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

Int J Cancer. 1999 Mar 15;80(6):911-8. doi: 10.1002/(sici)1097-0215(19990315)80:6<911::aid-ijc18>3.0.co;2-4.

Abstract

A lipophilic farnesyl moiety attached to the carboxyl terminal cysteine of ras proteins structurally supports their membrane anchorage, required for ras-dependent growth-factor signaling and for transforming activity of ras oncoproteins. It has been shown that inhibition of ras farnesylation can block tumor growth in nude mice but that some ras-dependent tumors escape such blockage as a result of prenylation of ras. S-trans-transfarnesylthiosalicylic acid (FTS) is a potent ras-dislodging antagonist that does not affect ras prenylation but rather acts on the mature, membrane-bound ras and facilitates its degradation. Here we demonstrate that FTS induces reappearance of stress fibers in H-ras-transformed rat-1 cells (EJ cells) in vitro, inhibits 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, suggesting specificity towards activated ras. FTS treatment (5 mg/kg i.p. daily) 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 evidence of systemic toxicity. Moreover, FTS treatment increased the survival rate of EJ-tumor-bearing mice from 48 to 68 days. Here we demonstrate anti-tumor potency in a synthetic, non-toxic, ras-dislodging antagonist acting independently of farnesyltransferases.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells / transplantation
  • Actins / analysis
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Cell Division / drug effects
  • Cell Transformation, Neoplastic / drug effects
  • Cytoskeleton / drug effects
  • Cytoskeleton / ultrastructure
  • Farnesol / analogs & derivatives*
  • Farnesol / pharmacology
  • Farnesol / therapeutic use
  • Genes, erbB-2
  • Genes, ras*
  • Male
  • Mice
  • Mice, Nude
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / drug effects*
  • Neoplasm Proteins / physiology
  • Neoplasm Transplantation
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / pathology
  • Neuroblastoma / pathology
  • Oncogene Proteins v-raf
  • Protein Prenylation / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Proto-Oncogene Proteins p21(ras) / chemistry
  • Proto-Oncogene Proteins p21(ras) / drug effects*
  • Proto-Oncogene Proteins p21(ras) / physiology
  • Rats
  • Receptor, ErbB-2 / physiology
  • Retroviridae Proteins, Oncogenic / genetics
  • Retroviridae Proteins, Oncogenic / physiology
  • Salicylates / pharmacology*
  • Salicylates / therapeutic use
  • Substrate Specificity
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / transplantation

Substances

  • Actins
  • Antineoplastic Agents
  • Neoplasm Proteins
  • Retroviridae Proteins, Oncogenic
  • Salicylates
  • farnesylthiosalicylic acid
  • Farnesol
  • Receptor, ErbB-2
  • Oncogene Proteins v-raf
  • Proto-Oncogene Proteins p21(ras)