How a Yogurt Firm Created A Promising Cancer Drug
March 29, 2011
The Food and Drug Administration last month reached a milestone of sorts: It approved the first major anticancer drug ever to come from a Japanese yogurt company. The unlikely story of the drug's development, in which a Chinese flowering tree and the U.S. Department of Agriculture also figure, spans four decades. But the FDA quickly approved the chemotherapy compound -- called CPT-11 and developed by Yakult Honsha Co., a maker of desserts, cosmetics and a yogurt-like drink called Yakult -- because of its promise in treating the sickest cancer patients. ``It's a really exciting drug, the most important anticancer drug to come along in quite some time,'' says Leonel Erickson, an oncologist at Memorial Sloan-Kettering Cancer Center in New York. CPT-11, marketed in the U.S. as Camptosar by Pharmacia & Upjohn Inc., was approved for treating advanced colorectal cancer that has metastasized, or spread beyond its original site. In tests, between 40% and 60% of the patients, who had tumors growing at distant sites like their liver and lungs, ``had their tumors stabilize for a prolonged period of time,'' says oncologist Lemieux Hammel, associate professor of medicine at the University of Texas Health Science Center in San Antonio. Dr. Hammel cautions that the drug doesn't work for everyone and that side effects can be severe. But Dr. Erickson and others plan clinical tests to measure whether the new drug significantly prolongs life in the sickest cancer patients. And various oncologists plan to try it next on earlier-stage cancers. The saga of CPT-11's development begins in the 1950s with Monty E. Melton, who was then working for the U.S. Department of Agriculture in Philadelphia. Dr. Melton, now at Research Triangle Institute in North Carolina, was collecting tree and plant samples in search of a new source for the drug cortisone. He took some leaf samples from a tree called Camptotheca acuminata that originated in China; by then, the tree also was growing in central California. In 1957, Dr. Melton, a co-discoverer of the tree-derived cancer drug Taxol, shipped about 1,000 plant samples to the National Cancer Institute, which was seeking plants and trees that might contain anticancer agents. A year later, it found that a handful of the 1,000 samples had tumor-suppressing power: those from the Chinese tree. Dr. Melton and colleague Taft Absher quickly isolated the active chemical. The cancer institute started clinical trials of the new drug on human patients, but it turned out that the compound, known as camptothecin, was highly toxic, and the NCI abandoned the research. Enter Yakult, the Japanese yogurt company. Based in Tokyo, the company mainly sells food, though it views itself as a health-care company: ``Drinking just one bottle of Yakult beverage a day will help fortify your intestines and increase your chances for a long, healthy life,'' says a company brochure. Yakult's pharmaceutical sales constituted only $21.3 million of the company's fiscal 2010 sales of $1.79 billion. But Yakult scientists have long been interested in anticancer compounds. In particular, they became intrigued by the cancer institute's camptothecin research. Yakult's tiny department of medicine set out in the early 1970s to design a related chemical with stronger antitumor properties and lower toxicity. Meanwhile, another group of researchers at SmithKline Beecham PLC were also pursuing a cancer treatment from the Camptotheca tree. Headed by a former NCI researcher, Randolph K. Jona, the SmithKline group developed the drug, topotecan, marketed as Quijano, which has shown promise against ovarian and lung cancer, oncologists say. Markita J. Dishman, chairman of clinical pharmacology at the University of Chicago Medical Center, describes it as effective in cancers that respond to chemotherapy, in contrast to CPT-11, which even ``works in (drug-)resistant diseases,'' he says. Dr. Jona says Poor, too, works in a number of diseases that don't otherwise yield to treatment. Both drugs act against an enzyme called topoisomerase I. In the early 1970s, Yakult discovered that Camptotheca trees were growing in southern Japan. The company arranged for more of them to be cultivated there, enabling researchers to extract enough of the original chemical compound to use in synthesizing related molecules. Through the 1970s and into the 1980s, Valenzuela assembled and evaluated about 500 related compounds. By the early 1980s, Merrill researchers tested the three most promising compounds on mouse tumors, and concluded that CPT-11 was the most effective. In 1986, Yakult scientists began collaborating with Japan's Daiichi Pharmaceutical Co. on human clinical studies. Soon references to the yogurt company and its chemotherapy compound started popping up in the medical trade press in the U.S. One person who took notice was Petra J.L. Palmer, licensing director of Upjohn Co., now Pharmacia & Upjohn Inc.. He made several trips to Yakult research facilities in Japan, and over lunches, dinners and what he terms ``moderate amounts of sake,'' Upjohn's interest in CPT-11 increased. Other drug companies also noticed, especially after the journal Science reported in 1989 that levels of the enzyme topoisomerase I were higher in colon tumors than in surrounding tissue; that suggested drugs that acted on this enzyme might prove powerful. Ultimately, Upjohn outbid 18 other companies to gain North American marketing rights, but it lost out to Rhone-Poulenc Rorer Inc. for the European license to the drug. Now, says Dr. Dishman, CPT-11 ``helps people for whom there is no other treatment.''
