Therapeutic activity of the topoisomerase I inhibitor J-107088 [6-N-(1-hydroxymethyla-2-hydroxy) ethylamino-12,13-dihydro-13-(β-D-gluco pyranosyl)-5H-indolo[2,3-a]-pyrrolo[3,4-c]-carbazole-5,7(6H)-dione] against pediatric and adult central nervous system tumor xenografts

Abstract.

Purpose: The in vivo antitumor activity of a novel topoisomerase I inhibitor, J-107088, was tested in athymic nude mice bearing subcutaneous or intracranial pediatric and adult malignant CNS tumor-derived xenografts. Methods: J-107088 was administered to animals on days 1–5 and 8–12 via intraperitoneal injection at a dose of 54 mg/kg (162 mg/m²) per day in 10% dimethyl sulfoxide in 0.9% saline. The xenografts evaluated were derived from a childhood glioblastoma multiforme (D-456 MG), a childhood medulloblastoma (D-341 MED), an adult anaplastic astrocytoma (D-54 MG), an adult glioblastoma multiforme (D-245 MG), and a procarbazine-resistant subline of D-245 MG [D-245 MG (PR)]. Results: J-107088 produced regressions and significant growth inhibition in all five of the xenograft lines growing subcutaneously. Growth delays ranged from 7.6 days with D-245 MG to 62.1 days with D-456 MG (P<0.001). J-107088 also produced an 83% increase in survival in mice bearing intracranial D-456 MG (P<0.001). Conclusion: These results indicate that J-107088 may be active in the treatment of childhood and adult malignant brain tumors and provide the rationale for initiation of clinical trials with this agent.