α-Difluoromethylornithine or DFMO, which was developed as a cancer therapy and later shelved because of toxicity concerns, has been around since the 1970s. But over the past five years, it has undergone a rebirth as a chemoprevention agent, first showing efficacy in animal models of human cancer and more recently in human prostate and colon cancer. A recent study shows that it likely works in a large cast of tumors, even those having poor prognosis, like high-risk neuroblastoma (a childhood malignancy of the sympathetic nervous system, that accounts for accounts for nearly eight percent of all childhood cancers and 15 percent of pediatric cancer-related deaths. Its solid tumors arise from developing nerve cells, most commonly in the adrenal gland, but also in the abdomen, neck, and chest. Neuroblastoma usually occurs in infants and young children, appearing twice as frequently during the first year of life than in the second.
The best-known genetic alteration involved in neuroblastoma is the amplification of the proto-oncogene—a molecule that when overexpressed can cause cancer—called MYCN. Amplification of MYCN occurs in about 20 percent of all neuroblastoma and is associated with the high-risk form of the disease. Targeting this and related genes directly might be therapeutically tempting, the study noted, but highly problematic because the oncoproteins they produce are also required for the growth of most normal cell types. And that is why Dr. John Cleveland and colleagues focused on inhibiting ornithine decarboxylase (Odc), a protein that contributes to cancer cell growth and that is a target of the proto-oncogene MYCN. Increased levels of Odc are common in cancer, and forced Odc expression in animal models has been shown to lead to increased tumor incidence. Recent findings have shown that Odc overexpression is also an indication of poor prognosis in neuroblastoma. DFMO, the drug used by the Cleveland team, inhibits the activity of Odc. One mor interesting is at lower dose the drug is specific and it has impact on Odc only. Though the toxicity ealrier reported has to be still ascertained, it may be time to revisit the issue as the study showed that transient treatment with DFMO is sufficient to provide chemoprevention and may show benefit for this otherwise lethal malignancy. Hope the detailed study will have something inthe near future....
The best-known genetic alteration involved in neuroblastoma is the amplification of the proto-oncogene—a molecule that when overexpressed can cause cancer—called MYCN. Amplification of MYCN occurs in about 20 percent of all neuroblastoma and is associated with the high-risk form of the disease. Targeting this and related genes directly might be therapeutically tempting, the study noted, but highly problematic because the oncoproteins they produce are also required for the growth of most normal cell types. And that is why Dr. John Cleveland and colleagues focused on inhibiting ornithine decarboxylase (Odc), a protein that contributes to cancer cell growth and that is a target of the proto-oncogene MYCN. Increased levels of Odc are common in cancer, and forced Odc expression in animal models has been shown to lead to increased tumor incidence. Recent findings have shown that Odc overexpression is also an indication of poor prognosis in neuroblastoma. DFMO, the drug used by the Cleveland team, inhibits the activity of Odc. One mor interesting is at lower dose the drug is specific and it has impact on Odc only. Though the toxicity ealrier reported has to be still ascertained, it may be time to revisit the issue as the study showed that transient treatment with DFMO is sufficient to provide chemoprevention and may show benefit for this otherwise lethal malignancy. Hope the detailed study will have something inthe near future....
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