Intracerebral penetration and tissue distribution of 2,5-diaziridinyl 3,6-bis(carboethoxyamino) 1,4-benzoquinone (AZQ, NSC-182986)

Abstract

[14C]AZQ (2-4 mg/m2, 100-200 mCi) was administered at varying times to five patients undergoing surgical resection of intracerebral tumors. Plasma, cerebrospinal fluid (CSF), edematous brain, and tumor specimens were obtained during surgery and the concentration of AZQ was determined radiochemically and chromatographically. Total [14C]AZQ equivalent concentration in tumor for two patients was determined to be 47.5% and 85% of concurrent plasma concentration which was similar to that found in normal brain (60.4% and 75.5% respectively). Only 18-45% of the total radioactivity in tumor tissue and 30-56% in plasma were accounted for by unchanged AZQ. These findings suggest that AZQ may be metabolized to a certain extent. Tissue samples from various organs were obtained during autopsy in a patient who expired ten days after AZQ administration. The highest AZQ concentration was found in the liver, followed by the kidney. Comparable amounts were found in normal brain and brain tumor (22 ng/g vs. 31 ng/g respectively). These results indicate that AZQ penetrates readily into the normal brain and brain tumor with a tendency to persist.

Combined intraommaya methotrexate, cytosine arabinoside, hydrocortisone and thio-TEPA for meningeal involvement by malignancies

“…Secondly, systemic chemotherapy with drugs that do not cross the intact blood-brain or blood-CSF barrier is effective against meningeal carcinomatosis in rats [24]. Thirdly, we have been able to demonstrate that many different chemotherapeutic agents are capable of reaching high concentrations in human intracerebral tumors despite poor penetration into the normal central nervous system [25][26][27][28][29][30][31][32][33][34][35]. Fourthly, intraOmmaya chemotherapy by itself would not be likely to be effective against thick meningeal tumor deposits and tumor deposits deep in the VirchowRobin spaces [6,11].…”

A phase II trial of 2,5,-diaziridinyl 3,6-bis (carboethoxy amino) 1,4-benzoquinone (AZQ, NSC 182986) in recurrent primary brain tumors

“…It was also effective against IC LI210 and P388 leukemia. Preliminary data in humans indicated AZQ penetrates readily into the normal brain and brain tumor with a tendency to persist (6). A phase I evaluation of *Supported by NCI Contract NOI-CM-97277 AZQ has been recently completed at University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, in which the drug was administered intravenously on a 5-day schedule (7).…”

Aziridinylbenzoquinone (AZQ) in the treatment of recurrent pediatric brain and other malignant solid tumors

“…Nine patients with brain tumors and 14 with solid tumors were inevaluable because of refusal of therapy [13], inadequate trial, i.e. less than one course of treatment [5], protocol violation [1], inadequate data [2] or being ineligible [2]. There were 19 early deaths (9 children with brain tumors and 10 with solid tumors).…”

“…Aziridinylbenzoquinone (AZQ) is a synthetic quinone with pharmacologic properties favoring entry into the central nervous system [1,2]. AZQ was synthesized with the hopes of providing an agent with particular activity against central nervous system tumors.…”