Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy.
We examined the cytotoxicity of the immunosuppressant agent rapamycin and its analogue CCI-779 in human brain tumor cell lines in vitro and in vivo as single agents and in combination with standard chemotherapeutic drugs. In the rapamycin-sensitive PNET/MB cell line DAOY, rapamycin exhibited additive cytotoxicity with cisplatin and with camptothecin. In vivo, CCI-779 delayed DAOY xenograft growth by 160% after 1 week and 240% after 2 weeks of systemic treatment, compared with controls. Single high-dose treatment induced 37% regression of tumor solume. Growth inhibition of DAOY xenografts was 1.3 times greater after simultaneous treatment with CCI-779 and cisplatin than after cisplatin alone. Interestingly, CCI-779 also produced growth inhibition of xenografts derived from U251 malignant glioma cells, a human cell line resistant to rapamycin in vitro. These studies suggest that the rapamycin analogue CCI-779 is an important new agent to investigate in the treatment of human brain tumors, particularly PNET/MB.
Division of Neuro-Oncology, Hospital of the University of Pennsylvania, Philadelphia 19104, USA.
B
B
Geoerger
K
K
Kerr
C B
CB
Tang
K M
KM
Fung
B
B
Powell
L N
LN
Sutton
P C
PC
Phillips
A J
AJ
Janss
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy*; D002166:Camptothecin / Q000008:administration & dosage; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004357:Drug Synergism; D005260:Female; D005910:Glioma / Q000188:drug therapy; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D018242:Neuroectodermal Tumors, Primitive / Q000188:drug therapy*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D006131:Growth Inhibitors; C401859:temsirolimus; D002945:Cisplatin; D020123:Sirolimus; D002166:Camptothecin