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Antisense Therapy Prevents Burkitt's Lymphoma In Mice

Thomas Jefferson University

Researchers at Jefferson Medical College have used DNA therapy and the host immune system to stave off the development of cancer in mice. Pharmacologist Eric Wickstrom, Ph.D., and research associate Janet B. Smith, Ph. D, have used a treatment called antisense therapy to prevent the development of Burkitt's lymphoma in laboratory mice, showing that this protection is aided by the mouse's own immunity.

One of the limitations of effectively treating Burkitt's lymphoma with chemotherapy is that the drugs eventually wear off, says Dr. Wickstrom, professor of microbiology and immunology and a member of Jefferson's Kimmel Cancer Center and the Cardeza Foundation for Hematological Research. The cancer cells often develop resistance to chemotherapy and the cancer returns.

In the study, normal mice were injected with Burkitt's lymphoma mouse tumor cells. The mice were given complementary DNA therapy for seven consecutive days. The scientists found that not only did the antisense treatment delay the onset of tumor development, it also decreased the size and mass of any resulting tumors. In one mode of treatment, tumors were totally blocked from forming.

The scientists think that this strategy--using antisense therapy while at the same time revving the immune system--may also work in human patients who have relapsed after chemotherapy effectively halted their disease. In addition to Burkitt's lymphoma, such a therapy might be applied against many types of lymphoma, leukemia, multiple myeloma, breast cancer, ovarian cancer, lung cancer and colon cancer.

The next step, Dr. Wickstrom says, is to test the therapy in humans. "My clinical colleagues here at Jefferson would like to test this therapy in a small group of patients. We've asked the National Cancer Institute for assistance with that trial."

Their results appear in the August issue of the Journal of the National Cancer Institute.

Antisense therapy aims to turn off the mutated genes that cause cancer. In contrast to the shotgun approach of chemotherapy, which kills both normal and cancerous cells, antisense attacks the cause of cancer. When the genes are turned off, they can no longer make the protein products that lead to disease.

Antisense DNA drugs work by binding to RNA messages from disease genes, so that the genetic code in the RNA cannot be read. The RNA message copied from a gene carries the genetic code for a specific protein, which is called the sense orientation. The complementary strand in a double helix is called antisense. The antisense DNA drug attached to the sense RNA message prevents the code from being read, so the disease gene can't produce the disease-causing protein.

In the lymphoma experiment, antisense DNAs were made to bind to RNA messages of the c-myc cancer gene so that they can no longer generate excess myc proteins that lead to uncontrolled blood-cell proliferation and cancer.

Dr. Wickstrom notes that antisense therapy currently is being studied in clinical trials by some researchers. In his newly published book, "Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors," he and his coauthors describe various preclinical and clinical studies in the United States and other countries.

In the book's preface, Dr. Wickstrom asserts that "cloning and sequencing pathogenic genes in the past two decades has made possible a direct genetic approach to the treatment of disease using nucleic acid therapeutics or vectors."

He adds that "the ability to turn off or correct individual disease-causing genes, or to replace them at will in a patient's cells provides a powerful therapeutic intervention in genetic diseases. Gene-specific nucleic acid therapy has gone from theory to practical possibility in a short time.

"It's clear that all disease results from incorrect gene expression, one way or another," he notes. "By turning off some genes or correcting others, we may be

able to treat each disease at its point of origin." In earlier work, Dr. Wickstrom and his colleagues prevented tumor formation in mice predisposed to Burkitt's lymphoma. In the longest test of antisense DNA therapy in animals to date, three-week-old mice without tumors were treated for six weeks with a gene-targeted drug. The study appeared in the September 1995 issue of Molecular Medicine and represented the first demonstration of antisense DNA therapy to prevent tumor onset.

Burkitt's lymphoma is 1 of 10 types of non-Hodgkin's lymphoma -- cancer of the lymphatic system. It is found most often in children, but is also a known complication in adults infected with human immunodeficiency virus type 1 (HIV-1). Because there is lymph tissue in many parts of the body, a tumor can start almost anywhere. Up to 90 percent of Burkitt's lymphoma tumors are intra-abdominal. Other sites of involvement may include testis, nasal sinuses, bone, peripheral lymph nodes, skin, bone marrow and the central nervous system.

Burkitt's lymphoma is found in higher rates in central Africa, but is reported from many other areas. The Epstein-Barr virus, a herpes virus, has been isolated from Burkitt's lymphoma tumors and has been implicated as a causative agent in about 25 percent of cases. Those afflicted with the disease express a characteristic chromosomal crossover between chromosomes 8 and 14, and more rarely, 8 and 22, and 2 and 8. Each of these translocations causes the c-myc gene to be produced in large amounts, which leads to tumors.

Dr. Wickstrom's work is supported by the National Cancer Institute.


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