Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Carmustine”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 469 records · Page 26Linked to original sources
PubMed2003

BCNU-loaded poly(D, L-lactide-co-glycolide) wafer and antitumor activity against XF-498 human CNS tumor cells in vitro.

Implantable polymeric device that can release chemotherapeutic agent directly into central nervous system (CNS) has had an impact on malignant glioma therapy. The purpose of our study was to develop an implantable polymeric device, which can release intact 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) for long-term period over 1 month, and to evaluate its cytotoxicity against XF 498 human CNS tumor cells in vitro. BCNU was incorporated into biodegradable poly(D,L-lactide-co-glycolide) (PLGA), by using spray-drying method. BCNU-loaded PLGA microparticles were characterized by scanning electron microscopy (SEM), powder X-ray diffraction, and differential scanning calorimetry. SEM observation of the microparticles showed that the microparticles were spherical, i.e. microspheres. Homogeneous distribution of BCNU in PLGA microsphere was confirmed by significant reduction of crystallinity of BCNU. Microspheres were fabricated into wafers with flat and smooth surface by direct compression method. In vitro release of BCNU in pH 7.4 phosphate buffered saline was prolonged up to 8 weeks after short initial burst period. Antitumor activity of BCNU-loaded PLGA wafer against XF 498 human CNS tumor cells continued over 1 month and, PLGA only did not affect the growth of the cells. Meanwhile, the cytotoxic activity of BCNU powder disappeared within 12 h. These results strongly suggest that the BCNU/PLGA formulations increase release period of carmustine in vivo and also be useful in the development of implantable polymeric device for malignant glioma.

Antineoplastic Agents, Alkylating↗
PubMed2000

The role of reduced glutathione and glutathione reductase in the cytotoxicity of chromium (VI) in osteoblasts.

It is accepted that to exert cytotoxicity and carcinogenicity chromium VI has to be reduced inside cells. The role of reduced glutathione (GSH) and glutathione reductase in the intracellular reduction of Cr VI was investigated using an immortalized rat osteoblast cell line, FFC. Alkaline phosphatase activity was the index of cytotoxicity measured. To investigate the role of GSH in Cr VI toxicity, GSH levels in the cells were elevated by pretreatment with L-cysteine, and depleted using buthionine sulfoximine (BSO), an inhibitor of GSH synthesis. Intracellular GSH levels were not depleted during the metabolism of Cr VI. Depletion of GSH by BSO caused the cells to be more resistant to the toxicity of Cr VI, indicating that GSH is involved in reduction of the Cr VI. Inhibition of glutathione reductase by carmustine (BCNU) partially protected against the cytotoxicity of Cr VI irrespective of the intracellular GSH. The cytotoxic response was similar if cells were pretreated with BCNU plus L-cysteine, or with BCNU plus BSO, although the GSH levels were markedly different. The results indicate that glutathione reductase plays an important role in the intracellular reduction of Cr VI in osteoblasts.

Alkaline Phosphatase↗
PubMed1998

A retrospective study of the value of chemotherapy as adjuvant therapy to surgery and radiotherapy in grade 3 and 4 gliomas.

The aim of this retrospective study was to evaluate the effect of adjuvant chemotherapy among patients < 55 years of age with anaplastic gliomas (historical grade 3, n = 85) with four cycles 4 weeks apart of 160 mg carmustine (BCNU) infused into the internal carotid artery, combined with vincristine 2 mg and procarbazine 50 mg x 3 for 1 week (i.a.BCNU-PV) versus no adjuvant chemotherapy. In glioblastomas (histological grade 4, n = 257) the same chemotherapy was evaluated versus two cycles 4 weeks apart of 160 mg lomustine (CCNU) orally instead of BCNU, combined with vincristine and procarbazine (PCV) versus no chemotherapy. All patients in both groups received radiotherapy. Among glioblastoma patients < 55 years of age there was a significant (P = 0.03), but moderately increased survival in the i.a.BCNU-PV group versus the two other arms that did not differ from each other. This difference could be explained by an uneven distribution of prognostic factors, especially age group (< 50 years versus 50-54 years) in favour of the i.a.BCNU-PV group. In anaplastic gliomas, the median survival in the i.a.BCNU-PV group was 80 months versus 25 months for the no chemotherapy arm (P = 0.004). No significant differences in the distribution of prognostic factors were found between the two therapy arms. We suggest that the role of adjuvant chemotherapy in glioblastomas is unclear, while i.a.BCNU-PV as adjuvant chemotherapy among patients < 55 years of age and with anaplastic gliomas increased survival markedly.

