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RAS and leukemia: from basic mechanisms to gene-directed therapy
1Department of Bioimmunotherapy, the University of Texas M.D. Anderson Cancer Center, Houston, 77030, USA.
Purpose And Design:
The purpose of this review is to provide an overview of the literature linking Ras signaling pathways and leukemia and to discuss the biologic and potential therapeutic implications of these observations. A search of MEDLINE from 1966 to October 1998 was performed.
Results:
A wealth of data has been published on the role of Ras pathways in cancer. To be biologically active, Ras must move from the cytoplasm to the plasma membrane. Importantly, a posttranslational modification--addition of a farnesyl group to the Ras C-terminal cysteine--is a requisite for membrane localization of Ras. Farnesylation of Ras is catalyzed by an enzyme that is designated farnesyltransferase. Recently, several compounds have been developed that can inhibit farnesylation. Preclinical studies indicate that these molecules can suppress transformation and tumor growth in vitro and in animal models, with little toxicity to normal cells.
Conclusion:
An increasing body of data suggests that disruption of Ras signaling pathways, either directly through mutations or indirectly through other genetic aberrations, is important in the pathogenesis of a wide variety of cancers. Molecules such as farnesyl transferase inhibitors that interfere with the function of Ras may be exploitable in leukemia (as well as in solid tumors) as novel antitumor agents.
Insights
Ras signaling pathways are crucial in cancer development. Farnesyl transferase inhibitors, which block Ras farnesylation, show promise as novel leukemia treatments with minimal toxicity.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Ras signaling pathways are implicated in various cancers.
- Ras protein requires membrane localization for biological activity.
- Farnesylation, a posttranslational modification, is essential for Ras membrane localization.
Purpose of the Study:
- To review the literature on Ras signaling pathways and leukemia.
- To discuss the biological and therapeutic implications of Ras pathway involvement in leukemia.
Main Methods:
- MEDLINE database search from 1966 to October 1998.
- Review of published literature on Ras pathways in cancer and leukemia.
Main Results:
- Ras pathway disruption is significant in the pathogenesis of many cancers.
- Farnesyltransferase inhibitors block Ras farnesylation, suppressing tumor growth in preclinical models.
- These inhibitors demonstrate low toxicity in normal cells.
Conclusions:
- Ras signaling pathway alterations are key in cancer development.
- Farnesyl transferase inhibitors represent potential novel therapeutic agents for leukemia and solid tumors.