St. Keir et al., Therapeutic activity of 7-[(2-trimethylsilyl)ethyl)]-20 (S)-camptothecin against central nervous system tumor-derived xenografts in athymic mice, CANC CHEMOT, 48(1), 2001, pp. 83-87
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.