Isotype-specific Ras.GTP-levels predict the efficacy of farnesyl transferase inhibitors against human astrocytomas regardless of Ras mutational status

• Published in: Cancer research (Chicago, Ill.) Vol. 61; no. 11; pp. 4425 - 4431
• Main Authors: FELDKAMP, Matthias M, LAU, Nelson, RONCARI, Luba, GUHA, Abhijit
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.06.2001
• Subjects: Alkyl and Aryl Transferases - antagonists & inhibitors; Animals; Antineoplastic agents; Astrocytoma - drug therapy; Astrocytoma - metabolism; Astrocytoma - pathology; Biological and medical sciences; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell Division - drug effects; Chemotherapy; Enzyme Inhibitors - pharmacology; Farnesyltranstransferase; Genes, ras - genetics; Glioblastoma - drug therapy; Glioblastoma - metabolism; Glioblastoma - pathology; Guanosine Triphosphate - metabolism; Humans; Immunohistochemistry; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, Nude; Mice, SCID; Monomeric GTP-Binding Proteins - metabolism; Mutation; Pharmacology. Drug treatments; Piperidines - pharmacology; Pyridines - pharmacology; ras Proteins - genetics; ras Proteins - metabolism; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Antineoplastic agent; GTP; Explant; Activation; Farnesyl-diphosphate farnesyltransferase; Bound form; Malignant glioma; Specificity; Established cell line; Tumor; Astrocytoma; Human; Nervous system diseases; Enzyme; Transferases; Treatment efficiency; Rodentia; Oral administration; Enzyme inhibitor; Isotype; Malignant tumor; Glioblastoma multiforme; In vitro; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Glioma; Mouse; Animal; Central nervous system disease; Onc gene
• ISSN: 0008-5472; 1538-7445

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.