Local and sustained delivery of 5-fluorouracil from biodegradable microspheres for the radiosensitization of glioblastoma: a pilot study.

BACKGROUND: The authors have developed a new method of drug delivery into the brain using implantable biodegradable microspheres. In this study, this method was used to provide localized and sustained delivery of 5-fluorouracil (5-FU) after the surgical resection of glioblastoma. This antimetabolite and radiosensitizing drug was selected in an attempt to decrease the rate of local recurrence of the tumor. METHODS: Eight patients with newly diagnosed glioblastoma were included in the study and 2 increasing amounts of 5-FU were studied (70 mg and 132 mg). After surgical resection of the tumor, poly(D-L lactide-co-glycolide) 5-FU-loaded microspheres with an average dimension of 45 microm were implanted in the wall of the surgical bed. External beam radiation (59.4 grays) was initiated before the seventh postsurgical day. Patients were followed by clinical examination, magnetic resonance imaging, and 5-FU assays in the blood and cerebrospinal fluid (CSF). RESULTS: 5-FU assays confirmed sustained concentrations in the CSF for at least 1 month. Concentrations of 5-FU in the blood were lower and transitory. Systemic tolerance to the treatment was good; one case of recurrent brain swelling was observed at the higher dose studied. At the time of last follow-up the overall median survival time was 98 weeks from the time of implantation and 2 patients had achieved disease remission at 139 and 153 weeks, respectively. CONCLUSIONS: This study demonstrates that biodegradable microspheres are efficient systems for drug delivery into the brain and may have future application in the treatment of brain tumors. Further studies are needed to confirm the potential of 5-FU-loaded microspheres for the radiosensitization of glioblastoma. [Please see editorial on pages 197-9, this issue].

Transnasal delivery of 5-fluorouracil to the brain in the rat.

The purpose of this research is to clarify the feasibility and to determine the extent of transnasal drug delivery to the brain through the cerebrospinal fluid (CSF) in the rat, using 3H-5-fluorouracil (5FU) as a model drug. It was confirmed first that the concentration of 5FU in the CSF was significantly higher following nasal administration compared with intravenous injection, indicating direct transport of 5FU from the nasal cavity to the CSF. Concentration-time profiles of 5FU in the plasma and in the cerebral cortex were determined following intravenous infusion, nasal instillation and nasal perfusion. In order to evaluate the extent of drug transport from the nasal cavity to the cerebral cortex by way of the CSF, the apparent brain uptake clearances were calculated. The uptake clearance following nasal perfusion (8.65 microl/min/g tissue) was significantly large (p < 0.001) in comparison with that following intravenous infusion (6.20 microl/min/g tissue), while that following nasal instillation (6.94 microl/min/g tissue) was not. Consequently, significant amount of 5FU is transported from the nasal cavity to the brain through the CSF and thus, the delivery of the hydrophilic drug to the brain is augmented by nasal drug application.

Intrathecal 5-fluorouracil in the rhesus monkey.

Because meningeal spread of both leukemia and solid tumors remains a difficult therapeutic problem, there is a compelling need to develop new agents for intrathecal administration. 5-Fluorouracil (5FU), an active anticancer agent, penetrates into the central nervous system to some degree following intravenous dosing. Significant systemic toxicity, however, is associated with this route of administration. Therefore, the pharmacokinetic behavior of 5FU following its intrathecal administration was studied in a rhesus monkey model. After a 10-mg intraventricular dose, the disappearance of the drug from ventricular cerebrospinal fluid was monoexponential, the half-life being 51 min; the area under the concentration-time curve (AUC) being greater than 18 mM h-1; and the peak ventricular 5FU concentrations ranging between 10 and 15 mM. After a 1-mg intralumbar dose, the AUC was 1235 microM h-1. No toxicity was observed following intraventricular administration of 5FU. After intralumbar administration of either a 10-mg or a 1-mg dose, however, local toxicity was observed in the lumbar spinal cord. These findings suggest that intrathecal administration of 5FU is not presently a feasible means of achieving cytotoxic cerebrospinal fluid concentrations.

Familial deficiency of dihydropyrimidine dehydrogenase. Biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity.

