Isotype-specific Ras.GTP-levels predict the efficacy of farnesyl transferase inhibitors against human astrocytomas regardless of Ras mutational status.
Previous studies have demonstrated that astrocytomas express elevated levels of activated Ras.GTP despite the absence of activating Ras mutations. Farnesyl transferase inhibitors (FTIs) exert their antitumor effect in part through inhibition of Ras-mediated signaling. SCH66336 is a potent FTI presently undergoing clinical trials in patients with solid tumors. We evaluated the efficacy of SCH66336 against a panel of eight human astrocytoma cell lines and three human astrocytoma explant xenograft models in NOD-SCID mice. SCH66336 demonstrated variable antiproliferative effects against the cell lines, with IC(50) ranging from 0.6 microM to 32.3 microM. Two of the three human glioblastoma multiforme (GBM) xenografts demonstrated substantial growth inhibition in response to SCH66336, with up to 69% growth inhibition after 21 days of treatment. Drug efficacy could be accurately predicted using a combination of the H-, K-, and N-isotype-specific Ras.GTP levels. These data indicate that the absence of Ras mutations does not preclude chemotherapeutic efficacy by FTIs, that Ras is likely a major target of FTIs regardless of Ras mutational status, and that isotype-specific Ras.GTP levels are a promising marker of drug efficacy.
Feldkamp
M M
MM
Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada M5G-1X8.
Lau
N
N
Roncari
L
L
Guha
A
A
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D001254:Astrocytoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D011905:Genes, ras / Q000235:genetics*; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006160:Guanosine Triphosphate / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D009154:Mutation; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D003986:Dibenzocycloheptenes
D019883:Alkyl and Aryl Transferases; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D006160:Guanosine Triphosphate; D020559:Monomeric GTP-Binding Proteins; D010880:Piperidines; D011725:Pyridines; D018631:ras Proteins; C115354:lonafarnib; D003986:Dibenzocycloheptenes