Growth inhibition of ras-dependent tumors in nude mice by a potent ras-dislodging antagonist

A lipophilic farnesyl moiety attached to the carboxyl terminal cysteine of ras proteins structurally supports their membrane anchorage, required for r as-dependent growth-factor signaling and for transforming activity of ras o ncoproteins. It has been shown that inhibition of ras farnesylation can blo ck tumor growth in nude mice but that some ras-dependent tumors escape such blockage as a result of prenylation of ras. S-trans-transfarnesylthiosalic ylic acid (FTS) is a potent ras-dislodging antagonist that does not affect ras prenylation but rather acts on the mature, membrane-bound ras and facil itates its degradation. Here we demonstrate that FTS induces reappearance o f stress fibers in H-ras-transformed rat-1 cells (EJ cells) in vitro, inhib its their anchorage-independent growth in vitro, and blocks EJ-tumor growth in nude mice. The anchorage-independent growth of cells expressing ErbB2 ( B104), but not that of v-raf-transformed cells, is also inhibited by FTS, s uggesting specificity towards activated ras. FTS treatment (5 mg/kg i.p. da ily) caused inhibition (75-80%) of tumor growth in nude mice implanted with EJ, but not in mice implanted with v-raf-transformed cells, with no eviden ce of systemic toxicity. Moreover, FTS treatment increased the survival rat e of EJ-tumor-bearing mice from 48 to 68 days. Here we demonstrate anti-tum or potency in a synthetic, non-toxic, ras dislodging antagonist acting inde pendently of farnesyltransferases. Int. J. Cancer 80:911-918, 1999. (C) 199 9 Wiley-Liss, Inc.