One of the nitrosourea compounds developed in Japan is ACNU (1-(4-amino-2-methyl pyridimine-5-yl)-methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride), a drug that is soluble in water as well as in lipids, as shown by its low log p (1-octanol/water partition coefficient) of 0.92.14 In Japan, ACNU has been widely used in treating malignant brain tumors. Its clinical effectiveness by intra-arterial and systemic intravenous administration has been described in several reports.7,14,16,24 One disadvantage of intra-arterially injected nitrosoureas is the occasional toxicity to vision that is probably related to the ethanol solvent.9 No such toxicity has been reported with water-soluble ACNU.16,24
Criticisms concerning chemotherapy of brain tumors have included the difficulty in attaining an effective drug concentration in the areas adjacent to the main tumor.1 A high concentration is desired because of the infiltrative character of most malignant brain tumors and because of the infiltration of malignant cells into areas of normal brain before neovascularization is induced by tumor. Unlike the primary tumor, the permeability characteristics in these regions are determined by normal or nearly normal capillaries. Lipophilic drugs such as BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) have proven to be more effective than water-soluble drugs with respect to the concentration of drug in the brain adjacent to tumor.6,11,12,23
In one study in which ACNU was injected intra-arterially into rat brain tumors, a higher concentration of ACNU was obtained in the tumor tissue than in other parts of the brain.8 One method of increasing ACNU levels in tumor tissue as well as in the surrounding tumor-infiltrated brain is to open the BBB with a hyperosmotic agent before intra-arterial drug injection.19–21
In this paper we summarize clinical studies that we performed in an attempt to clarify the advantage of intra-arterial over intravenous injection and also the advantage of moderate BBB opening plus intra-arterial injection over intra-arterial injection alone in enhancing the tissue concentration of ACNU.
Levin VALandahl HDFreeman-Dove MA: The application of brain capillary permeability coefficient measurements to pathological conditions and the selection of agents which cross the blood-brain barrier. J Pharmacokinet Biopharm 4:499–5191976J Pharmacokinet Biopharm 4:
Muraoka K: [ACNU delivery to malignant brain tumor tissue and serum: route of administration and combined use of phenobarbital.] No To Shinkei 35:1199–12061983 (Jpn)Muraoka K: [ACNU delivery to malignant brain tumor tissue and serum: route of administration and combined use of phenobarbital.] No To Shinkei 35:
Nakamura KAsami MKawada Ket al: [Quantitative determination of ACNU (3-[(4-amino-2-methyl-5-pyrim-idinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride), a new water-soluble anti-tumor nitrosourea, in biological fluids and tissues of patients by high-performance liquid chromatography. I. Analytical methods and pharmacokinetics.] Ann Rep Sankyo Res Lab 29:66–741977 (Jpn)Ann Rep Sankyo Res Lab 29:
Neuwelt EAHill SAFrenkel EP: Osmotic blood-brain barrier modification and combination chemotherapy: concurrent tumor regression in areas of barrier opening and progression in brain regions distant to barrier opening. Neurosurgery 15:362–3661984Neurosurgery 15:
Syringe infusion pump, Model STC-521, manufactured by Terumo, Japan.