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Metastatic malignant melanoma, a type of skin cancer that has spread to other parts of the body often is resistant to the chemotherapy drugs used for its treatment. Now, researchers from Austria report that combining chemotherapy with a new agent, called an antisense product G3139, may help overcome such disease resistance and improve treatment outcomes.

Malignant melanoma is a serious form of skin cancer. Treatment options for malignant melanoma depend on the

stage of disease (extent of cancer at diagnosis), and may include surgery, chemotherapy, radiation therapy and/or biologic therapy.

Early-stage melanoma (stages 0, I) is characterized by the presence of cancer cells in the skin only, and can often be cured with surgery alone.

Advanced or

metastatic melanoma (stages III, IV) is cancer that began in the skin and has spread to the nearby lymph nodes or to other parts of the body. Advanced or metastatic melanoma is often treated with surgery, followed by chemotherapy, to control the symptoms of disease, enhance quality of life, and prolong survival time.

Some advanced-stage cancers, including some melanomas, can develop a

resistance to chemotherapy drugs, making the drugs less effective or ineffective against the cancer. One factor in the development of disease resistance in some cancers (melanoma included) is thought to be an abnormal gene, called the

bcl-2 gene. This defective gene produces an excess amount of protein, which in turn helps protect cancer cells from

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apoptosis, the process by which the body normally kills abnormal cells. The overproduction of this protein gives cancer cells a survival advantage over normal cells and helps the cancer cells develop a resistance to radiation therapy and some chemotherapy drugs. Researchers have been working to develop drug products that may help overcome such resistance by targeting the bcl-2 gene, providing more effective treatment options to persons with advanced melanoma and certain other cancers.

A new type of agent, called an

antisense compound, is currently being studied for its potential ability to target the bcl-2 gene, slowing the production of its protein. Genes use mRNA to carry the genetic information used to produce their proteins. The antisense compounds are synthetic DNA strands that bind to and destroy a gene’s mRNA, thereby preventing the gene from producing an excess amount of its protein. Researchers recently treated persons with advanced melanoma with chemotherapy and a new antisense compound, currently named


Researchers in Austria treated 17 persons with advanced melanoma, most of whom had disease that was resistant to standard treatments. All patients received monthly cycles of the chemotherapy drug dacarbazine and the antisense compound G3139 for up to 1 year. The findings showed that this treatment regimen resulted in decreased bcl-2 protein levels and increased apoptosis of melanoma cells. Six of the 14 patients who could be evaluated experienced a shrinkage of the cancer. One person had a complete response to treatment. Two persons had more than a 50% reduction in cancer size, and 3 had less than a 50% reduction in cancer size. For some patients, the responses to treatment have lasted for more than 1 year. The G3139 treatment was well tolerated.

These findings represent the first of their kind: the successful use of an antisense compound to decrease the amount of bcl-2 gene protein produced. The combination of dacarbazine and G3139 appears to produce responses in persons with advanced melanoma, despite resistance to other treatments. In addition, the bcl-2 gene protein is thought to play a role in the progression of several other cancers, including prostate cancer, non-Hodgkin’s lymphoma, and breast cancer. G3139 is currently undergoing further study in Europe and the United States for the treatment of melanoma and these other bcl-2–related cancers. Antisense G3139 has not yet been approved by the USA Food and Drug Administration and continues to be developed in clinical trials. Two sources of information on ongoing clinical trials that can be discussed with a doctor include a comprehensive, easy-to-use service provided by the National Cancer Institute

( and the Clinical Trials section and service offered by Cancer

( (

American Association for Cancer Research Annual Meeting, Abstract LB23, 2000)

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