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Biomedical subjects

V A Levin

Publications and source records attributed to V A Levin.

At least 145 records · Page 8Linked to original sources
PubMed1985

Central nervous system toxicity and cerebrospinal fluid pharmacokinetics of intraventricularly administered bleomycin in beagles.

The neurotoxic effects and cerebrospinal fluid (CSF) pharmacokinetics of bleomycin were evaluated in beagles after chronic intraventricular administration twice a week for 8 consecutive weeks. Bleomycin was reasonably well tolerated at doses of 0.067 to 0.3 mg/week. Doses higher than 0.3 mg/week produced marked elevation of CSF protein levels and a necrotizing vasculitis within the central nervous system. Pharmacokinetic studies were performed approximately 1 month after the completion of the toxicity studies. [3H]inulin was used as a reference compound. Both [3H]inulin and bleomycin were cleared from the CSF more slowly than in previous studies and more slowly than in normal dogs, which suggests that bulk CSF absorption was reduced by the drug, probably secondary to protein-induced blockage of the arachnoid granulations through which CSF is normally absorbed. Because a "minimally toxic" dose of bleomycin (approximately 0.1 mg/week) produces a CSF C X t of only 1.9 mg/min/ml, we believe that a Phase I clinical trial would be too dangerous given the limited therapeutic potential that a dose of 0.1 mg/week could achieve.

Animals↗
PubMed1985

Chemotherapy of primary brain tumors.

This article covers chemotherapy of malignant astrocytomas, ependymoma, and medulloblastoma. The future direction of anticancer drugs is discussed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1985

Central nervous system toxicity and cerebrospinal fluid pharmacokinetics of intraventricular 3-[(4-amino-2-methyl-5-pyrimidinyl)ethyl]-1-(2-chloroethyl)-1-nitro soureas and other nitrosoureas in beagles.

The central nervous system toxicity and cerebrospinal fluid (CSF) pharmacokinetics of 3-[(4-amino-2-methyl-5-pyrimidinyl)ethyl]-1-(2-chloroethyl)-1- nitrosoureas, a (ACNU) were determined in beagles and compared to those for three other nitrosoureas, 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea, 1,3-bis(2-chloroethyl)-1-nitrosourea, and chlorozotocin. Of the four drugs, ACNU was tolerated best and at doses of 0.2 to 0.8 mg/week for 8 consecutive weeks. We found that the average half-time for CSF elimination of ACNU was 18 min (range, 12 to 38 min). This value exceeded the known rate of ACNU decomposition in aqueous solution (28 to 29 min), implying that the disappearance of ACNU from CSF was due to hydrolytic decomposition and cellular entry and/or transcapillary loss across central nervous system capillaries. The drug exposure integral (C X t) of ACNU in the CSF after a "toxic dose low" of 0.8 mg in the dogs would achieve the equivalent of in vitro cell kills in excess of 3 logs for rat 9L and human glioma 126 cells. As a potential therapeutic agent for meningeal neoplasia, the major limiting factor may be that the CSF elimination of ACNU is rapid compared to its equilibration time from ventricle to spinal- and cerebral convexity-subarachnoid space. Based on these results, we have instituted clinical Phase I trials of intra-CSF ACNU.

Animals↗
PubMed1985

Modification of uptake and antiproliferative effect of methylglyoxal bis(guanylhydrazone) by treatment with alpha-difluoromethylornithine in rodent cell lines with different sensitivities to methylglyoxal bis(guanylhydrazone).

Uptake characteristics and growth-inhibitory effects of methylglyoxal bis(guanylhydrazone) (MGBG), a competitive inhibitor of S-adenosylmethionine decarboxylase, were investigated in 9L rat brain tumor cells and in V79 hamster lung cells. Proliferation of 9L cells was only slightly inhibited by treatment with 40 microM MGBG alone, but when used in combination with 0.5 mM alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, proliferation was much more effectively inhibited. The intracellular concentration of MGBG was approximately 2-fold higher 4 days after cells were treated with both DFMO and MGBG, either simultaneously or when MGBG was added after a 48-hr DFMO pretreatment, than that in cells treated with MGBG alone. Polyamine levels in DFMO- and MGBG-treated cells correlated with the antiproliferative effects of the drugs. Used either alone or in combination with 1 mM DFMO, 0.5 microM MGBG inhibited the growth of and eventually killed V79 cells. Simultaneous or sequential treatment with DFMO and MGBG increased intracellular concentrations of MGBG at 4 days by 2- and 3-fold, respectively, compared to treatment with MGBG alone. Intracellular polyamine levels did not correlate with the antiproliferative effect of the two drugs in V79 cells. In both cell lines, polyamines and MGBG share a common transport system. The net transport of polyamines and MGBG was more temperature dependent and up to 10-fold more active in V79 cells than in 9L cells. The Km and Vmax values for spermidine and MGBG measured 10 sec after addition (initial permeation) were not affected by DFMO pretreatment in either cell line. However, 1 hr after administration, the Vmax values for spermidine and MGBG uptake were doubled in V79 cells pretreated for 48 hr with DFMO; no significant change occurred in 9L cells. Mitochondrial function, assessed by pyruvate oxidation, was substantially impaired by MGBG in V79 cells but not in 9L cells when the intracellular concentrations of MGBG were equal in each cell line. Pretreatment with DFMO did not increase MGBG-induced inhibition of pyruvate oxidation in V79 cells. These results show that, compared with V79 cells, the decreased sensitivity of 9L cells to MGBG may be related to decreased intracellular MGBG accumulation but not to cellular permeation such as carrier transport. Results of measurements of both polyamine levels and mitochondrial function indicate that V79 cells may be more susceptible to nonpolyamine-dependent effects of MGBG than are 9L cells.

