Activity of temozolomide in the treatment of central nervous system tumor xenografts.
The activity of 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin- 4(3H)-one (temozolomide) in the treatment of a panel of xenografts derived from ependymoma, medulloblastoma, and childhood and adult high-grade glioma was evaluated in athymic nude mice bearing s.c. and intracranial tumors. Temozolomide administered daily for a total of five doses demonstrated marked activity against a panel of Mer+ xenografts despite marginal to moderate activity of 1,3-bis(2-chloroethyl)-1-nitrosourea. The growth delays produced by temozolomide in these xenografts were 1.8-7.5-fold greater than those produced by procarbazine. Although temozolomide demonstrated marginal activity against the Mer+ cell line D341 Med when a 5-day schedule was used, a high-dose 1-day schedule resulted in moderate activity. Temozolomide produced increases in median survival of 1285% (adult glioma D-54 MG), 323% (childhood glioma D-456 MG), and 68% (ependymoma D612 EP). Pretreatment of mice with O6-benzylguanine increased temozolomide-induced mortality, requiring reduction of the dosage from 1200 to 750 mg/m2 on the single-day regimen. O6-Benzylguanine pretreatment of mice bearing Mer+ D341 Med increased the growth delay of temozolomide, in duplicate experiments, from -3.1 to 4.8 and 1.1 to 4.9 days. These studies suggest that temozolomide may be active in the treatment of a broad spectrum of central nervous system cancers, including Mer+ tumors resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea.
Friedman
H S
HS
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA.
Dolan
M E
ME
Pegg
A E
AE
Marcelli
S
S
Keir
S
S
Catino
J J
JJ
Bigner
D D
DD
Schold
S C
SC
D000818:Animals; D002330:Carmustine / Q000627:therapeutic use; D016543:Central Nervous System Neoplasms / Q000188:drug therapy*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D005260:Female; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D008297:Male; D008780:Methyltransferases / Q000037:antagonists & inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D019853:O(6)-Methylguanine-DNA Methyltransferase; D011344:Procarbazine / Q000627:therapeutic use; D000077204:Temozolomide; D014183:Transplantation, Heterologous
C064976:O(6)-benzylguanine; D011344:Procarbazine; D006147:Guanine; D003606:Dacarbazine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine; D000077204:Temozolomide