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News News volving several Italian research institutes has produced encouraging results. The trial, conducted by the European Institute of Oncology, the National Cancer Institute in Milan, and others found that fenretinide given by itself reduced the incidence of cancer in the contralateral breast by 40% among premenopausal women with a history of the disease. AnDr. Leslie Ford other trial combining fenretinide and tamoxifen is ongoing. JoAnne Zujewski, M.D., of NCI's Medicine Branch, said she is using oral tamoxifen and fenretinide in a pilot trial to study tissue modification in 20 patients at increased risk for breast cancer, with the idea that "it's unlikely any one drug will be the answer." Peter Ho, M.D., Ph.D., of NCI's Investigational Drug Branch, is conducting Phase I studies combining 9-cisretinoic acid with tamoxifen in patients with advanced breast cancer. Lavender Other scientists are going farther afield in the quest for breast cancer preventers, studying chemicals derived from plants, including lavender. The idea of using lavender to treat cancer might not have surprised English harvesters of centuries ago, who wore sprigs under their hats to prevent sunstroke and headaches. As dubious as that practice might be, the herb has a long history of medicinal uses and is still a focus of medical research. 1102 NEWS Lavender is a source of perillyl alcohol, which when fed to rats in experiments at the University of Wisconsin, Madison, prevented tumors from developing and caused complete regression of advanced mammary tumors. Based on these early results, about 20 patients with a variety of advanced cancers, including breast, ovarian, and prostate, are enrolled in a phase I study in which they take 20 to 30 capsules a day, each containing 250 milligrams of perillyl alcohol in soy oil. Because soy products may also be anti-carcinogenic, the question arises: Could the oil confound the study results? "The oil is always a consideration," said Michael Gould, Ph.D., professor of human oncology at the university. "If we found that it was the oil that was causing an (anti-carcinogenic) effect, I'd be very happy. It would be a very simple treatment. And it would be less expensive than perillyl alcohol." Although this trial and planned phase II studies both involve advanced cancer patients who are resistant to treatment, the intent is to develop perillyl alcohol as a singleagent, primary treatment, Gould said. Like tamoxifen, the substance will also be investigated for its preventive properties. The agent blocks cell division, induces apoptosis, and in some cases induces differentiation, Gould said. Side effects include nausea, but not severe enough to prevent normal eating. The only caution so far is against spicy foods. "If you were on this for a long period of time, you wouldn't want to eat tacos every day," he said. — Jan Ziegler Scientists Figure Out What Makes HIV Stick One of the enduring challenges in AIDS research is figuring out exactly how gpl20, the large, spike-like protein on the surface of HIV, sticks to human cells as the very first step in HIV infection. Solving this puzzle will have important implications for the future design of drugs and vaccines to block HIV from binding to cells. In the mid-1980s, several studies implicated a short region of gpl20, called C4, as the likely first point of contact between HIV and its target, a protein receptor known as CD4 that sits on the surface of human cells. But subsequent studies yielded mixed results, leaving scientists awash in questions about whether C4 was really the sole binding site on gpl20. Now a team of researchers at the National Institutes of Health may have the answer.Writing recently in the Journal of Biological Chemistry, t h e N I H re ~ searchers report that they were able to create synDr. Frank Robey thetic, threedimensional copies of C4 that in laboratory studies hook onto CD4-positi ve cells and block the binding of gp 120 to the receptor. This, they said, provides strong evidence that C4 alone binds to the CD4 receptor as the first step in HIVinfection. Journal of the National Cancer Institute, Vol. 88, No. 16, August 21, 1996 News News Taking this finding one step further, the NIH scientists said they also have discovered the precise part of C4 that recognizes CD4. They found that when twisted into its 3-D structure, C4 contains a hydrophobic (water-resistant) surface that is identical almost down to the last amino acid in HTV-1, HTV-2, and the simian immunodeficiency virus (SIV). According to Frank Robey, Ph.D., lead author of the paper and a physical chemist at the National Institute for Dental Research, "the hydrophobic region could be the common thread that explains how HTV-1 and HTV-2, two genetically divergent viruses, maintain the fundamental ability to anchor onto immune cells and initiate HIV infection." He said the conservation of the hydrophobic region is all the more striking because most of the amino acids that fall outside of the hydrophobic region vary in HTV-1 and HTV-2. Robey and colleagues said the new results offer AIDS researchers a more coherent molecular picture of that first step in HIV infection and could be useful in designing new drugs and vaccines to fight the virus. "If we can block the initial interaction between HIV and cells, we can inhibit infection," said Marjorie Robert-Guroff, Ph.D., a coauthor on the paper and a scientist at the National Cancer Institute. 'Today's results give us a better theoretical game plan to go in and block that very first step in the cascade of events that leads to HIV infection and ultimately AIDS." Although experts have responded favorably to the paper, they also have mentioned the need to confirm the data using other strategies. "This finding further refines the mechanisms of CD4gpl20 binding," noted Carl Diefenbach, Ph.D., associate director of the Basic Sciences Program in the Division of AIDS at NIH's National Institute of Al- lergy and Infectious Diseases. "Only through crystallography studies of these same proteins interacting will the importance of the work be defined." Still, the finding brings exciting news to AIDS researchers during a summer that has yielded other hot leads in the study of HIV infection. Earlier this summer, several AIDS researchers made headlines when they reported that The predicted similarities in helical C4 among HIV-1 (rounded amino acids) and HIV-2 (hexagonal amino acids) are shown above. Shared amino adds are in violet HFV anchors not only to CD4, but also to other protein receptors sitting on the cell surface called fusin and CC-CKR-5. These coreceptors serve as gateways for HTV to enter cells after the virus sticks toCD4. Until now, scientists have been stymied in studying C4 and its interactions with cells, such as human T cells and macrophages. Current techniques for determining protein structure have yet to provide a detailed picture of the large and complex gpl20, making it impossible to study its actual 3-D conformation. Another strategy has been to churn out laboratory-made copies of C4 as substitutes for the real thing. But the syn- Journal of the National Cancer Institute, Vol. 88, No. 16, August 21, 1996 thetic peptides, numbering just 18 amino acids in length, are too short to assume the natural 3-D shape that they have in gpl20. This means scientists have had to study linear versions of C4 that don't have the same chemical properties that the actual 3-D peptide has in the body. New Approach To attack these problems, Robey and colleagues spent over 10 years inventing a new approach for probing the structure of C4 and other HTV peptides. After some trial and error, they succeeded in developing a method of chemically linking peptides, like links in a chain, into a repeating string of peptides called a peptomer. Once anchored within a peptomer, the scientists found the individual peptides assumed a 3-D form. In the case of C4, Robey and colleagues reported last year that the peptide likely twists into a helical structure in solutions with acid levels comparable to those in the human body. They also found these amino acids equally separate, like oil and vinegar, into hydrophobic and hydrophilic surfaces. Following up on this work and serving as the source of the recent paper, Robey et al. conducted a series of experiments to test the binding ability of the helical C4 to the human T-cell receptor CD4. Their experiments showed that helical C4, but not the linear version, locks onto CD4 and blocks gpl20 from binding to the receptor. Based on these results, Robey said he and his colleagues are now using the C4 peptomer as a research tool to help them track the cascade of cellular events that lead to HIV infection. He added that AIDS vaccine studies using the peptomer are also in the works. — Bob Kuska NEWS 1103