Why Cancer Researchers Are Tackling Twists In DNA

In the preface to The Double Helix, James Watson wrote of his intuition that DNA's structure would be "simple as well as pretty." While the double-helical molecule turned out to be elegant indeed, its structure poses complex problems. For example, how does DNA undergo replication - which involves unraveling and supercoiling - without tying itself into a mass of knots and tangles? The solution to DNA's topological problems comes in the form of enzymes called topoisomerases that serve as "swivels" and allow the molecule to perform its requisite acrobatics. Type I topoisomerase breaks one strand of the DNA, and Type II topoisomerase breaks both strands of the helix. Since 1980 there has been a notable increase in research on topoisomerases. The number of 1988 papers indexed in the Institute for Scientific Information's on-line database SciSearch having the word topoisomerase and variants in their titles was 10 times the number indexed in 1980 (see accompanying graph). James C. Wang, Harvard University, a key player in this field who first identified the enzyme in 1971, confirmed that the 1980s has been a period of rapid growth in topoisomerase research. He noted, however, that The Scientist's graph might slightly underrepresent the amount of work produced in 1980-1982, since the term topoisomerase was not coined until 1979, and it took a few years before it was universally recognized and used. What sparked the upsurge in topoisomerase research at mid-decade was the discovery that antitumor drugs such amsacrine, etoposide, and teniposide turn topoisomerase II into a poison (a "cleavable complex") that inhibits growth and induces cell death. After that the field became a focus for cancer researchers and clinicians. Leroy F. Liu, who identified topoisomerase II as the target of certain antitumor drugs in 1984, and Annette L. Bodley, both of the Johns Hopkins School of Medicine, Baltimore, noted in a recent review that "the rapid development in this new area of research will significantly improve our general understanding of the principles involved in cancer chemotherapy" (Bio/Technology, November 1988, page 1318). To determine which nations, U.S. states, and institutions were recently leading the race to learn more about topoisomerases, The Scientist examined ISI's 1987 Research Front database and located the specialty area "DNA topoisomerases as targets for select anticancer drugs." This specialty consists of 737 1987 papers and the 60 earlier or "core" publications that the 737 consistently cite. Included are papers on the biochemistry of topoisomerases, papers on the use of topoisomerase-targeting drugs in treating cancer, and other topoisomerase-related papers that are tied to this group by consistent citation of the core publications. The ranking of nations, states, and institutions participating in this field was achieved by analysis of the author affiliations listed on the 737 1987 papers. In the accompanying table, the percentage share represents the degree to which each entity contributed to topoisomerase research in 1987. As the table shows, U.S. scientists published 54.2%, or more than half, of all work in this field in 1987. The second-ranking country was the United Kingdom, with 6.3% representation. The states of New York and Maryland, however, each produced more than the U.K. did. And, as for institutions, the University of Texas, Houston, and, specifically, scientists at the M.D. Anderson Hospital and Tumor Institute, conducted more work in this area than the entire country of Japan. But "Japan appears to be increasing its commitment to this area," observes Michael Mattern, a topo- isomerase researcher at Smith, Kline & French Laboratories, Philadelphia, the only industrial firm in the top 10. "We hear through the grapevine of more people and more laboratories there that are now investigating topisomerases."

Why Cancer Researchers Are Tackling Twists In DNA

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