Therapeutic activity of 7-[(2-trimethylsilyl)ethyl)]-20 (S)-camptothecin against central nervous system tumor-derived xenografts in athymic mice.
OBJECTIVE
Camptothecins have emerged as an important new class of antitumor drugs. Camptothecin derivatives such as CPT-11 and topotecan are commercially available and approved for the treatment of colorectal (CPT-11) and ovarian and small-cell lung cancer (topotecan). This study was designed to test the efficacy of karenitecin, a novel highly lipophilic camptothecin derivative, against a panel of human tumor xenografts derived from adult and pediatric central nervous system malignancies growing in athymic nude mice.


METHODS
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), medulloblastomas (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 given at 1.0 mg/kg per dose via intraperitoneal injection for a period of 10 consecutive days, which is the dosage lethal to 10% of treated animals.


RESULTS
Karenitecin produced statistically significant (P < or = 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. Karenitecin also produced statistically significant (P < or = 0.001) increases in survival of animals bearing D-341 MED intracranial xenografts (69% increase) and those bearing D-456 MG xenografts (62% increase).


CONCLUSIONS
These preclinical studies confirm that karenitecin is active against human central nervous system xenografts and should undergo clinical evaluation in patients with malignant central nervous system tumors.
Keir
S T
ST
Brain Tumor Center at Duke, Durham, NC 27710, USA.
Hausheer
F
F
Lawless
A A
AA
Bigner
D D
DD
Friedman
H S
HS
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014183:Transplantation, Heterologous
D000972:Antineoplastic Agents, Phytogenic; C406143:cositecan; D000077146:Irinotecan; D002166:Camptothecin