The development of protein farnesyltransferase and other ras-directed therapeutics for malignant diseases

Abstract

Ras is a guanine nucleotide-binding protein that plays a critical role in cell growth and malignant transformation. Following stimulation by various growth factors and cytokines, Ras activates several downstream effectors, including the Raf-1/MAP kinase pathway and the Rac/Rho pathway. In approximately 30% of human cancers, including a substantial proportion of pancreatic and colon adenocarcinomas, mutated ras genes produce mutated Ras proteins that remain locked in an active state, thereby relaying aberrant proliferative signals. After synthesis, Ras undergoes a series of post-translational modifications, the most important of which is the addition of a lipophilic farnesyl isoprenoid moiety in a reaction catalysed by the enzyme protein farnesyltransferase (FTase). The farnesylation of Ras allows it to interact with other proteins in close proximity to the plasma membrane. Inhibiting FTase would prevent Ras from maturing into its biologically active form and, therefore, FTase is of considerable interest as a potential therapeutic target. Various classes of FTase inhibitors have been identified that interfere with the farnesylation of Ras, reverse Ras-mediated cell transformation in human cell lines and inhibit the growth of human tumour xenografts. In transgenic mice with established tumours, with various ras mutations. FTase inhibitors cause regression in some tumours, which appears to be mediated through both apoptosis and cell cycle regulation. There is also ample, intriguing evidence indicating that FTase inhibitors are active in malignancies without ras mutations. In addition, there is experimental evidence indicating that FTase inhibitors enhance the cytotoxic effects of other therapeutic modalities including radiation and several types of cytotoxic chemotherapy. To date, FTase inhibitors have been well-tolerated in both animal studies and early clinical trials and do not seem to produce the generalised cytotoxic effects in normal tissues, that are a major limitation of most conventional anticancer agents. Clinical evaluations of FTase inhibitors to determine the feasibility of administering them as single agents and in combination with other therapeutic modalities on dose schedules that portend optimal therapeutic indices in preclinical studies are ongoing. However, because of the unique biological aspects of FTase, designing disease-directed Phase II and III evaluations of their effectiveness presents formidable challenges.

• cancer
• farnesylation
• geranylgeranylation
• protein farnesyltransferase
• Ras protein
• Ras antisense
• ras oncogenes
• signal transduction.