Evaluation of in vitro and in vivo antitumor activity of BCNU-loaded PLGA wafer against 9L gliosarcoma.

The purpose of the present study was to develop implantable BCNU-loaded poly(D,L-lactide-co-glycolide) (PLGA) wafer for the controlled release of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and to evaluate its in vitro and in vivo antitumor activity. The release rate of BCNU from PLGA wafer increased with the increase of BCNU amount loaded and the release was continued until 7 days. In vitro and in vivo antitumor activity of BCNU-loaded PLGA wafer was investigated using in vitro cytotoxicity against 9L gliosarcoma cells and a subcutaneous (s.c.) solid tumor model of 9L gliosarcoma, respectively. The wafers containing BCNU showed more effective cytotoxicity than BCNU powder due to its short half-life and inhibited the proliferation of 9L gliosarcoma cells. BCNU-loaded PLGA wafer delayed the growth of the tumors significantly and increasing the dose of BCNU in the wafer resulted in a substantial regression of the tumor. These results of antitumor activity of BCNU-loaded PLGA wafer demonstrate the feasibility of the wafers for clinical application.

Plasma pharmacokinetics and bioavailability of 1-(2-chloroethyl)-3-sarcosinamide-1-nitrosourea after intravenous and oral administration to mice and dogs.

PURPOSE: Chloroethylnitrosoureas are among the most widely used chemotherapeutic agents for the treatment of brain tumors. SarCNU (1-(2-chloroethyl)3-sarcosinamide-1-nitrosourea) is an investigational nitrosourea analogue that has shown greater antitumor activity and a more favorable toxicity profile than 1,3-bis(2-chloroethyl)-1-nitrosourea in preclinical studies. The purpose of the present study was to characterize the plasma pharmacokinetics and oral bioavailability of SarCNU in mice and dogs treated by intravenous infusion and gastric intubation. METHODS: SarCNU was administered to mice by i.v. injection or orally at doses ranging from 10 to 100 mg/kg. Plasma samples were obtained from groups of five animals at each time-point at intervals ranging from 3 min to 2.5 h after dosing. A group of three male beagle dogs were treated with Sar CNU 10 mg/kg given both by i.v. infusion and orally in a crossover design. The concentration of SarCNU in plasma was measured by high-performance liquid chromatography. RESULTS: During the initial 90 min after i.v. injection to mice, SarCNU was eliminated from plasma in a monoexponential manner with a mean half-life of 9.8 +/- 0.8 min. The total plasma clearance was 47.3 +/- 8.7 ml/min per kg and the apparent volume of distribution was 0.7 +/- 0.1 l/kg. SarCNU exhibited linear pharmacokinetic behavior following both i.v. and oral administration of doses ranging from approximately 10 to 100 mg/kg. Peak plasma levels provided by a dose of 100 mg/kg given by the i.v. and oral routes were 142.4 microg/ml (0.5 min) and 27.8 microg/ml (9.8 min), respectively. The mean oral bioavailability of the drug was 57.3 +/- 12.6% in mice. In comparison, the disposition of SarCNU in dogs after rapid i.v. injection was biexponential, with half-lives of 5.4 +/- 8.4 min and 40.8 +/- 9.0 min for the initial and terminal disposition phases, respectively. Mean values of the total plasma clearance and apparent volume of distribution were 17.8 +/- 1.8 ml/min per kg and 1.1 +/- 0.3 l/kg, respectively. The Cmax was 18.5 +/- 6.5 microg/ml after i.v. injection and 8.5 0.4 microg/ml after oral administration of a 10 mg/kg dose. Oral bioavailability of the drug in dogs (71.7 +/- 21.2%) was greater than that observed in mice. CONCLUSIONS: SarCNU exhibited linear and consistent pharmacokinetics in mice and dogs with very good oral bioavailability in both species. These findings support the rationale for evaluating SarCNU given by the oral route of administration in phase I clinical trials.

Timing of hypertonic glucose and thermochemotherapy with 1-(4-amino-2-methylpyrimidine-5-yl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) in the BT4An rat glioma: relation to intratumoral pH reduction and circulatory changes after glucose supply.

