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At least 919 records · Page 51Linked to original sources
PubMed1999

Dose-intensive, time-compressed procarbazine, CCNU, vincristine (PCV) with peripheral blood stem cell support and concurrent radiation in patients with newly diagnosed high-grade gliomas.

The dose intensity of the PCV regimen can be doubled using peripheral blood stem cell (PBSC) support. This study sought to determine the feasibility of giving dose-intensive PCV concurrently with radiation therapy. Twelve patients, age 3.2-22.7 years, median 7.5 years, with newly diagnosed high grade gliomas were enrolled. Diagnoses included diffuse intrinsic brainstem gliomas (BSG) (n = 6), glioblastoma (n = 4), anaplastic astrocytoma (n = 2). PBSCs were harvested prior to chemotherapy with G-CSF priming. Chemotherapy consisted of CCNU 130 mg/m2 and vincristine 1.5 mg/m2 on day 0, and procarbazine 150 mg/m2 on days 1-7. PBSCs were reinfused on day 9 of each course. Four courses of chemotherapy were administered every 28 days or when blood counts recovered. The first course was administered the week prior to RT, the second course began on week 3 of RT and the third and fourth course were given after RT. Hematologic toxicity was mild and the majority of courses were given on schedule. Five of six patients with diffuse BSG showed clinical improvement and three showed a radiographic response; however, only one remains alive 12+ months from diagnosis. All four patients with non-brainstem large-volume tumors showed clinical deterioration and radiographic progression during or shortly after RT. MRI scans showed massive edema and enhancement. Median time to radiographic progression was five months. Median overall survival was 11 months. We conclude that dose-intensive, time-compressed PCV given concurrently with large-volume RT appears to result in unacceptable toxicity in patients with large residual tumors.

Adolescent↗
PubMed2000

Distinct radiochemotherapy protocols differentially influence cellular proliferation and expression of p53 and Bcl-2 in glioblastoma multiforme relapses in vivo.

Several protocols for the adjuvant treatment of glioblastoma multiforme (GBM) are currently being evaluated. In this context, little is known about the influence of radiochemotherapy on apoptosis and the expression of apoptosis-related proteins in vivo. We have analyzed the incidence of apoptosis using in situ nick translation (ISNT) and expression of Ki-67 (MIB- 1), p53 (DO-1 and DO-7), Bcl-2 and transglutaminase II (TGase II) by immunohistochemistry in 41 patients with GBM and their matched relapses. Sixteen patients received radiochemotherapy, 18 irradiation and 7 no treatment. Radiochemotherapy resulted in an increase in Bcl-2+ cells (p = 0.013). Irradiation caused the reduction of MIB-1+ (p = 0.0015), DO-7+ (p = 0.0043) and the increase of Bcl-2+ cells (p = 0.016). We calculated a positive correlation between high TGase II scores in patients preceding radiochemotherapy (p = 0.0186) and no treatment (p = 0.0158), low ISNT scores (p = 0.0018) and high DO-1 scores (p = 0.0233) in patients preceding irradiation and short time to progression. These data show that distinct postsurgical radiochemotherapy protocols differentially alter cellular proliferation and expression of p53 and Bcl-2 in GBM relapses. Furthermore, we show that ISNT, DO-I and TGase II labeling scores are therapy-specific predictors of time to progression in GBM patients.

Adult↗
PubMed2000

Relapses of childhood anaplastic large-cell lymphoma: treatment results in a series of 41 children--a report from the French Society of Pediatric Oncology.

PURPOSE: To study response to chemotherapy and the outcome of children treated for a relapsed anaplastic large-cell lymphoma (ALCL) and to evaluate the role of bone marrow transplantation (BMT) in these patients. PATIENTS AND METHODS: Clinical data concerning the 41 relapses that occurred in 119 patients with ALCL enrolled in 3 consecutive studies since 1975 were analysed. First-line treatment consisted of intensive chemotherapy according to the COPAD protocol for the first series of 12 patients treated between 1975 and 1989 and to the SFOP (French Society of Pediatric Oncology) HM protocols for the 30 patients treated between 1989 and 1997. Twenty-eight patients were treated with CV(B)A (CCNU, vinblastine, ara-C with or without bleomycin), and the others with miscellaneous protocols for recurrent disease. Fifteen patients underwent autologous BMT and 1 allogeneic BMT while in CR2. RESULTS: Thirty-six of forty-one (88%) patients achieved CR2. With a median follow-up of 5 years, 12 patients died, 9 of their disease and 29 patients are alive in CR2 (20 patients), CR3 (5 patients), CR4 (2 patients), CR5 (1 patient) or CR6 (1 patient). Overall and disease-free survival are respectively 69% (53%-82%) and 44% (29%-61%) at three years. In univariate analysis, patients treated with ABMT while in CR2 did not appear to have a better outcome than the other. Remarkably, a long-lasting remission was obtained in 8 of 13 patients treated with weekly vinblastine for a relapse including 6 relapses occurring after ABMT. CONCLUSIONS: Relapsed ALCL are highly chemosensitive but over 40% of the patients experience several relapses. Prolonged conventional chemotherapy based on vinblastine might, in some cases, be as efficient as short intensive treatment with ABMT.

