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Ras protein farnesyltransferase: A strategic target for anticancer therapeutic development
E K Rowinsky1, J J Windle, D D Von Hoff
1Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229-3272, USA. erowinski@saci.org
Abstract:
Ras proteins are guanine nucleotide-binding proteins that play pivotal roles in the control of normal and transformed cell growth and are among the most intensively studied proteins of the past decade. After stimulation by various growth factors and cytokines, Ras activates several downstream effectors, including the Raf-1/mitogen-activated protein 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 proteins that remain locked in an active state, thereby relaying uncontrolled proliferative signals. Ras undergoes several posttranslational modifications that facilitate its attachment to the inner surface of the plasma membrane. The first-and most critical-modification is the addition of a farnesyl isoprenoid moiety in a reaction catalyzed by the enzyme protein farnesyltransferase (FTase). It follows that inhibiting FTase would prevent Ras from maturing into its biologically active form, and FTase is of considerable interest as a potential therapeutic target. Different classes of FTase inhibitors have been identified that block farnesylation of Ras, reverse Ras-mediated cell transformation in human cell lines, and inhibit the growth of human tumor cells in nude mice. In transgenic mice with established tumors, FTase inhibitors cause regression in some tumors, which appears to be mediated through both apoptosis and cell cycle regulation. FTase inhibitors have been well tolerated in animal studies and do not produce the generalized cytotoxic effects in normal tissues that are a major limitation of most conventional anticancer agents. There are ongoing clinical evaluations of FTase inhibitors to determine the feasibility of administering them on dose schedules like those that portend optimal therapeutic indices in preclinical studies. Because of the unique biologic aspects of FTase, designing disease-directed phase II and III evaluations of their effectiveness presents formidable challenges.
Insights
Protein farnesyltransferase (FTase) inhibitors show promise in cancer therapy by blocking Ras protein activation. These inhibitors reverse cell transformation and inhibit tumor growth with good tolerability in preclinical studies.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Ras proteins are key regulators of cell growth, and mutations lead to uncontrolled proliferation in many cancers.
- Ras activation requires posttranslational modification, including farnesylation catalyzed by protein farnesyltransferase (FTase).
- FTase is a significant therapeutic target for cancer treatment due to its role in Ras activation.
Purpose of the Study:
- To investigate the therapeutic potential of FTase inhibitors in cancer treatment.
- To evaluate the efficacy of FTase inhibitors in preclinical cancer models.
- To assess the safety and tolerability of FTase inhibitors.
Main Methods:
- Identification and characterization of different classes of FTase inhibitors.
- Assessment of FTase inhibitors' ability to block Ras farnesylation and reverse Ras-mediated cell transformation in vitro.
- Evaluation of FTase inhibitors' efficacy in inhibiting human tumor cell growth in vivo using nude mouse models.
- Analysis of tumor regression, apoptosis, and cell cycle regulation in response to FTase inhibitors in transgenic mouse models.
- Assessment of FTase inhibitor tolerability and toxicity in animal studies.
Main Results:
- FTase inhibitors effectively block Ras farnesylation, reverse Ras-mediated cell transformation, and inhibit tumor cell growth.
- In vivo studies showed tumor regression in some cases, mediated by apoptosis and cell cycle regulation.
- FTase inhibitors demonstrated good tolerability in animal studies, without generalized cytotoxic effects on normal tissues.
Conclusions:
- FTase inhibitors represent a promising therapeutic strategy for cancers with mutated Ras.
- The unique biological profile of FTase inhibitors warrants further clinical investigation.
- Designing effective clinical trials for FTase inhibitors presents unique challenges due to their specific mechanism of action.