Administration, Oral↗
PubMed2000

Transplantation of highly purified CD34+Thy-1+ hematopoietic stem cells in patients with metastatic breast cancer.

We report here the transplantation of extensively purified "mobilized" peripheral blood CD34Thy-1 hematopoietic stem cells from 22 patients with recurrent or metastatic breast cancer. Patients were mobilized with either high-dose granulocyte colony-stimulating factor (G-CSF) alone or cyclophosphamide plus G-CSE Median purity of the stem cell product at cryopreservation was 95.3% (range, 91.1%-98.3%), and viability was 98.6% (range, 96.5%-100%). After high-dose chemotherapy with carmustine, cisplatin, and cyclophosphamide, CD34+Thy-1 cells at a median dose of 11.3 x 10(5) per kilogram (range, 4.7-163 x 10(5) per kilogram) were infused. No infusion-related toxicity was observed. Neutrophil recovery was prompt, with median absolute neutrophil count >500/microL by day 10 (range, 8-15 days) and >1000/microL by day 11 (range, 8-17 days). Median platelet recovery (>20,000/microL) was observed by day 14 (range, 9-42 days) and >50,000/microL by day 17 (range, 11-49 days). Tumor cell depletion below the limits of detection of a sensitive immunofluorescence-based assay was accomplished in all patients who had detectable tumor cells in apheresis products before processing. Although CD4+ T-cell reconstitution was slow, no unusual infections were observed. Neither early nor late graft failure was observed, and no patient required infusion of unmanipulated backup cells. At a median follow-up of approximately 1.4 years and a maximum follow-up of 2.5 years, 16 of the 22 patients remain alive, with 9 free of disease progression, and have stable blood counts. In summary, highly purified CD34+Thy-1+ cells used as the sole source of the hematopoietic graft result in rapid and sustained hematopoietic engraftment.

Adult↗
PubMed2000

Four-cycle high-dose therapy with hematopoietic support for metastatic breast cancer: no improvement in outcomes compared with single-course high-dose therapy.

Multiple-cycle high-dose therapy with autologous hematopoietic progenitor cell (AHPC) support has been used to deliver dose-intensive therapy. We have used this approach as well as single-cycle high-dose therapy in treating patients with metastatic breast cancer. We present the outcomes of multiple-cycle high-dose therapies and compare them with those resulting from single-course high-dose therapies performed at a single institution. Fifty-five patients received 4 cycles of intensive chemotherapy with AHPC support. Three multicycle regimens were sequentially applied. Twenty patients were enrolled to receive 4 cycles of high-dose mitoxantrone, thiotepa, and cyclophosphamide. Nineteen subsequent patients received this regimen modified by the incorporation of paclitaxel. Sixteen patients received 2 cycles of high-dose melphalan, thiotepa, and paclitaxel and 2 cycles of mitoxantrone, thiotepa, and paclitaxel. The results of all 3 multiple-cycle therapies are compared with those of 55 contemporaneous patients with metastatic breast cancer who received a single course of high-dose cyclophosphamide and thiotepa or cyclophosphamide, cisplatin, and BCNU (carmustine) with hematopoietic cell rescue. Multiple-cycle therapy was associated with more infectious complications, increased transfusion requirements, and increased hospital admissions. However, there were no significant differences in outcomes between the groups. For 55 patients who received multiple-cycle therapy, the actuarial 3-year overall survival rate was 36% (95% confidence interval [CI] 23%-49%); freedom from progression and event-free survival were both 15% (CI 5%-25%). The median time to disease progression and median survival were 1.0 and 1.6 years, respectively. For the 55 patients who underwent a single course of high-dose therapy, the 3-year overall survival was also 36% (CI 18%-54%), whereas freedom from progression and event-free survival were both 19% (CI 7%-31%). The median time to progression and median survival were 0.8 and 2.2 years, respectively. Within the constraints of this patient population, the outcomes of 4 cycles of high-dose therapy with AHPC support were not superior to those resulting from single courses of high-dose therapy in the treatment of patients with metastatic breast cancer.

