Therapeutic activity of 7-[(2-trimethylsilyl)ethyl)]-20 (S)-camptothecin against central nervous system tumor-derived xenografts in athymic mice

Purpose: Camptothecins have emerged as an important new class of antitumor drugs. Camptothecin derivatives such as CPT-I I and topotecan are commercia lly available and approved for the treatment of colorectal (CPT-11) and ova rian and small-cell lung cancer (topotecan). This study was designed to tes t the efficacy of karenitecin, a novel highly lipophilic camptothecin deriv ative, against a panel of human tumor xenografts derived from adult and ped iatric central nervous system malignancies growing in athymic nude mice. Me thods: Xenografts evaluated were derived from childhood high-grade gliomas (D-212 MG, D-456 MG), adult high-grade gliomas (D-54 MG, D-245 MG), medullo blastomas (D-341 MED, D-487 MED), and ependymomas (D-528 EP, D-612 EP), as well as sublines with demonstrated resistance to procarbazine (D-245 MG (PR )) and busulfan (D-456 (BR)). In replicate experiments, karenitecin was giv en at 1.0 mg/kg per dose via intraperitoneal injection for a period of 10 c onsecutive days, which is the dosage lethal to 10% of treated animals. Resu lts: Karenitecin produced statistically significant (P less than or equal t o 0.001) growth delays in all subcutaneous xenografts tested, including the sublines resistant to procarbazine and busulfan. Growth delays ranged from 12.1 days in D-456 MG (BR) to 90 + days in D-212 MG and D-341 MED. Karenit ecin also produced statistically significant (P less than or equal to 0.001 ) increases in survival of animals bearing D-341 MED intracranial xenograft s (69% increase) and those bearing D-456 MG xenografts (62% increase). Conc lusion: These preclinical studies confirm that karenitecin is active agains t human central nervous system xenografts and should undergo clinical evalu ation in patients with malignant central nervous system tumors.