Animals↗
PubMed1985

Potential antiglioma activity of 9-hydroxy-2-N-methylellipticine as determined by pharmacological and human tumor clonogenic cell studies.

The antiglioma activity of elliptinium (HME) was investigated in a human glioma clonogenic cell assay. Early passage cells of three human glioma cell lines (SF126, SF375, and SF407) were exposed to HME at the clinically achievable dose of 3 microM for 3 h. At this HME concentration, clonogenic cell survival was reduced by more than 3 logs in SF126 and SF375, and by 0.8 logs in SF407. A study of the kinetics of cell kill showed that whereas at moderate (less than or equal to 1.5 microM) HME doses cell kill increased with treatment time up to a maximum at approximately 3 h, cytotoxicity was more dose than time dependent at higher doses. Flash treatment of SF375 cells with 3 microM HME resulted in more than 2 logs clonogenic cell kill. Using high-pressure liquid chromatography, we investigated the in vitro decay kinetics of HME under our in vitro drug treatment conditions and observed a very rapid, protein nondependent 40% drop in HME concentration which was dose dependent and was probably due to HME adsorption on the surface of tissue culture plasticware. Subsequent decay of the drug was very slow, with a decay rate constant of 0.022/h and a half-life of 298 h. In order to determine whether HME crosses the blood-brain barrier, we measured the rat brain capillary permeability coefficient, P, of [3H]HME and [14C]HME. The mean P value of 2.2 X 10(-6) cm/s +/- 16% (SD) suggests that HME crosses the blood-brain barrier (t 1/2 = 46 min) consistent with its molecular size and octanol-water partition coefficient.

Alkaloids↗
PubMed1984

CNS toxicity and CSF pharmacokinetics of intraventricular DFMO and MGBG in beagle dogs.

We have developed a beagle dog model to study the pharmacology and toxicology of anticancer drugs administered through the 3rd or lateral ventricles. A Foltz-type reservoir was implanted SC and connected by tube into a cerebral ventricle. Drugs were administered directly into the reservoir; CSF sampling of drugs administered into the ventricle was achieved directly by tapping the reservoir or by percutaneous puncture of the cisterna magna. In the current study, we evaluated the CSF pharmacokinetics and CNS toxicity of two inhibitors of polyamine metabolism, alpha-difluoromethylornitine (DFMO) and methylglyoxal bisguanylhydrazone (MGBG). Both drugs were judged too toxic to justify intrathecal or intraventricular studies with these agents in patients.

Animals↗
PubMed1984

Evaluation of desmethylmisonidazole-induced neurotoxicity in the rat using brainstem auditory evoked potentials.

Brainstem auditory evoked responses (BAEPs) and a scale that evaluates clinical signs of neurotoxicity were used to measure the onset of neurotoxic effects seen in rats after chronic injection of 400 mg/kg/day of the radiosensitizer desmethylmisonidazole (DMM) for 5 days/week for 7 weeks. A significant neurotoxic effect was indicated by increases in the latencies of peaks 4 and 5 of the BAEP after the 24th injection of DMM; clinical signs of neurotoxicity were observed after the 30th injection. Histologic examination of brainstems from rats sacrificed after selected number of injections during treatment showed that the onset of lesions in the brainstem was gradual but not extensive. Pentobarbital used as an anesthetic agent had no effect on the induction of neurotoxicity.

Anesthesia↗
PubMed1984

Phase I study of intravenous bromodeoxyuridine used concomitantly with radiation therapy in patients with primary malignant brain tumors.