Adjuvants, Pharmaceutic↗
PubMed2003

The value of augmented preparative regimens combined with an autologous bone marrow transplant for the management of relapsed or refractory Hodgkin disease: a Southwest Oncology Group phase II trial.

Several single-institution pilot studies have suggested that augmented preparative regimens, including those containing total body irradiation combined with an autologous bone marrow transplantation, are superior to standard regimens for the treatment of relapsed or refractory Hodgkin disease. On the basis of these data, we undertook, in the cooperative group setting, a phase II trial of augmented preparative regimens for patients experiencing treatment failure with conventional chemotherapy. Eighty-one patients with either sensitive or refractory (induction failures or chemoresistant) relapse received etoposide (60 mg/kg), cyclophosphamide (100 mg/kg), and either total body irradiation (12 Gy) or, if previously irradiated, carmustine (15 mg/kg), followed by an autologous bone marrow transplantation. Progression-free (PFS) and overall (OS) survival were estimated, and a Cox regression model was used to assess potential prognostic variables. The 5-year PFS and OS for the 74 eligible patients treated at 20 Southwest Oncology Group centers were 41% (95% confidence interval [CI], 29%-53%) and 54% (95% CI, 43%-65%), respectively, despite a median remission after initial chemotherapy of only 6 months. The 3-year OS for those whose induction therapy failed was 72% (95% CI, 52%-93%). There was 1 (1.4%) early treatment-related death, 2 late deaths due to lung toxicity, and only 1 death due to myelodysplasia. There were no differences in PFS or OS on the basis of regimen or chemosensitivity. A Cox prognostic factor analysis determined that >2 prior regimens, relapse in a radiated field, and extranodal disease were adverse prognostic factors. Among the 46 patients who received prior radiotherapy, the 5-year OS was 38% (95% CI, 14%-61%) for patients with 2 or 3 adverse factors, versus 60% (95% CI, 42%-78%) for those with 0 factors or 1 adverse factor. Augmented preparative regimens seem promising for the treatment of relapsed or refractory Hodgkin disease, without an increase in regimen-related mortality. A poor-prognosis group was identified that should be treated with novel therapies.

Adolescent↗
PubMed2000

Treatment of cutaneous T-cell lymphomas.

Primary cutaneous T-cell lymphomas (CTCL), representing a heterogeneous group of non-Hodgkin's lymphomas (NHL), can be defined as clonal proliferation of skin-infiltrating T lymphocytes primarily presenting in the cutaneous compartment. They show a considerable variation in clinical presentation, histology, immunophenotype, and prognosis, which is best reflected by the proposal of the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer (EORTC). Due to the heterogeneity of CTCL and the lack of curative therapy regimens, multiple strategies have been proposed for the management of the different CTCL entities. This includes topical application of corticosteroids, nitrogen mustard or carmustine (BCNU), radiotherapy, including total skin electron beam irradiation, photo(chemo)therapy, biological response modifiers, cytostatic chemotherapy, and combined regimens. More recently, fusion proteins and peptide vaccines have been introduced in the management of CTCL. Classification, staging, and treatment modalities are discussed in detail and summarized in a stage-adapted therapy regimen for CTCL.

Adjuvants, Immunologic↗
PubMed1995

O6-methylguanine-DNA methyltransferase in tumors and cells of the oligodendrocyte lineage.

