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In 1966, Monroe Wall and Mansukh Wani found a potential cure for cancer in the bark of the happy tree (Camptotheca acuminata), a rare plant native to China. Wall and Wani were in the process of screening a large number of natural substances for anticancer activity, hoping to find chemicals that might prove effective in cancer treatment. They discovered that an extract from the happy tree was effective in treating leukemia in mice. Through chemical analysis, they were able to isolate the active compound, which was dubbed camptothecin.

In the 1970s, physicians administered camptothecin to patients with incurable cancers. Although the drug showed some anticancer activity, it had toxic side effects. Eventually, chemists synthesized several analogs of camptothecin that were less toxic and more effective in cancer treatment. Two of these analogs, topotecan and irinotecan, are used today for the treatment of ovarian cancer, small-cell lung cancer, and colon cancer.

For many years, the mechanism by which camptothecin compounds inhibited cancer was unknown. In 1985, almost 20 years after its discovery, scientists at Johns Hopkins University and Smith Kline and French Laboratories (now GlaxoSmithKline) showed that camptothecin worked by inhibiting an important component of the DNA-synthesizing machinery in humans, an enzyme called topoisomerase I.

Cancer chemotherapy is a delicate task because the target cells are the patient’s own and the drugs must kill the cancer cells without killing the patient. One of the hallmarks of cancer is proliferation: cancer-cell division is unregulated and many cancer cells divide at a rapid rate, giving rise to tumors with the ability to grow and spread. As we learned in Chapter 2, before a cell can divide it must successfully replicate its DNA so that each daughter cell receives an exact copy of the genetic material. Checkpoints in the cell cycle ensure that cell division does not proceed if DNA replication is inhibited or faulty, and many cancer treatments focus on interfering with the process of DNA replication.

DNA replication is a complex process that requires a large number of components, the actions of which must be intricately coordinated to ensure that DNA is accurately copied. An essential component of replication is topoisomerase. As the DNA unwinds in the course of replication, strain builds up ahead of the separation and the two strands writhe around each other, much as a rope knots up as you pull apart two of its strands. This writhing of the DNA is called supercoiling (see Chapter 11). If the supercoils are not removed, they eventually stop strand separation and replication comes to a halt.

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Topoisomerase enzymes remove the supercoils by clamping tightly to the DNA and breaking one or both of its strands. The strands then revolve around each other, removing the supercoiling and strain. After the DNA has relaxed, the topoisomerase that removed the supercoils reseals the the broken ends of the DNA.

Camptothecin works by interfering with topoisomerase I. The drug inserts itself into the gap created by the break in the DNA strand, blocking the topoisomerase from resealing the broken ends. Researchers originally assumed that camptothecin trapped the topoisomerase and blocked the action of other enzymes needed for synthesizing DNA. However, recent research indicates that camptothecin poisons the topoisomerase so that it is unable to remove supercoils ahead of replication. Accumulating supercoils halt the replication machinery and prevent the proliferation of cancer cells. Like many other cancer drugs, camptothecin also inhibits the replication of normal, noncancerous cells, which is why chemotherapy makes many patients sick.