Adolescent↗
PubMed2001

PCV chemotherapy for oligodendroglioma: response analyzed on T2 weighted-MRI.

OBJECTIVE: Because oligodendroglioma are infiltrative tumors, the Mac Donald's response criteria, usually used for solid and contrast-enhanced tumors, seem not to be adapted. To precise more relevant radiological criteria, the radiological response of oligodendroglioma to PCV chemotherapy was evaluated on T2 weighted-MRI sequences only. METHODS: 25 patients with oligodendroglioma grade A or B were retrospectively analyzed. They were treated with up to six cycles of PCV standard regimen. Tumor size was calculated before and at the end of the treatment, on T2 weighted-MRI, by two methods: volumetric reconstruction (method 1) and maximal cross-sectional area (method 2). Responses were defined according to new criteria on T2 weighted-MRI. RESULTS: According to these criteria and with the method 1, 7 of 25 patients (28%) had a partial response to the PCV, 14 patients (56%) had stabilized disease, and 4 patients (16%) had progressive disease. With the method 2, 6 had partial response (24%), 18 had stabilized disease (72%) and 1 had progressive disease. CONCLUSION: Response rate to PCV chemotherapy in this study was lower than response observed in the literature. Because of the infiltrative feature of oligodendroglioma, we think that the radiological response of these tumors should be evaluated on T2 weighted-MRI. The two methods of tumor size estimation used in this study were almost equivalent. Then, the maximal cross-sectional area measurement, more practical, could be retained.

Adolescent↗
PubMed1992

Improved delivery through biological membranes. XLV. Synthesis, physical-chemical evaluation, and brain uptake studies of 2-chloroethyl nitrosourea delivery systems.

The dihydropyridine in equilibrium with pyridinium redox chemical delivery system (CDS) was supplied to two 2-chloroethylnitrosoureas, i.e., HECNU and CCNUOH, and the physicochemical properties of the delivery systems were studied to assess their potential as improved delivery forms to the CNS. Detailed physicochemical evaluation and brain uptake studies were performed on one of the delivery systems (CCNUOH-CDS) derived from trans-4-hydroxy-CCNU, an active metabolite of CCNU. Two aqueous-based formulations derived from hydroxypropyl-beta-cyclodextrin (HP beta CD) and Tween 80:ethanol:water system were developed for CCNUOH-CDS to overcome the poor aqueous solubility conferred upon it by its high lipophilicity. The formulations enabled a 200- to 400-fold improvement in the water solubility of CCNUOH-CDS. Dose- and vehicle-dependent comparative tissue distribution studies in rats indicated improved brain-to-organ ratios of the delivery system at lower doses.

Animals↗
PubMed1988

Capillary gas chromatography and thermionic N-P-specific detection of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in stability and pharmacokinetic studies.

An expedient, rapid, and sensitive capillary gas chromatographic method for the analysis of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in plasma is described. Separation of the underivatized nitrosourea compounds was performed on a 0.33-mm-i.d., 25-m fused-silica, SE-30 capillary column, and detection was carried out using a thermionic N-P-specific detector. The compounds were extracted from plasma with benzene with a yield of greater than 87%. The assay was linear in the ranges of 0.001 to 0.5 and 0.5 to 25 micrograms/ml for CCNU or 0.003 to 0.50 and 0.5 to 25 micrograms/ml for BCNU, with correlation coefficients from 0.9914 to 0.9999 and coefficients of variation (CV) of less than 3.3%. Other antineoplastic agents did not interfere in the assay. The method was employed to study the pharmacokinetics of BCNU in rabbits. The plasma concentration-time curves were fit to a two-compartment model with a mean (SE) alpha, beta, and total-body clearance of 2.898 (0.913) hr-1, 0.1228 (0.0179) hr-1, and 7.211 (2.862) liters/hr.kg, respectively. Further, the stability of BCNU and CCNU in solution was examined at different temperatures. Both compounds were stable in benzene or acetone (4 to 37 degrees C) but labile in plasma even if refrigerated. The apparent rate constants for degradation of BCNU and CCNU were 0.09921 and 0.02853 hr-1 at 4 degrees C and 5.998 and 2.553 hr-1 at 37 degrees C, respectively.