We report here the results of a Phase I study conducted to determine the toxicity and serum levels that could be tolerated by patients receiving i.v. bromodeoxyuridine (BUdR) concomitantly with radiation therapy. Because of severe thrombocytopenia and leukopenia that was produced in three patients treated by a 96 hour infusion of BUdR at a dose of 1.5 g/m2/24 hours, the dose was reduced to 0.8 g/m2/24 hours in these patients and the remaining 9 patients in the study group. Even at this dosage, myelotoxicity was observed. BUdR levels were measured by an isocratic high performance liquid chromatographic (HPLC) method developed for this study. Results of in vitro studies conducted by others suggest that serum levels produced in our patients by administration of doses of 0.6 to 0.8 g/m2/24 hours should be adequate to achieve a therapeutic effect.

Adult↗
PubMed1984

5-Fluorouracil and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) followed by hydroxyurea, misonidazole, and irradiation for brain stem gliomas: a pilot study of the Brain Tumor Research Center and the Childrens Cancer Group.

Twenty-eight evaluable children with the diagnosis of brain stem glioma were treated with 5-fluorouracil and CCNU before posterior fossa irradiation (5500 rads); during irradiation, the children received hydroxyurea and misonidazole. The treatment was well tolerated, and minimal toxicity was produced. The median relapse-free survival was 32 weeks, and the median survival was 44 weeks. Analysis of covariates showed that, in patients between the ages of 2 and 19 years, survival was longest in the older children (P less than 0.02). Tumor histology, sex, extent of operation (if any), Karnofsky score, and radiation dose did not correlate with survival.

Adolescent↗
PubMed1984

Brachytherapy of recurrent malignant brain tumors with removable high-activity iodine-125 sources.

Thirty-seven patients harboring recurrent malignant primary or metastatic brain tumors were treated by 40 implantations of high-activity iodine-125 (125I) sources. All patients had been treated with irradiation and most had been treated with chemotherapeutic agents, primarily nitrosoureas. Implantations were performed using computerized tomography (CT)-directed stereotaxy; 125I sources were held in one or more afterloaded catheters that were removed after the desired dose (minimum tumor dose of 3000 to 12,000 rads) had been delivered. Patients were followed with sequential neurological examinations and CT scans. Results of 34 implantation procedures were evaluable: 18 produced documented tumor regression (response) for 4 to 13+ months; five, performed in deteriorating patients, resulted in disease stability for 4 to 12 months. The overall response rate was 68%. In 11 patients, implantation did not halt clinical deterioration. At exploratory craniotomy 5 to 12 months after implantation, focal radiation necrosis was documented in two patients whose tumor had responded initially and then progressed, and in three patients whose disease had progressed initially (four glioblastomas, one anaplastic astrocytoma); histologically identifiable tumor was documented in two of these patients. All improved after resection of the focal necrotic mass and are still alive 10, 15, 19, 24, and 25 months after the initial implantation procedure; only one patient has evidence of tumor regrowth. The median follow-up period after implantation for the malignant glioma (anaplastic astrocytoma and glioblastoma multiforme) group is 9 months, with 48% of patients still surviving. While direct comparison with the results of chemotherapy is difficult, results obtained in this patient group with interstitial brachytherapy are probably superior to results obtained with chemotherapy.

Adolescent↗
PubMed1984

Supratentorial malignant gliomas of childhood. Results of treatment with radiation therapy and chemotherapy.

Twenty-seven patients aged 1 to 18 years harboring supratentorial (20 in the cerebrum and seven in the thalamus) malignant gliomas were treated between 1975 and 1982. There were four glioblastomas multiforme, 14 anaplastic astrocytomas, and nine malignant gliomas. All patients had a subtotal resection or biopsy as the initial procedure and received postoperative radiation therapy (RT). Fifteen of 27 patients were treated by RT alone; 14 had tumor progression with a median time to tumor progression (MTP) of 65 weeks. Twelve patients were treated with chemotherapy as an adjuvant to RT; only seven had tumor recurrence, with an MTP of 130 weeks. Of the 21 patients with recurrent tumors in both groups, 18 were treated with chemotherapy alone, or chemotherapy with a second surgical procedure or second course of RT. For all histological grades of tumor, the MTP for first recurrence was 75 weeks and the median survival time was 180 weeks. Age at initial diagnosis was found to be a statistically significant prognostic factor, with patients younger than 10 years of age surviving longer than patients aged over 10 years (p = 0.02).

Adolescent↗
PubMed1984

Phase II evaluation of dibromodulcitol in the treatment of recurrent medulloblastoma, ependymoma, and malignant astrocytoma.

The authors have conducted a Phase II trial to evaluate orally administered dibromodulcitol in the treatment of 40 evaluable patients with recurrent medulloblastoma, ependymoma, and malignant astrocytoma. Ten of 20 patients harboring medulloblastoma responded to therapy with a median time to tumor progression (MTP) of 40 weeks, and four of 20 patients had no sign of progression of disease 4 years after treatment was begun. The MTP for all 12 patients with ependymoma was 30 weeks. Nine of these 12 patients had stabilization of their disease with an MTP of 67 weeks; three of these 12 patients had no signs of progression for 1 to 3 years after treatment was begun. Of six patients harboring supratentorial gliomas, none responded to dibromodulcitol. Two patients, one with a primitive neuroectodermal tumor and the other with a metastatic carcinoma of the breast, had stabilization of disease for more than 4 and 2 years, respectively.

