Obituary

Tolstoy wrote that an individual's passion often proves his undoing. For those of us passionately dedicated to the care and cure of cancer patients, the ultimate irony is to face cancer in our personal lives. And, all too often, the life of a colleague, relative, spouse, or cancer researcher is lost to the disease. Our dear friend, scientific colleague, and mentor, Takashi Tsuruo, died on December 16, 2008 after a 6-month ordeal with non-small cell lung cancer. Never a smoker, Dr Tsuruo had early evidence of a lung tumor on routine screening films, but the presence of the tumor was not appreciated until he developed symptoms and the tumor was far advanced. Sadly, the tumor did not carry a mutation in the epidermal growth factor receptor gene and proved unresponsive to heroic chemotherapy efforts. Through it all, he maintained his fervent interest in his laboratory, witnessed the marriage of his daughter, Ikuko, to Ryohei Katayama, one of his most promising junior faculty members, and became a constant source of strength and affection for his wife, family, and friends. His loss to all of us and to the world of cancer research is a tragedy beyond words. Dr Tsuruo was born into a family of business people in 1943 and received his education at the University of Tokyo's Faculty of Pharmaceutical Sciences. In 1975, he directed his first postgraduate efforts toward virology, first as a Research Associate with Dr Maurice Green at St Louis University and later, in 1977, with Dr Marcel Baluda at the University of California in Los Angeles. Accepting a faculty position at the Japanese Foundation for Cancer Research, he became fascinated with the process of cancer metastasis and returned again to the United States in 1980 to work at the National Cancer Institute with Josh Fidler, a distinguished scientist, who became his life-long friend. His brief, 3-month tenure with Fidler led to three papers that identified him as a future star. That star ascended with Dr Tsuruo's remarkable subsequent work on p-glycoprotein, a mediator of drug efflux and a breakthrough in understanding multidrug resistance. His seminal papers in 1983–4 showed that multidrug resistance (MDR) and p-glycoprotein function could be blocked by alternative substrates such as verapamil, a calcium channel blocker. His laboratory proceeded to clone the MDR gene and purify the protein, and described its ATP dependency, its phosphorylation, its classification as an ABC cassette transporter, and its broad range of substrate specificities. During this period of intense productivity, Dr Tsuruo and his family spent 1 year as a visiting researcher at the National Cancer Institute (NCI) in the Division of Cancer Treatment. During this time, my wife, Davi, and I got to know his wonderful family. From his first day at NCI, Dr Tsuruo was a gentle whirlwind of energy, ideas, and hard work. He wasted no time in defining his own lab space with Bob Ozols and consulting with Mike Gottesman (now the Scientific Director of the National Institutes of Health), the notable NCI expert on MDR. With Ozols, he spent a productive year working on the problem of reversal of MDR in ovarian cancer with verapamil. His year in Bethesda led to collaborations and friendships that lasted throughout his career (see Fig. 1). Takashi Tsuruo and his wife, Etsuko, during a trip with the Chabners and Akihiro ‘Sam’ Shimosaka to Shanghai in 1996. Sam, Takashi, and my wife and I could usually be found on a golf course, even in China. Returning to the University of Tokyo, his stature as a biochemist, pharmacologist, and biologist grew with each year. From 1999 to 2003, he served as the Director of the Institute of Molecular and Cellular Biosciences of the University of Tokyo. In 2006, we joined the celebration of his retirement from the University, and he became Director of the pre-eminent Cancer Chemotherapy Center of the Japanese Foundation for Cancer Research (JFCR), a position that he occupied until his death. Throughout his career, he was known as a kind and thoughtful mentor, an adviser for many successful young scientists, and a colleague who maintained communication with his fellow researchers throughout the world. A host of Americans, including this writer, owe our continuous, long-term relationship with colleagues in the Far East to the efforts of Dr Tsuruo and his mentor, Dr Sugano, who organized yearly symposia on chemotherapy and new drug discovery. These trips, initiated and sponsored by the JFCR, were instrumental in creating scientific exchange, fostering collaborations, and sharing early research results. Worldwide, the specific interest of Dr Tsuruo and colleagues has grown from a focus on the MDR protein to a much larger field of research involving transport of natural products, anti-infective agents, hormones, and metallo-organic compounds by hundreds of different membrane proteins, akin to the explosive development of the protein tyrosine kinases. Dr Tsuruo and his colleagues Michael Gottesman, Ira Pastan, and Tito Fojo (NCI), Piet Borst (Netherlands), Susan Horwitz (Einstein), and Victor Ling (Toronto) were the intellectual force behind this development. There were other, less public aspects of Dr Tsuruo's life that are worth noting. He was a potter whose weekend retreat near Mt Fuji (see Fig. 2) provided an opportunity for working with his hands and for reflection. The location was important, as the mountain's presence reminds its visitors of the larger purpose in life and the spirit that watches over us. He loved golf, and was extremely proud of – and at times surprised by – the elegance of his own shots. His eyes would open wide, and he would rise up on his tip toes in admiration of the small white ball bouncing toward the green. He was always fun to be with, even in his hospital room during the last days. He was the protective spirit for his family and friends, never missing the opportunity to instruct us to ‘take care of your health.’ He invariably anticipated the comforts and needs of visitors to Tokyo. On my last visit to that wonderful city, only a few days before he died, he would not delegate responsibility for all the arrangements, but managed the details from his hospital bed. Only rarely are sensibility, kindness, and passion so wedded in a single person, as they were in Takashi Tsuruo. Mt Fuji, the site of Dr Tsuruo's favorite retreat for pottery-making and relaxation. We leave Dr Tsuruo with great sadness, with even greater admiration and affection, and with the sincerest of condolences to his devoted family, his wife Etsuko, and his daughters Sachiko and Ikuko. Like Mt Fuji among the mountains, he was, and is, a unique and towering figure among men.

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