Animals↗
PubMed1999

Lipid association increases the potency against primary medulloblastoma cells and systemic exposure of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in rats.

PURPOSE: To reduce the systemic toxicity and prolong the systemic presence of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), a lipid-based drug carrier was designed and characterized. METHODS: The degree of CCNU association with lipid vesicles composed of 1, 2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol (DMPG) (1:1, m/m) was characterized and the drug decomposition rates of lipid-drug complexes were monitored. Effects of lipid association on drug potency against medulloblastoma cells and total systemic drug exposure in rats were determined. RESULTS: At a CCNU:lipid molar ratio greater than 1:5, more than 90% of the drug was associated with the lipid vesicles. In aqueous suspensions, lipid association significantly reduced the first-order drug decomposition rate. In addition, lipid-associated CCNU exhibited a 4-fold increase in drug sensitivity with medulloblastoma cells. IC50 values for CCNU admixed and encapsulated with lipid vesicles were 18+/-4.9 and 14.0+/-2.2 microM, respectively, compared to 83+/-11.0 microM for free CCNU. When administered to rats, lipid-associated CCNU increased the AUC (area under the concentration-time curve) of CCNU by approximately 2-fold (20.46+/-2.15 compared to 39.59+/-1.87 microg x min/ml), and the terminal half-life (t1/2beta) by almost 9-fold (17+/-9 compared to 147+/-48 min) over free CCNU. Despite the increase in total systemic drug exposure, rats treated with lipid-associated CCNU exhibited a significantly lower frequency of acute neurotoxicity. CONCLUSIONS: These data indicate that CCNU associated with lipid vesicles may increase drug stability, potency, and systemic exposure in rats.

Animals↗
PubMed2002

Complete response of a recurrent, multicentric malignant glioma in a patient treated with phenylbutyrate.

Sodium phenylbutyrate is a biological-response modifier that acts as a dose-dependent inhibitor of glioma cell proliferation, migration, and invasiveness in vitro, possibly by inhibition of urokinase and c-myc pathways. Despite its biological activity in vitro, there have not been any prior reports of efficacy in the treatment of human malignant gliomas. We report a 44-year-old female with a recurrent, multicentric, malignant glioma who experienced a durable remission lasting more than four years. The patient initially presented with seizures caused by a biopsy-proven anaplastic astrocytoma of the frontal lobe. The patient was treated with radiation therapy and Procarbazine-CCNU-Vincristine (PCV). However, the tumor progressed and extended to the corpus callosum with midline shift, refractory to four cycles of continuous 72-h infusion of BCNU/Cisplatinum. Additional enhancing lesions appeared in the left frontal and left temporal lobes. The patient was started on sodium phenylbutyrate, 18 g daily in three divided oral doses, and reduced to 9 g/day and eventually to 4.5 g/day to eliminate mild, reversible side effects. Four years later, the patient has a KPS functional score of 100%. Phenylbutyrate is a well-tolerated, oral agent that shows potential for the treatment of malignant gliomas. Further studies should be considered to identify a subset of patients that have tumors sensitive to phenylbutyrate, either as a single agent or in combination with radiation therapy or other chemotherapeutic agents.

Adult↗
PubMed2003

Tolerance of nitrosurea-based multiagent chemotherapy regime for low-grade pediatric gliomas.