Adolescent↗
PubMed1984

Misonidazole neurotoxicity in rats: Part I. Evaluation of misonidazole neurotoxicity in rats by analysis of brain stem auditory and cortical evoked potentials.

The effects of misonidazole (MISO) on brain stem evoked potentials (BAEPs) and cortical evoked potentials (CEPs) were evaluated in 16 Sprague-Dawley rats treated with the agent. As found in previous studies, serial BAEP values were diagnostic of the onset of MISO toxicity before clinical signs and symptoms appeared. However, MISO had no effects on CEPs, which remained essentially unchanged through the course of the experiment. At histologic examination, significant changes were found in the area of the brain stem, but there was no histologic evidence of damage to cortical or subcortical structures caused by MISO administration. The results of this study suggest that the neurotoxic effects of MISO are species-specific, and that while the rat model may be useful for comparison of the relative toxic effects of nitroimidazole radiosensitizers, it is not a model suited for measurement of neurotoxicity caused by MISO in humans and nonhuman primates.

Animals↗
PubMed1984

Misonidazole neurotoxicity in rats: Part II. Effect of pre- and intermittent treatment with pentobarbital on misonidazole neurotoxicity in the rat.

Rats pretreated for 5 days with 50 mg/kg of pentobarbital tolerated statistically significant higher doses of misonidazole before the onset of misonidazole-induced neurotoxicity than rats treated intermittently with the same dose of pentobarbital. Presumably in pretreated rats, pentobarbital induced an increase in the activities of hepatic microsomal enzymes that led to a more rapid metabolism of misonidazole than in rats treated only intermittently.

Animals↗
PubMed1983

Improvement in survival produced by sequential therapies in the treatment of recurrent medulloblastoma.

Thirty-six patients with recurrent medulloblastoma were treated with various combination chemotherapy protocols after initial treatment (usually irradiation) failed. Use of systemic chemotherapy was limited by depressed bone marrow reserves secondary to previous craniospinal irradiation. Intraventricular and intrathecal therapies included cytosine arabinoside (Ara-C), methotrexate, and thio-tepa given as single agents. Major systemic agents used alone or in combination included CCNU, procarbazine, vincristine, and the hexitol epoxides. Patients were reirradiated with or without misonidazole when there was definite tumor progression after all other therapies failed and/or because myelosuppression was so severe that further chemotherapy was not possible. Sequential systemic or intrathecal chemotherapy and reirradiation produced median survivals of two years and 25% quartile survivals of 2.9 years. The prognosis for patients harboring recurrent medulloblastoma has improved considerably over the years because of the therapeutic approaches reported here.

Adolescent↗
PubMed1983

Possible role of DT-diaphorase in the bioactivation of antitumor quinones.

Menadione derivatives that are toxic to tumor cells are believed to be reduced intracellularly to species that react with DNA. In this communication, we report evidence that one of these derivatives, 3-bromomethylmenadione, is reduced by DT-diaphorases present in rat liver cytosol and in rat 9L brain tumor cells. Dicoumarol, an inhibitor of DT-diaphorases was found to inhibit both the reduction of 3-bromomethylmenadione and its mutagenicity to Salmonella typhimurium TA 97. Homogenates of rat 9L cells were found to contain relatively high levels of DT-diaphorase, suggesting that these tumor cells may be relatively sensitive to antitumor quinones that are activated by this enzyme.

Animals↗
PubMed1983

Brain, CSF, and tumor pharmacokinetics of alpha-difluoromethylornithine in rats and dogs.

We have determined the pharmacokinetic parameters for diffusion of alpha-[5-14C]-difluoromethylornithine (DFMO) from blood to brain, blood to cerebrospinal fluid (CSF), 9L rat brain tumor to adjacent brain, and blood to the subcutaneously-implanted 9L tumor in rats, and within the CSF of beagle dogs. DFMO diffusion across the blood-brain and blood-CSF barriers is quite restricted in both rats and dogs, but diffusion across the defective capillary system of both subcutaneous and intracerebral 9L tumors in rats is not. Under steady-state plasma conditions in rats, uptake of DFMO by the intracerebral 9L tumor and diffusion from tumor 5-6 mm into adjacent brain is not restricted; tissue/plasma ratios were approximately 1. Therapeutic efficacy will therefore not be limited by transport of DFMO into tumor or to the extracellular environment of tumor.

Animals↗