Severe neurotoxicity due to 5-fluorouracil (FUra) has previously been described in a patient with familial pyrimidinemia. We now report the biochemical basis for both the pyrimidinemia and neurotoxicity in a patient we have recently studied. After administration of a "test" dose of FUra (25 mg/m2, 600 microCi[6-3H]FUra by intravenous bolus) to a patient who had previously developed neurotoxicity after FUra, a markedly prolonged elimination half-life (159 min) was observed with no evidence of FUra catabolites in plasma or cerebrospinal fluid and with 89.7% of the administered dose being excreted into the urine as unchanged FUra. Using a sensitive assay for dihydropyrimidine dehydrogenase in peripheral blood mononuclear cells, we demonstrated complete deficiency of enzyme activity in the patient and partial deficiency of enzyme activity in her father and children consistent with an autosomal recessive pattern of inheritance. Patients who are deficient in this enzyme are likely to develop severe toxicity after FUra administration.

Passage of 5'-dFUrd and its metabolites 5-FU and 5-FUH2 to CSF in a clinical phase 1 study.

Lumbar puncture was performed on eight patients in a clinical Phase 1 study of doxifluridine (5'-dFDrd). 5'-dFUrd, 5'FU, and 5-FUH2 were shown to cross the blood-brain barrier to CSF. The maximal concentrations of 5'-dFUrd and 5-FUH2 were about 1-3% of the maximal concentrations in plasma, and were reached within 1-4 h after the end of iv infusion of 5'-dFUrd. 5-FUH2 showed a marked increase in CSF between 3 and 4 h to about 40-60% of the maximal plasma concentration in 5 of the patients, indicating a possible further increase after 4 h. The relationship between the concentrations of 5'-dFUrd and its metabolites in the CSF, and CNS toxicity is discussed.

Effect of intravenous dose and schedule on cerebrospinal fluid pharmacokinetics of 5-fluorouracil in the monkey.

There is little information regarding the pharmacology of 5-fluorouracil (5-FUra) in the central nervous system (CNS), despite its role in the treatment of diseases with CNS metastases and recent reports of neurotoxicity. In this study, the plasma and cerebrospinal fluid (CSF) pharmacokinetics of 5-FUra were examined in a primate model. Following a bolus dose, the area under the concentration versus time curves for 5-FUra in CSF was 48% of the plasma area under the concentration versus time curves. For continuous infusion of 5-FUra, the area under the concentration versus time curves ratio for CSF:plasma was 20 or 11%, depending upon the infusion rate. The mechanism for variations in CSF exposure based upon the pattern of plasma delivery is consistent with local metabolism of 5-FUra in the CNS. These findings should be considered in the evaluation of delivery schedules which are intended to maximize drug delivery to the CNS and/or minimize neurotoxicity.

[FT-207 and 5-FU concentrations in brain tumor tissues, plasma and CSF after administration of FT-207 suppository].

FT-207 suppository was administered to 19 patients with brain tumors. FT-207 and 5-FU concentrations in tumor tissues and plasma were measured using chemical assay method. After operation, FT-207 and 5-FU concentrations in plasma and CSF were measured serially for 24 hours in some patients following administration of FT-207 suppository. Following results were obtained. 1) The level of 5-FU concentration in tumor tissues was higher than that of in plasma while the level of FT-207 concentration in tumor tissues was lower than that of in plasma. 2) The level of 5-FU concentration in CSF had been kept highly very longer time, compared with that of in plasma. On the other hand the level of FT-207 concentration in plasma and CSF decreased rapidly. 3) About 0,05 mcg/ml of 5-FU in CSF would be maintained for 24 hours in patients following administration of FT-207 suppository (1 g, daily) for 3 days or more.

[Cerebrospinal fluid distributions of systemically administered fluorinated pyrimidines].

Transfer of systemically administered fluorinated pyrimidines (Tegafur, TAC-278, HCFU and FD-1) to cerebrospinal fluid was studied in 7 patients primary brain tumors. Seven patients had had irradiation and also had V-P shunt operation for hydrocephalus 5-FU concentration in CSF was extremely high in FD-1 and TAC-278 administration, but not in Tegafur and HCFU administration. In addition, Tegafur and HCFU did not reveal any cumulative effects of 5-FU in CSF by continuous prolonged systemic administration. The facts suggest strongly the usefullness of the agents in the treatment of intracranial neoplasms, which have high CSF concentrations. However, intermediate metabolites of 5-FU in CSF are different from those in systemic pathway, and FD-1 and TAC-278 produce CNS toxicities. Therefore, further extensive studies are necessary to utilize these agents for the treatment of intracranial neoplasms.