TY - JOUR
T1 - Therapeutic activity of 7-[(2-trimethylsilyl)ethyl)]-20 (S)-camptothecin against central nervous system tumor-derived xenografts in athymic mice
AU - Keir, S. T.
AU - Hausheer, F.
AU - Lawless, A. A.
AU - Bigner, D. D.
AU - Friedman, H. S.
PY - 2001
Y1 - 2001
N2 - Purpose: 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 ≤ 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 ≤ 0.001) increases in survival of animals bearing D-341 MED intracranial xenografts (69% increase) and those bearing D-456 MG xenografts (62% increase). Conclusion: 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.
AB - Purpose: 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 ≤ 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 ≤ 0.001) increases in survival of animals bearing D-341 MED intracranial xenografts (69% increase) and those bearing D-456 MG xenografts (62% increase). Conclusion: 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.
KW - Camptothecin derivatives
KW - Central nervous system malignancies
KW - Human tumor xenografts
KW - Karenitecin
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U2 - 10.1007/s002800000274
DO - 10.1007/s002800000274
M3 - Article
C2 - 11488529
AN - SCOPUS:0034917320
SN - 0344-5704
VL - 48
SP - 83
EP - 87
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 1
ER -