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Ras Proteins, the Cell Cycle and Cancer - Page 2

© David Olle

Development of ras protein inhibitors

The development of drugs that function as ras protein inhibitors has been more difficult than originally thought by the researchers. Emerging details have shown that ras proteins can signal through at least four distinct pathways which made designing an effective target for a drug more challenging.

Recently, the most promising approach has been drugs that inhibit the farnesyl transferase enzyme. As described above, this enzyme is necessary to catalyze a step for the ras protein to function. The recent 10th European Cancer Conference 2 described the results of many Phase 1 Clinical Trials that have taken place over the last 18-24 months using this approach. Although the primary functions of Phase 1 Trials are to evaluate toxicity, dosage levels and routes of administration, several patients with colorectal or non-small cell lung cancer saw stabilization of their conditions.

A review article in Gastroenterology 4 (as well as other sources) describes another approach that is just starting to enter clinical trials, namely immunotherapy. The abnormal ras proteins have changes in amino acid sequences that can serve as antigens for T cells to detect. Laboratory studies have shown that an immunotherapy approach may increase the sensitivity of ras cancer cells to radiation therapy. Researchers found that the ras cancer cells may be resistant to radiation due to an inhibition of the p53 tumor suppressor protein 3. Administration of antibodies against ras cancer cells (via an adenovirus) resulted in an increased radiosensitivity against malignant but not normal cells.

Another approach targets the oncogene itself rather its protein product. Studies with rats have demonstrated the effectiveness of an antisense oligonucleotide that binds to the RNA transcript of the ras oncogene.

References:

1. Angier, N. Researchers track pivotal pathway that makes cells divide. New York Times, June 29, 1993, pages C1 and C10.

2. Khuri, F. The Race is On: New Drugs in Clinical Trials for Solid Tumors 10th European Cancer Conference Medscape

3. McCormick, F. Ras suppresses the activity of p53 and renders cells radioresistant. Oncolink Cell, October 13, 2000. (Reported by Reuters Health News)

4. Strul, H. and Arber, N. Focused Clinical Review: The Role of c-K-ras Mutations in Human Gastrointestinal Tumors. Gastroenterology 3(1), 2001

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