THERAPEUTIC EFFICACY OF THE TOPOISOMERASE-I INHIBITOR PIPERIDINO]-1-PIPERIDINO)-CARBONYLOXY-CAMPTOTHECIN AGAINST PEDIATRIC AND ADULT CENTRAL-NERVOUS-SYSTEM TUMOR XENOGRAFTS

Therapy of patients with malignant central nervous system tumors is fr equently unsuccessful, reflecting limitations of current surgical, rad iotherapeutic, and pharmacotherapeutic treatments. The camptothecin de rivative irinotecan (CPT-11) has been shown to possess antitumor activ ity in phase II trials for patients with carcinoma of the lung, cervix , ovary, colon, or rectum and for patients with non-Hodgkin's lymphoma . The current study was designed to test the efficacy of the drug agai nst a panel of human tumor xenografts derived from adult and pediatric central nervous system malignancies. Tumors included childhood high-g rade gliomas (D-212 MG, D-456 MG), adult high-grade gliomas (D-54 MG, D-245 MG), medulloblastomas (D341 Med, D487 Med), ependymomas (D528 EP , D612 EP), and a rhabdomyosarcoma (TE-671), as well as sublines with demonstrated resistance to busulfan (D-456 MG (BR)), cyclophosphamide (TE-671 CR), procarbazine (D-245 MG (PR)) or melphalan (TE-671 MR), gr owing subcutaneously and intracranially in athymic nude mice. In repli cate experiments, CPT-11 was given at a dosage of 40 mg/kg per dose vi a intraperitoneal injection in 10% dimethylsulfoxide on days 1-5 and 8 -12, which is the dosage lethal to 10% of treated animals. CPT-11 prod uced statistically significant (P < 0.001) growth delays in all subcut aneous xenografts tested, including those resistant to busulfan, cyclo phosphamide, procarbazine, and melphalan, with growth delays ranging f rom 21.3 days in D487 Med to 90 + days in several tumor lines. Further , tumor regression was evident in every treated animal bearing a subcu taneous tumor, with some xenografts yielding complete tumor regression . Statistically significant (P < 0.001) increases in survival were dem onstrated in the two intracranial xenografts - D341 EP (73.0% increase ) and D-456 MG (114.2% increase) - treated with CPT-11. These studies demonstrate that, of over 40 drugs evaluated in this laboratory, CPT-1 1 is the most active against central nervous system xenografts and sho uld be advanced to clinical trial as soon as possible.