Intra-arterial ACNU therapy for malignant brain tumors

Abstract

The authors examined the growth rate of mouse 203 glioma cells in vitro and found it to be markedly inhibited after exposure to ACNU for 5 minutes at a drug concentration of 100 micrograms/ml. Rats that had undergone intracranial implantation of T1 neurogenic tumor were treated by 5 mg/kg of ACNU administered either intravenously or intra-arterially. The median survival times for the control animals and the animals undergoing intravenous or intracarotid administration of ACNU were 23, 29, and 46 days, respectively. The difference in survival time between the intravenous and intracarotid administration groups was statistically significant (p less than 0.01) when examined by the Cox-Mantel test. In a clinical trial, 17 patients with glioblastoma were treated by ACNU, eight intravenously and nine by the intra-arterial route. The drug was given in doses of 2 to 3 mg/kg at least twice before and twice after a course of postoperative radiotherapy. Intra-arterial administration was performed over a period of 5 minutes under local anesthesia. The median postoperative survival time for the patients in the intra-arterial group was 12.5 months, compared with 9.0 months for those in the intravenous group. The survival rate for the intra-arterial group was slightly higher, although statistically not significant, probably because the number of cases was small. The degree of thrombocytopenia due to ACNU tended to be less marked in the intra-arterially treated patients. The theoretical advantages of the intra-arterial administration of ACNU are discussed.

Brain necroses after intraarterial chemotherapy and irradiation of malignant gliomas ? a complication of both ACNU and BCNU?

“…ACNU (3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-l-2-chloroethyl)-l-nitrosourea) has been favoured, as a water soluble drug, for intraarterial (ia) application because of (at least theoretically) fewer side effects [1][2][3][4]. Therefore we used ia AC-NU in a prospective, controlled study in addition to surgery and irradiation from March 1987 to April 1988 for the treatment of malignant gliomas.…”

Modulation of BUdR labeling index in rat brain tumors following intracarotid ACNU administration

“…Intracarotid infusion of chemotherapeutic agents has been expected to play an important role in enhancing therapeutic efficacy in the treatment of malignant gliomas [3][4][5][6][7]. The intracarotid administration may facilitate rapid crossing through the blood-brain barrier, and attain an effective level of agents in tumors as well as the surrounding and infiltrative zones without BBB disruption.…”

“…The intracarotid administration may facilitate rapid crossing through the blood-brain barrier, and attain an effective level of agents in tumors as well as the surrounding and infiltrative zones without BBB disruption. In practice, intracarotid administration has yielded a modest benefit on patient survival [3][4][5][6], and resuited in occasional ocular lesions with loss of visual acuity [4][5][6]. A renewed development of new drugs and techniques of intracarotid catheterization have been encouraging us to proceed with intracarotid infusion therapy.…”

“…Local therapy including surgery, radiation, and chemotherapy is theoretically applicable, because malignant brain tumors are relatively localized within the skull and have less propensity for extracranial metastasis. Intracarotid administratio _n of CENU may have the advantage of raising drug concentration reaching tumors [3][4][5][6][7].…”

Sensitivity of human malignant intracranial tumors against MCNU in vitro in comparison to ACNU and BCNU

“…ACNU (nimustine) was used in Japan and Europe as an alternative to BCNU because of its better solubility in water [10]. Subsequently, ACNU has been introduced into therapy studies concerning intraarterial infusion [11,12]. In 1970, methyl 6-[3-(2-chloroethyl) -3-nitrosureido] -6-deoxy-a-D-glucopyranoside (ranomustine; MCNU) was developed out of streptozotocin as a water soluble nitrosourea which should be less myelotoxic and less diabetogenic than related drugs [13].…”