BACKGROUND: Oligodendrogliomas respond to nitrosourea-based chemotherapy and are induced in rats following transplacental exposure to ethylnitrosourea, observations suggesting that neoplastic and normal cells of the oligodendrocyte lineage are "sensitive" to nitrosoureas. Nitrosoureas alkylate DNA at O6-guanine with repair mediated by O6-methylguanine-DNA methyltransferase (MGMT). The cytotoxic and carcinogenic properties of the nitrosoureas appear related to MGMT activity. METHODS: To explore why oligodendrogliomas respond to chemotherapy, we measured MGMT activity in five chemosensitive human oligodendrogliomas and in rat oligodendrocyte lineage cells. We also measured MGMT activity in rat astrocytes and compared the cytotoxic effects of carmustine (BCNU) on oligodendrocyte lineage cells and astrocytes. RESULTS: Low levels of MGMT activity were found in five of five human oligodendrogliomas. Cultures of neonatal rat glia enriched for oligodendrocyte lineage cells also had low levels of MGMT activity, approximately one-third that found in astrocytes (p < 0.02), and oligodendrocyte lineage cells were more sensitive to BCNU than astrocytes. CONCLUSIONS: Low MGMT activity may contribute to the chemosensitivity of some human oligodendrogliomas and rat oligodendrocyte lineage cells also have low levels. If drug resistance mechanisms in tumors reflect the biochemical properties of their cells of origin, then normal glia may serve as a laboratory substitute for human glioma.

Adult↗
PubMed1997

Advantage of treating anaplastic gliomas with aggressive protocol combining chemotherapy and radiotherapy.

We devised a treatment protocol for anaplastic gliomas consisting of:(a) chemotherapy prior to radiotherapy (b) a second chemotherapy regimen at tumor recurrence (c) repeated surgery whenever possible. 41 Anaplastic Astrocytoma (AA), 16 Anaplastic oligoastrocytoma (AOA) and 14 anaplastic oligodendroglioma (AOD) patients were treated. After surgery all patients received 5-6 cycles of carmustine+Cisplatinum chemotherapy. Radiotherapy was started during the last 2-3 cycles of chemotherapy. 17 patients (30.5%) were reoperated on at recurrence. All recurring patients underwent PVC chemotherapy. At this moment disease recurred in 56 patients. Median TTP was 24.5, 38.7 and 58.2 months for AA, AOA and AOD respectively. Median ST was 38.8, 71.8 and 73 months. In conclusion our sandwich protocol of prior chemotherapy, overlapping irradiation with second chemotherapy and, in favourable cases, a second surgical intervention, is of benefit in patients with anaplastic gliomas.

Adolescent↗
PubMed1998

High dose chemotherapy with autologous bone marrow rescue for children with diffuse pontine brain stem tumors. Children's Cancer Group.

PURPOSE: Diffuse pontine tumors are highly lethal, and there are few long-term survivors with the standard treatment of external beam irradiation. We investigated the effectiveness of high-dose thiotepa and etoposide-based chemotherapy regimens with autologous bone marrow rescue (ABMR) in children with pontine tumors. PATIENTS AND METHODS: Sixteen children with diffuse pontine tumors were treated. Ten had resistant or recurrent tumors. All ten had previously received irradiation; five had also received chemotherapy and one, beta-interferon. Three high-dose chemotherapy regimens were employed. Six patients received three days of thiotepa (300 mg/m2/day) and etoposide (250-500 mg/m2/day) (TE); two received three days of carmustine (BCNU) (200 mg/m2/day divided every 12 hours) followed by TE (BTE); and two received three days of carboplatin (500 mg/m2/day) followed by TE (CTE). Six other patients had newly-diagnosed tumors and had not received any prior treatment. They all received the BTE regimen and subsequently were treated with hyperfractionated irradiation (7200-7800 cGy) beginning approximately six weeks post-ABMR. RESULTS: There were two toxic deaths (13%), both in previously treated patients, due to multiorgan system failure and Candida septicemia in one case each. Median survival of the patients with resistant or recurrent disease was 4.7 months (range 0.1-18.7) from time of ABMR. Median survival of the newly-diagnosed patients was 11.4 months (range 7.6-17.1) from the time of ABMR. CONCLUSION: High-dose chemotherapy utilizing these regimens followed by ABMR did not appear to prolong survival compared to conventional therapy in these children with pontine tumors. Alternative strategies need to be developed for this highly lethal disease.

Adolescent↗
PubMed1998

Bone marrow metastasis in astrocytic gliomata.