PURPOSE: Intraperitoneal hypertonic glucose has previously been shown to induce hyperglycemia, hemo-concentration, and to influence systemic and tumor circulation, and, thus, enhance the effect of thermochemotherapy with 1-(4-amino-2-methylpyrimidine-5-yl)methyl-3-(2-chloroethyl)-3-nitrosoure a (ACNU) and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). However, the optimal timing and the precise mechanisms responsible are not known. The effect of different time intervals between glucose load and thermochemotherapy with ACNU in the treatment of BT4An tumors, therefore, was investigated. Changes of serum glucose (Se-glucose), hemoglobin, systemic circulation parameters, tumor pH, and tumor temperature, induced by intraperitoneal glucose and/or hyperthermia, were measured to assess their effect on tumor growth. METHODS AND MATERIALS: (a): Inbred BD IX rats with BT4An tumors on the hind leg were treated with ACNU 7 mg/kg intravenously just before waterbath hyperthermia, and intraperitoneal hypertonic glucose (6 g/kg) at different time intervals before (240-0 min) or immediately after thermochemotherapy. (b): Intratumoral pH and temperature were measured at different intervals after intraperitoneal glucose, and during hyperthermia with or without previous glucose. (c): Hemoglobin, hematocrit, and Se-glucose were measured at different times after intraperitoneal glucose. (d): Mean arterial pressure, pulse pressure, and heart rate were measured for 120 min after intraperitoneal glucose. RESULTS: (a): The number of tumor controls and the growth delay was greatest with glucose 45 min before thermochemotherapy, and least with a time interval of 240 min. Glucose after thermochemotherapy delayed tumor growth. (b): After intraperitoneal glucose alone, intratumoral pH decreased gradually from 6.76 to 5.86 after 240 min. Hyperthermia 120 min after glucose induced a rapid further pH drop, while hyperthermia alone had no significant influence on pH. Intratumoral temperature was higher during hyperthermia in animals given glucose. (c): A substantial rise of Se-glucose and hemoglobin developed. The hemoconcentration was maintained also after reduction of Se-glucose towards normal values. (d): An initial tachycardia, and a reduction of the mean arterial pressure of about 10% 5-45 min after was measured. CONCLUSION: The data indicate that a complex interaction between gradually reduced tumor pH, hyperglycemia, hemoconcentration, and reduced tumor blood flow, and not a breakdown of systemic circulation, is responsible for the effect of intraperitoneal glucose on thermochemotherapy with ACNU. Interestingly, enhancement of thermochemotherapy effect was also seen when intraperitoneal glucose was given after heat and ACNU.

Neurotoxicity after intracarotid 1,3-bis(2-chloroethyl)-1-nitrosourea administration in the rat: hemodynamic changes studied by double-tracer autoradiography.

Changes in blood-brain (BBB) permeability and local cerebral blood flow after intracarotid administration of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) were examined quantitatively in rats with double-tracer autoradiography using [14C]alpha-amino-isobutyric acid and [18F]fluoroantipyrine. Forty-eight female Wistar rats were divided into four groups. The control group (Group 1) received 1 ml of 5% dextrose. The other three groups received three different doses of BCNU dissolved in 5% dextrose: Group II rats received 1 mg, Group III 3 mg, and Group IV 10 mg. The tracer study was performed on Day 1 or Days 4 to 12 after intracarotid administration of BCNU. In 11 rats in Group II, there were no changes of BBB permeability. Transient BBB permeability changes were seen in the striatum or hippocampus in 3 of the 5 rats (60%) in Group III within 24 hours. In 8 of 9 rats (89%) in the same group, late BBB permeability changes were observed in the hypothalamus with or without histological changes. BBB permeability changes were seen in all rats of Group IV. Focal increase of local cerebral blood flow on the infused side compared with the non-infused side of the brain was observed, although not at a significant level, in 5 of 25 rats examined with [18F]fluoroantipyrine. The results of BBB permeability and histological examinations and study of heterogenous distribution by [18F]fluorodeoxyglucose indicated that the ipsilateral subcortical structures such as the hypothalamus, amygdala, internal capsule, and caudate putamen have the highest incidence of neurotoxicity, which are closely related to histopathological damage seen in human BCNU leucoencephalopathy.(ABSTRACT TRUNCATED AT 250 WORDS)