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Methylglyoxal bis(guanylhydrazone) (MGBG; NSC 32946) is currently being reevaluated for its clinical antineoplastic activity against both hematological and solid tumors. MGBG (100 to 200 mg/sq m) was administered by slow infusion over 3 hr to six patients during surgical resection of intracerebral tumors. Excised tumor tissue and plasma were assayed for MGBG by high-pressure liquid chromatography. In all cases, MGBG penetrated rapidly into brain tumor tissue. Viable tumor tissue contained greater concentrations of MBGB than did necrotic tumor tissue. In two patients with glioblastoma multiforme, MBGB concentrations in brain tumor tissue were five- to 19-fold higher than concurrent plasma samples. However, MGBG did not penetrate well into the cerebrospinal fluid of two patients with Ommaya reservoirs given i.v. MGBG (200 mg/sq m). The highest MGBG concentration in cerebrospinal fluid reached only 22% of the concurrent plasma levels. These studies suggest that MGBG may be a useful agent in the treatment of intracerebral tumors but may not be effective against meningeal leukemia and meningeal carcinomatosis.

A phase I study of intracarotid cis-diamminedichloroplatinum was performed in 11 patients with intracerebral tumors (five glioblastoma, four melanoma, one meningeal sarcoma, and one lung carcinoma) progressing after radiation +/- chemotherapy. The internal carotid artery was temporarily cannulated by a percutaneous transfemoral approach. All patients received i.v. heparin, mannitol, and fluids; seven received dexamethasone, 50 mg i.v., twice the day before and the day of treatment. Intracarotid cis-diamminedichloroplatinum, 60 to 100 mg/sq m in 175 to 250 ml 0.45% NaCl solution with 1000 units heparin, was infused over 1 hr. Six patients received two or more courses (maximum of 6) at 2- to 8-week intervals. Gastrointestinal toxicity was mild to moderate. Ototoxicity was minor. Central nervous system (CNS) toxicity was focal, severe, permanent, and possibly due to embolus in one patient at 75 mg/sq m; focal and reversible in one patient at 100 mg/sq m; and generalized but reversible in one patient at 75 mg/sq m. Possible CNS toxicity was noted in two additional patients. Two patients with CNS toxicity developed permanent ipsilateral retinal toxicity, and one patients without CNS toxicity developed bilateral decreased visual and auditory acuity 2 weeks after his sixth treatment. Renal and hematological toxicity and orbital pain were mild. Response status included: early death, one; probable responses, six (2+ 4+, 6, 6+, 8, and 8+ months); stabilization, two (3+ and 4 months); and failure, two. We recommend cis-diamminedichloroplatinum (60 mg/sq m) every 2 to 4 weeks for Phase II studies. Severe CNS and retinal toxicity are possible.

The antitumor agent 3-deazauridine (DAU) was administered rapidly to four patients before surgical removal of intracerebral tumor. Tumor, adjacent brain tissue, and temporalis muscle were assayed for DAU by high-pressure liquid chromatography. DAU penetrated comparably into tumor, brain, and muscle; in one patient, tissue concentrations were higher than concurrent plasma concentrations. The active metabolite 3-deazauridine 5'-triphosphate was quantitated in one tumor sample and greatly exceeded its Ki for cytidine 5'-triphosphate synthetase. DAU was also present in autopsy brain specimens from two patients treated shortly antemortem. Cerebrospinal fluid concentrations were 22.1 and 59.0%, respectively, of concurrent plasma concentrations during continuous infusion of DAU in two patients. Cerebrospinal fluid concentration was 3.1 microgram/ml 2 hr after a 30-min infusion of 1.5 g of drug per sq m and fell to 1.9 microgram/ml at 16 hr. Thus, DAU is capable of penetrating into intracerebral tumor, brain, and cerebrospinal fluid and is worthy of investigation in the treatment of intracerebral and meningeal neoplasms.

Cerebrospinal fluid (CSF) was obtained from five patients by lumbar puncture and from two patients by Ommaya reservoir tap after the i.v. administration of the antitumor agent N-(phosphonacetyl)-L-aspartate (PALA). PALA was quantified enzymatically by inhibition of the target enzyme, aspartate carbamoyltransferase. After a 1-hr infusion of PALA, its CSF concentration steadily rose until the eighth hr, at which time it was 12 to 40% of concurrent plasma concentration. PALA concentration then declined more gradually in CSF than in plasma, and CSF concentrations exceeded plasma concentrations by 24 hr. PALA concentration X time product in CSF was 12 to 25% of that in plasma. PALA was infused i.v. for 30 to 60 min into eight patients undergoing surgical resection if intracerebral tumors. Its concentration in intracerebral tumor was greater than or comparable to concentration in temporalis muscle in four of six patients from whom muscle was obtained. The PALA concentration in edematous brain tissue was consistently lower than the concentration in tumor or muscle. In a patient undergoing occipital lobectomy, the PALA concentration in brain was inversely proportional to the distance from the tumor. PALA reached concentrations in intracerebral tumor that appeared to be similar to concentrations reported previously in s.c. tumors, although biopsy techniques and conditions differed.