With the increasing survival time of many pediatric patients with malignancies, unexpected symptoms or signs require diligent search for rare complications or second cancers related to the disease or treatment. We recently encountered a patient with extensive glioblastoma multiforme who developed pancytopenia six months after completion of treatment with craniospinal radiation and chemotherapy with etoposide and cyclophosphamide. Bone marrow aspirate and biopsy confirmed bone marrow metastasis from the brain tumor. He showed good partial remission with chemotherapy with carmustine and cis-platinum as demonstrated by serial bone marrow aspirate for cytology and cytogenetics and enjoyed good quality of life for eight months. 14 other patients with astrocytic glioma, two of whom are children, are reported in the literature to have diffuse bone marrow metastasis. Therefore, in patients with malignant astrocytic tumor, bone marrow metastasis, though not common, should be considered when bone pain or cytopenias occur, especially when prolonged.

Adolescent↗
PubMed1998

Use of tumor lines with selectable markers in assessing the effect on experimental metastases of combination chemotherapy with alkylating agents.

High-dose chemotherapy with a 3-day regimen of cyclophosphamide, cisplatin, and carmustine was used to treat mice bearing experimental lung metastases of mammary tumor cell lines with selectable markers (lines 66cl4 and 4TO7). Cloning of lung cells at various times after treatment revealed a rapid 3 to 4 log loss of clonogenic tumor cells, down to undetectable levels. However, after several weeks, clonogenic tumor cells reappeared in the lungs; few cures were obtained even when mice had a relatively low tumor burden when treated with chemotherapy. Splenocyte numbers and response to Concanavalin A indicated a transient immunosuppression. In one experiment, mice were treated with a second round of chemotherapy 3 weeks after the first. The number of clonogenic cells per lung again dropped, but regrowth of cells was rapid, and no cures were obtained. Inoculation of tumor-bearing mice s.c. after chemotherapy with lethally irradiated cells of the highly immunogenic tumor cell line 4TO7-IL-2 had little effect on the rate of reappearance of line 4TO7 in lungs, but subsequent growth of tumor cells in lungs was slowed. This model system can be used to test the efficacy of additional immunotherapy and chemotherapy regimens on minimal residual metastatic disease after high-dose chemotherapy, when remaining metastatic cells are apparently dormant.

Animals↗
PubMed1998

Modulation of angiogenesis by human glioma xenograft models that differentially express vascular endothelial growth factor.

To evaluate the potential actions of vascular endothelial growth factor (VEGF) on capillary permeability and drug transport, tumorigenic human glioma cell lines were developed that expressed different levels of VEGF. Three human glioma cell lines (i.e. U373, SF126, SF188) were screened for VEGF under normoxic and hypoxic (i.e. induced by CoCl2) conditions by Western blot analysis. Subsequent to these results, sense and antisense VEGF164 cDNA transfections were conducted. It was found that parental SF188 (SF188/V-) and SF188/V+ (sense transfected) cells could serve as an appropriate in vivo model based on their divergent levels of VEGF expression. Media derived from SF188/V+ cells stimulated endothelial cell growth by 30-60%, and enhanced endothelial cell clonogenicity by 5-10-fold compared to SF188/V- or empty vector transfected cells. Nude rats implanted with either SF188/V- or SF188/V+ cells subcutaneously and intracerebrally formed tumors, with those derived from SF188/V+ cells growing at a faster rate. Immunohistochemistry analysis indicated that the expression of VEGF and number of capillaries (factor VIII assay) were approximately 3-fold greater in SF188/V+ tumors compared to SF188/V- tumors. Pharmacological assays, such as measurements of cytotoxicity and DNA adducts, in SF188/V- and SF188/V+ cells treated with carmustine or temozolomide were similar. Therefore, other than differences in VEGF expression and growth in vivo, SF188/V- and SF188/V+ cells possess a similar phenotype, and can serve as models to evaluate the influence of VEGF on drug transport.

Animals↗
PubMed2002

Synergistic effect of genistein and BCNU on growth inhibition and cytotoxicity of glioblastoma cells.

