salvage chemotherapy. Based on these data, the authors believe that a Phase III trial comparing GDP with mini-BEAM or other platinum-containing regimens is warranted.

Adult↗
PubMed1989

H2-antagonists and carmustine.

The highly metabolized nitrosourea carmustine (BCNU) is an anticancer agent which alkylates DNA and is metabolized to both active and inactive species by cytochrome P-450 enzymes. Other highly metabolized anticancer drugs have altered toxicities when some histamine H2 antagonists are coadministered. To test this hypothesis with BCNU, DBA/2J male mice were given a single injection of cimetidine (CMT 100 mg/kg) or ranitidine (RNT 25 mg) at various times up to 30 min before, or up to 60 min after a BCNU injection. Spleen colony assays for normal bone marrow stem cell viability showed enhanced toxicity for BCNU when CMT was administered concomitantly. In P-388 leukemia-bearing DBA/2J mice, both CMT and RNT significantly enhanced the antitumor effects of BCNU doses of 30 mg/kg. Pharmacokinetic analyses of BCNU elimination in Cd-1 mice showed marked prolongation of BCNU elimination and increased (BCNU concentration) x time products when CMT was concomitantly administered. These results demonstrate that enhanced BCNU bone marrow toxicity and antitumor activity is produced by CMT. The effect appears to be related to impaired drug clearance when the two agents are administered concurrently. RNT slightly enhanced BCNU antileukemic effects, but it did not significantly alter BCNU myelotoxicity nor drug elimination patterns.

Animals↗
PubMed1994

Effect of pharmacologic doses of zinc on the therapeutic index of brain tumor chemotherapy with carmustine.

To evaluate the potential differential effect of pretreatment with pharmacologic doses of the trace element zinc on the chemosensitivity of glioma cells and bone marrow cells for carmustine (BCNU), we performed in vitro and in vivo studies of zinc toxicity as well as of the combined treatment with zinc and the anticancer drug. We studied the in vitro effects on established human and rat glioma cell lines using a microcolorimetric growth assay and on murine bone marrow using a clonogenic assay for committed progenitor cells of the granulocyte-monocyte lineage. Zinc exposures of up to 100 microM for 120 h did not influence the growth of six of seven human glioma cell lines. Only U87MG demonstrated statistically significant toxicity during high zinc exposure (100 microM over 120 h). Dose-response growth curves generated for BCNU did not show protection against the anticancer agents by a 48-h pretreatment with different zinc concentrations. The clonogenic capacity of bone marrow cells was slightly reduced by in vitro culture for 24 and 48 h. Although this effect appeared to be more prominent in the presence of zinc supplementation, overall a statistically significant inhibition was seen only after exposure to a concentration of 100 microM zinc over 48 h. As compared with chemotherapy alone, in vitro pretreatment with 50 microM zinc over 48 h followed by chemotherapy resulted in an increased number of colony-forming unit-granulocyte monocyte (CFU-GM): CFU-GM increased by a factor of 2 for BCNU (60 microM x 2 h). This statistically significant in vitro chemoprotection would translate into a dose-protection factor of 1.5, i.e., for the same level of myelosuppression, zinc pretreatment would allow administration of a 50% increased dose of BCNU. The in vivo studies were performed in an s.c. xenograft model of the human glioma cell line U87MG in athymic mice. The maximal tolerable pretreatment with zinc was determined to be a 10-day course of daily i.p. injections of 10 mg/kg ZnCl2. The subsequent i.p. administration of the dose lethal to 10% of the mice (LD10) and of a 1.5 x LD10 dose of BCNU resulted in less bone marrow toxicity in pretreated animals than in non-zinc-pretreated mice as determined in a CFU-GM assay. Glioma colony-forming efficiency (CFE) assays, on the other hand, did not show any zinc-related difference in the BCNU sensitivity of U87MG.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