The aim of this study was to compare tolerance of a nitrosurea-based regime with 'standard' therapy of vincristine (VCR) and carboplatin for low-grade gliomas. Ten children with low-grade gliomas received second line therapy consisting of thioguanine, procarbazine, CCNU and vincristine (TPCV). Two groups were identified, i.e. patients who had either experienced significant toxicity with carboplatin (reaction group) or had re-growth of their tumor (re-growth group) following first line therapy. Patients were evaluated for toxicity. Data was available on nine patients. Patients in the reaction group completed a mean of 3 cycles of TPCV (range 2-4). One patient stopped after 2 cycles of TPCV due to tumor progression and died 3 months later and one remained on therapy at the time of analysis. Patients in the re-growth group received a mean of 5.5 cycles of TPCV (range 4-8). Treatment was discontinued in one patient after 4 cycles due to hematological toxicity, one experienced tumor progression after 4 cycles and one stopped after 6 cycles because of neurological toxicity. There was no difference in the incidence of grade 3/4 neutropenia or thrombocytopenia, transfusion requirements or delays in chemotherapy between TPCV and VCR/carboplatin in either group. There were no serious infections or toxic deaths. Seven of nine patients had stable disease at a mean of 13 months of follow up. TPCV therapy is a well-tolerated regime with comparable bone marrow toxicity to VCR/carboplatin. Significant disease stabilization was observed with TPCV and hence this regime may be used as second line therapy.

Adolescent↗
PubMed2003

High-dose chemotherapy with stem cell rescue as initial therapy for anaplastic oligodendroglioma.

PURPOSE: Anaplastic oligodendroglioma is a chemosensitive glial neoplasm. To improve disease control and postpone cranial radiotherapy, we designed a phase II study of intensive procarbazine, lomunstine and vincristine followed by high-dose thiotepa with autologous stem cell rescue for patients with newly diagnosed anaplastic or aggressive oligodendroglioma. PATIENTS AND METHODS: Sixty-nine patients with a median age of 42 (range: 18-67) and a median Karnofsky Performance Score of 90 (range: 70-100) were enrolled. Sixteen patients had a prior diagnosis of low-grade oligodendroglioma and 16 had mixed oligoastrocytoma pathology. Only patients with demonstrably chemosensitive enhancing tumors or those free of enhancing tumor after surgery and induction therapy were eligible to receive high-dose thiotepa. RESULTS: Thirty-nine patients (57%) completed the transplant regimen; their estimated median progression-free survival is 69 months and median overall survival has not been reached. Twelve transplanted patients (31%) relapsed. Neither histology nor prior low-grade oligodendroglioma correlated with relapse; however, persistent non-enhancing tumor at transplant conferred an increased risk of relapse (p = 0.028). The transplant regimen was well-tolerated; median hospital stay was 20 days (range: 7-43) with a median time to ANC and platelet engraftment of 10 days. Thirty patients (43%) did not receive high-dose thiotepa because of stable or progressive disease (n = 21), excessive toxicity (n = 4), refusal of further therapy (n = 2), failure to obtain insurance coverage (n = 2), or other (n = 1). No treatment-related or long-term neurotoxicity was seen in the transplanted patients. CONCLUSIONS: High-dose chemotherapy with stem cell rescue as initial treatment for anaplastic oligodendroglioma is feasible and associated with prolonged tumor control in some patients.

Adolescent↗
PubMed2001

Multiple myeloma in elderly patients: presenting features and outcome.

Few studies have been performed regarding multiple myeloma (MM) in elderly patients. We report a retrospective series of 130 unselected patients with MM aged 75 yr or more at diagnosis. Presenting features were identical to those reported in younger patients, except for a higher rate of infection. Heavy comorbidity was characteristic of unselected geriatric patients. Ninety-four patients received conventional chemotherapy. The response rate was 62%. Treatment toxicity was mild. Median survival was 22 months. Durie-Salmon (DS) clinical stages II and III MM were severe and often led to death, while significantly more patients with DS stage I MM died from unrelated causes (p<0.0001). Univariate analysis showed that age > or = 85 yr, performance status > or = 2, creatinine level > or = 120 micromol/l, beta 2 microglobulin level > 4 mg/l, C-reactive protein level > 6 mg/l, platelet count < 100 x 10(9)/l, presence of infection and lack of response to chemotherapy were adverse prognostic factors for survival. In Cox multivariate regression analysis, age > or = 85 yr (p<0.0001), performance status > or = 2 (p<0.0001) and creatinine level > or = 120 micromol/l (p<0.0001) were independent factors in predicting short survival. This study provides evidence that in patients with symptomatic MM age should not be considered as a major obstacle to active treatment. Prospective clinical trials are needed in this population of patients and should include an assessment of quality of life.

Aged↗
PubMed2001

Protection of hematopoietic cells from O(6)-alkylation damage by O(6)-methylguanine DNA methyltransferase gene transfer: studies with different O(6)-alkylating agents and retroviral backbones.