OBJECTIVE: Recent experiments have shown that dietary soy isoflavones such as genistein can significantly suppress invasiveness and growth of a number of human malignancies. This study examined whether genistein, at a concentration typical of plasma levels following soy diet intake, in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU, carmustine) exhibited an additive or synergistic inhibitory effect on the growth of glioma cells. METHODS: The human glioblastoma multiforme (GBM) cell line U87 and the rodent C6 glioma were treated with genistein at 4 microM, combined with BCNU (0-50 microM). Monolayer cell growth and cytotoxicity, as measured by colonigenic survival in soft agarose, were then compared in control and drug-treated cultures. Presence of apoptosis, using the DNA ladder assay and laser scanning cytometry (LSC), was investigated in all cell lines at those concentrations where an enhancement of antiproliferative effect of BCNU in presence of genistein was observed. RESULTS: A 32-41% increase in monolayer growth inhibition and a 28-42% increase in colony cytotoxicity in the U87 cell line were observed when genistein (4 microM) was added to BCNU in the 0-10 microM dose range. In the C6 cell line, a 30-36% increase in monolayer growth inhibition and a 39-54% increase in colony cytotoxicity were observed with the BCNU dose range of 0-50 microM. All experiments showed a significant increase in growth inhibition and a decrease in colonogenic survival (P < 0.05). We were unable to detect apoptosis in any of the lines when genistein was combined with BCNU. CONCLUSION: These results indicate that genistein at typical adult dietary plasma levels can significantly enhance the antiproliferative and cytotoxic action of BCNU. The implication for treatment of GBM may be a reduction in the chemotherapeutic dose recommendations of these agents and subsequently a decrease in the risk of treatment sequelae for these patients.

Animals↗
PubMed1996

Morphological characterization of polyanhydride biodegradable implant gliadel during in vitro and in vivo erosion using scanning electron microscopy.

PURPOSE: The objectives of the current study are to characterize the distribution of the chemotherapeutic agent carmustine (BCNU) in spray dried polyanhydride microspheres and to describe the morphological changes that occur during the in vitro and in vivo erosion of the polyanhydride implant--GLIADEL, which consists of BCNU distributed in the copolymer matrix of poly(carboxyphenoxy propane:sebacic acid) in a 20:80 molar ratio (p(CPP:SA, 20:80)). METHODS: Scanning electron microscopy (SEM) was used to visualize the morphological changes of the polymer during the manufacturing process and in vitro and in vivo erosion. RESULTS: This study revealed that BCNU was homogeneously distributed within spray dried polyanhydride microspheres with no phase separation. The porosity of the wafer fabricated from spray dried polyanhydride microspheres gradually increased during erosion. During the initial period following wafer implantation in the brains of rats, erosion was mainly confined to the surface layer of the wafer with the majority of the wafer remaining intact. The eroding front gradually advanced from the surface to the interior of the wafer in a layerwise fashion, creating pores and connecting channel. Eventually both the interior and exterior of the wafers were eroded and the same porous structure was seen throughout the whole wafer. CONCLUSIONS: This study provides the first visual observation of the morphological changes of the GLIADEL(R) wafer during erosion of the polyanhydride matrix and release of the drug substance BCNU. The observations in this study support the conclusion that BCNU release from a polyanhydride wafer is controlled both by diffusion of the drug and erosion of the polymer matrix.

Anhydrides↗
PubMed2004

Recent advances in brain tumor therapy: local intracerebral drug delivery by polymers.

New approaches to malignant glioma are being actively investigated. Local drug delivery directly to the site of the tumor is one novel approach that has been approved by the US FDA and other regulatory agencies worldwide. This agent, Gliadel, delivers the chemotherapeutic drug carmustine (BCNU) from a biodegradable polymer placed in the resection cavity after brain tumor surgery. Gliadel represents the first clinical application of polymer delivery for brain tumors, but the potential for this new methodology is far greater. In this review, we will briefly summarize the development of Gliadel from a laboratory idea to its current role as an approved treatment for gliomas. Then we will present the most recent work being done to expand the potential benefits of polymeric delivery for brain tumors. This work includes trials for its use as the initial therapy for gliomas, as well as its use against metastasis. Further clinical trials exploring the maximum-tolerated dose and the combination of Gliadel with systemic chemotherapeutic treatments such as temozolamide and O(6)-benzylguanine will be reviewed. Finally, we will present preclinical work on the efficacy of polymeric methods for delivering other chemotherapeutic agents, and a variety of novel compounds that modify brain tumor biology. This latter work represents potential future clinical applications of local polymeric drug delivery to the brain and other sites where cancers can occur.

