Penetration of N-(Phosphonacetyl)-L-aspartateinto Human Central NervousSystem and Intracerebral Tumor

patients in this study. CSF was obtained by lumbar puncture from 5 patients who received PALA(800 to 3600 mg/sq m by 1- to 2-hr i.v. infusion) during Phase I evaluation of the drug. Patients with known intracerebral matastaseswere excluded, although one patient had meningeal lymphoma. Multiple CSF sampleswere obtained from 2 additional patients with perma nent indwelling s.c. (Ommaya)reservoirs. One female patient was in remissionfrom CNS metastasesfrom breast carcinoma following surgery, cranial irradiation, and systemic chemother apy; she received PALA in a dosage of 800 mg/sq m. The other patient had recently completed cranial irradiation for meningeal carcinomatosis and was receiving intraventricular methotrexate periodically. He was given 1000 mg/sq m of PALA. An additional 8 patients undergoing surgical resection of primary or metastatic intracerebral tumors received PALAat 200 to 1000 mg/sq m i.v. for 30 to 60 mm during the preop erative or intraoperative period. Diagnosesof patients studied included glioblastoma multiforme (one patient), metastatic ad enocarcinoma from breast, lung, endometrium, and unknown primary (4 patients), metastatic oat cell carcinoma of the lung (one patient), and metastatic malignantmelanoma(2 patients). Surgically resected tumor specimens were assayed for pres ence of drug. Temporalis muscle served as an extracerebral control, since it was readily accessible at the time of surgery. It is not known how PALA penetration into temporalis muscle compares to penetration into other extracerebral tissues. Edematousbrain tissue was also obtained from some patients. Generally, this consisted of small amounts of white matter adherent to resected tumor or of very small fragments of brain tissue in the tumor cavity that had inadvertently beendislodged during the course of surgery. Normal brain tissue was not removed, except in the patient with glioblastoma multiforme who underwent an occipital lobectomy. Plasmawas obtained by venipuncture with heparin as the anticoagulant. Materials.L-[U-”C]Aspartic acid(specificactivity,192 mCi/ mmol) was purchased from New England Nuclear, Boston, Mass. After purification (14), it was diluted to 0.25 to 0.38 mCi/mmol. The dilithium salt of carbamoylphosphatewas pur chased from Sigma ChemicalCo., St. Louis, Mo. 4-(2-Hydrox yethyl)-1-piperazineethanesulfonic acid buffer was obtained from Calbiochem-Behring Corp., La Jolla, Calif. , and Dowex 50W-X8 (H@) was from Bio-RadLaboratories, Richmond,Calif. The liquid scintillation fluid PCS was purchased from Amer sham/Searle Corp., Arlington Heights, III. Alamine was ob tamed from the McKerson Corp., and Freon was purchased from Ashland ChemicalCo. Tissue Preparation. Tissueswere weighed and homoge nized in 5 volumesof 0.4 M perchloric acid. The homogenates were centrifuged, and the supernatant was removed. The su pernatantswere neutralizedwith 0.4 MAlaminein Freon. They