Overexpression of O(6)-methylguanine DNA methyltransferase (MGMT) can protect hematopoietic cells from O(6)-alkylation damage. To identify possible clinical applications of this technology we compared the effect of MGMT gene transfer on the hematotoxicity induced by different O(6)-alkylating agents in clinical use: the chloroethylnitrosoureas ACNU, BCNU, CCNU and the tetrazine derivative temozolomide. In addition, various retroviral vectors expressing the MGMT-cDNA were investigated to identify optimal viral backbones for hematoprotection by MGMT expression. Protection from ACNU, BCNU, CCNU or temozolomide toxicity was evaluated utilizing a Moloney murine leukemia virus-based retroviral vector (N2/Zip-PGK-MGMT) to transduce primary murine bone marrow cells. Increased resistance in murine colony-forming units (CFU) was demonstrated for all four drugs. In comparison to mock-transduced controls, after transduction with N2/Zip-PGK-MGMT the IC50 for CFU increased on average 4.7-fold for ACNU, 2.5-fold for BCNU, 6.3-fold for CCNU and 1.5-fold for temozolomide. To study the effect of the retroviral backbone on hematoprotection various vectors expressing the human MGMT-cDNA from a murine embryonic sarcoma virus LTR (MSCV-MGMT) or a hybrid spleen focus-forming/murine embryonic sarcoma virus LTR (SF1-MGMT) were compared with the N2/Zip-PGK-MGMT vector. While all vectors increased resistance of transduced human CFU to ACNU, the SF1-MGMT construct was most efficient especially at high ACNU concentrations (8-12 microg/ml). Similar results were obtained for protection of murine high-proliferative-potential colony-forming cells. These data may help to optimize treatment design and retroviral constructs in future clinical studies aiming at hematoprotection by MGMT gene transfer.

Alkylating Agents↗
PubMed1975

Augmentation of cytotoxic drug action and X-irradiation by antibodies.

The effect of an antiserum containing antibodies against cell surface components of PyBHK cells on the action of certain anticancer agents has been studied using a colony formation inhibition assay. The effects of x-rays, chlorambucil, CCNU and possibly ICRF 159 are augmented by the antiserum whereas methotrexate and vinblastine are not.

Antibodies, Neoplasm↗
PubMed1975

Changes in sensitivity to cytotoxic agents occurring during the life history of monolayer cultures of a mouse tumour cell line.

Dose-response curves have been obtained for the response of EMT6 mouse tumour cells in vitro to adriamycin, actinomycin D, nitrogen mustard, BCNU and CCNU. The experiments have been carried out with exponentially growing cells and with cells in early and late plateau phase. The results are discussed with particular reference to discrepancies with the results obtained by other workers in similar systems.

Alkylating Agents↗
PubMed1976

The sensitivity to cytotoxic agents of the EMT6 tumor in vivo. Comparative response of lung nodules in rapid expotential growth and of the solid flank tumour.

Experiments are described in which dose-response data have been obtained for EMT6 mouse tumour cells growing in vivo and exposed to various cytotoxic agents. A comparison has been made of the response of solid tumours in the flank and of rapidly growing lung nodules. The results are discussed with regard to their cell kinetic implications and compared with our results for the chemosensitivity of EMT6 cells in exponential and plateau phase growth in vitro.

Animals↗
PubMed1977

Tumour volume response, initial cell kill and cellular repopulation in B16 melanoma treated with cyclophosphamide and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea.

The relationship between tumour volume response and cell kill in B16 melanoma following treatment in vivo with cyclophosphamide (CY) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) was investigated. Tumour volume response, expressed as growth delay, was estimated from measurements of tumour dimensions. Depression of in vitro colony-forming ability of cells from treated tumours was used as the measure of tumour cell kill. The relationship between these parameters was clearly different for the two agents studied. CY produced more growth delay (7.5 days) per decade of tumour cell kill than CCNU (2 to 3.5 days). The possibility that this was due to a technical artefact was rejected in favour of an alternative explanation that different rates of cellular repopulation in tumours treated with CY and CCNU might be responsible. Cellular repopulation was measured directly, by performing cell-survival assays at various times after treatment with doses of CY and CCNU which produced about 3 decades of cell kill. The rate of repopulation by clonogenic cells was much slower after treatment with CY than with CCNU, and this appears to account for the longer duration of the growth delay obtained with CY.

Animals↗