Animals↗
PubMed1987

Vidarabin-monophosphate, BCNU, VM26--an in vitro comparative study of active agents in the treatment of malignant human brain tumours.

BCNU (carmustine), VM26 (teniposide) and ARA-A5'P (vidarabin-monophosphate) were compared in their activity against 30 cell lines of primary (N = 21) and metastatic (N = 9) human brain tumours, which were characterized in tissue culture by cytochemical, immunological and cytogenetic criteria. In vivo achievable concentration-time products c X t were correlated with in vitro pharmacokinetic data in order to evaluate in vitro drug sensitivity at relevant exposure doses. A microcytotoxicity assay was employed to screen for drug toxicity in individual tumour cell lines. Following drug exposure and 5 to 8 population doubling times of untreated controls, RNA-synthesis - as a parameter of cell metabolism and proliferation - was determined by incorporation of [5,6-3H]-uridine into cellular RNA (liquid scintillation counting protocol). The cytotoxic effect of each drug on individual cell lines was expressed in terms of a sensitivity index (SI); by these means effects of different drugs on individual tumour cell lines could be compared. Mean sensitivity indices of ARA-A5'P, BCNU and VM26 for primary brain tumour cell lines were 0.59, 0.82 and 0.54. ARA-A5'P and VM26 had almost similar activities against brain tumour cell lines, whereas BCNU was significantly (P less than 0.001) less active. High grade gliomas were less sensitive to all three agents than low grade and infratentorial gliomas. ARA-A5'P was also able to effectively reduce colony formation in brain tumour cell lines. A cross-resistance of ARA-A5'P to either BCNU or VM26 could not be observed. Clearly, ARA-A5'P is an effective drug in treatment of brain tumour cells in vitro.

Adolescent↗
PubMed1993

Double megatherapy and autologous bone marrow transplantation for advanced neuroblastoma: the LMCE2 study.

In the LMCE1 study using a single course of megatherapy most of the relapses occurred during the first 2 years after autologous bone marrow transplantation. A second pilot study (LMCE2) was therefore set up using a double harvest/double graft approach with two different megatherapy regimens. Objectives were to test the role of increased dose intensity on response status, relapse pattern and overall survival. Thirty-three patients (20 boys, 13 girls) with a median age of 53 months at first megatherapy (range, 17-202 months) entered this study. They were cases either with refractory disease in partial response after second line treatment for stage 4 neuroblastoma (n = 25) or after relapse from stage 4 (n = 5) or stage 3 disease (n = 3). All patients received Etoposid and/or Cisplatinum (or Carboplatin) containing treatments before megatherapy. The first megatherapy regimen was a combination of Tenoposid, Carmustine and Cisplatinum (or Carboplatin), the second applied Vincristin, Melphalan and Total Body Irradiation. The first harvest was scheduled 4 weeks after the last chemotherapy, the second 60 to 90 days after megatherapy. All marrows were purged in vitro by an immunomagnetic technique. Median follow up time since first megatherapy is 56 months. Response rates for evaluable patients were 65% (complete response rate: 16%) for megatherapy 1 and 60% (complete response rate: 25%) for megatherapy 2. Considering that only patients with delayed response or relapse were eligible for this pilot study the overall survival was encouraging with 36% at 2 years and still 32% at 5 years. The costs for these survival rates were high in terms of morbidity (four early and four late toxic deaths; toxic death rate: 24%). Double harvesting may have the disadvantage of delayed engraftments related in part to a disturbance of marrow microenvironment by megatherapy 1. This double megatherapy approach achieved a prolonged relapse free interval (median 11 months, range 2-31 months) in patients reaching megatherapy 2 and justifies further evaluation of concepts with consecutive dose-escalation.

Adolescent↗