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.