In vitro and in vivo growth inhibition of human malignant astrocytoma cells by the farnesyltransferase inhibitor B1620.
p21-Ras, the protein product of the proto-oncogene Ras is overactivated in malignant astrocytomas despite the absence of mutation. It is known that p21-Ras participates in signaling events from membrane tyrosine kinase receptors and a variety of intracellular biochemical pathways to downstream targets. Signal transduction inhibition by targeting against Ras is now thought to be a promising therapeutic strategy for malignant astrocytomas. This study demonstrates that Ras pathway inactivation by a farnesyltransferase inhibitor, B1620, effectively inhibits in vitro and in vivo growth of human astrocytoma cells, although normal human astrocytes (NHA) derived from fetal brain are resistant to B1620. Anti-proliferative effect of B1620 on in vitro growth of astrocytoma cells was examined by MTT assays and soft agar colony formation assay. B1620 inhibited anchorage-dependent growth of six astrocytoma cell lines with a median effective dose (IC50) ranging from 2.0 to 20.7 microM. However, growth of NHA was not significantly affected by B1620 even at the concentration of 100 microM. All astrocytoma cells showed apoptotic figures after Hoechst 33258 staining, when treated for 5 days at each IC50 concentration against B1620. Anchorage-independent growth of these astrocytoma cell lines was inhibited at a much lower concentration than that of anchorage-dependent growth. Daily treatment of U87 xenograft-bearing athymic mice with B1620 at 100 or 50 mg kg(-1) resulted in significant inhibition of tumor growth. A histological study of the B1620-treated tumor tissue showed decreased vascularity with numerous TUNEL-positive apoptotic cells. These results suggest that the mechanism of the growth-inhibitory effect of B1620 is anti-angiogenesis, apoptosis induction and reversion of the transformed phenotype. The potential clinical use of B1620 could be expanded to malignant astrocytomas.
Kurimoto
Masanori
M
Department of Neurosurgery, Toyama Medical and Pharmaceutical University, Toyama, Japan. kuri3312@ms.toyama-mpu.ac.jp
Hirashima
Yutaka
Y
Hamada
Hideo
H
Kamiyama
Hironaga
H
Nagai
Shoichi
S
Hayashi
Nakamasa
N
Endo
Shunro
S
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001254:Astrocytoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D051231:Farnesyltranstransferase; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000627:therapeutic use*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D011355:Prodrugs / Q000627:therapeutic use*; D000090063:Proto-Oncogene Mas; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; C473828:B1620; D004791:Enzyme Inhibitors; D007546:Isoquinolines; C000715470:MAS1 protein, human; D011355:Prodrugs; D000090063:Proto-Oncogene Mas; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D015689:Oncogene Protein p21(ras)