Hawaiian Cancer Warriors Lead Research In Pacific

A university facility looks for tropical medicines while its epidemiology program tries to link disease and lifestyle HONOLULU -- An organism that Hawaiians call limu-make-o-hana thrives in the tide pools near the town of Hana, on the island of Maui, according to University of Hawaii chemist Richard Moore. And when Hawaiian warriors of the past, in search of a lethal poison, placed an exudate of this organism on their spear tips, they were on the right track, says Moore. Palytoxin is the exudate of the limu-make-o-hana (in Hawaiian, "the deadly seaweed of Hana," a misnomer since it is a sea anemone-like organism and not a seaweed). It is one of the most deadly cytotoxins known to man. One day, thanks to the efforts of Moore and colleagues at the Cancer Research Center of Hawaii (CRCH), palytoxin may be mounted on antibodies instead of spears for use as an immunotoxin in attacking cancer cells. Starting with a few faculty at the University of Hawaii who collaborated on cancer studies in the late 1960s, the university facility has developed into a research center with more than 100 research personnel and an annual budget of $5 million. The only cancer research institution in the Pacific, CRCH gets grants from the National Cancer Institute, the American Cancer Society, and the Hawaiian state government. John Bertram, who heads the Lab Sciences Program at CRCH, received his Ph.D. from the University of Manchester in England. While there, he worked in the area of chemical carcinogenesis in the Department of Pharmacology, where his research focused on bladder cancer. Bertram came to the United States in 1971 to study at the McCardle Laboratory for Cancer Research at the University of Wisconsin. In 1974 he went on to Roswell Park Memorial Institute in Buffalo, New York. In Roswell's Department of Experimental Therapeutics his research concentrated on the development of cancer chemo-preventive compounds, with particular emphasis on the novel retinoids. In 1984 Bertram came to CRCH, where his most recent work has focused on the role of the retinoids in intercellular communication. "We discovered this," he says, "and to my knowledge it is not going on anywhere else." His areas of interest have also broadened to include the carotenoids of fruits and vegetables, which are retinoid precursors. Now 46, Bertram has an American Cancer Society grant to study the chemo-preventive ability of the carotenoids and to describe their mechanism of action. --P.M. The center's principal programs are in epidemiology and lab sciences, but with the addition in 1988 of a new director, Brian Issell, who brings with him a solid background in the development of anticancer drugs, CRCH is developing a Natural Products Screening Program with eventual ties to the pharmaceutical industry. It is also initiating a Clinical Trials Program that will emphasize the special needs of Hawaii's multiethnic population. With as much as 85 percent of all human cancer believed to be caused by either environment or lifestyle, scientists are especially interested in the differing cancer rates of Hawaii's five major population groups: Caucasians, Japanese, Filipinos, native Hawaiians, and Chinese. Each has a distinct lifestyle and distinct diet, making Hawaii a "living laboratory" for studying differences in cancer risks and cancer survival rates among ethnic groups, according to Larry Kolonel, director of the Epidemiology Program. Kolonel says that between 30 percent and 35 percent of human cancer mortality is probably attributable to diet, "and that is where we will make our greatest impact." Already the program has made a mark in the areas of both nutrition-induced cancers, where it has contributed to the evidence implicating high fat diets, and in chemo-prevention, where recent local work has suggested that the carotenoids found in fruits and vegetables are protective. Confirming evidence for this latter finding is also beginning to trickle in from CRCH studies performed in Fiji and the Cook Islands. The Epidemiology Program has capitalized on Hawaii's multiethnic, minimally migrating population in several ways. The Health Surveillance Program of the Department of Health has surveyed the health habits of 2 percent of the state's residents almost every year since 1972. In the mid-'70s, according to Kolonel, "we persuaded them to add two pages to their questionnaire," which has been the source of dietary, smoking, drinking, weight, and height information for a 50,000-person random sample of the state's population. This Hawaii Population Database is unique because it is statewide and representative. The participants would be a prohibitively expensive group to follow if it were not for a second research asset, the state's Tumor Registry. The registry keeps track of all cases of cancer in the islands, a blanket resource few other states can boast. This means that in a long-term study the registry records can be inexpensively linked to the 50,000 study participants via machine comparison of the databases, rather than through costly telephone follow-ups. Unfortunately, the population database was set up before the Epidemiology Program focused its research on nutrition and cancer. As a result, its dietary information is not as detailed as it could be. To remedy this, Kolonel, joined by scientists at the Kenneth Norris Cancer Center at the University of Southern California in Los Angeles, is about to apply for "a sizable grant" to develop a multiethnic, 250,000- to 300,000-subject cohort study that would examine blacks, Chicanos, and Koreans from California alongside Hawaii's five ethnic groups, and contain more detailed dietary data. "This would be a rather monumental cohort," says Kolonel. The Lab Sciences Program under John Bertram is primarily interested in chemo-prevention that is, finding substances that will prevent cancer from striking. This dovetails nicely with the Epidemiology Program, according to Bertram, in which researchers have been implicating fruit and vegetable carotenoids as preventive agents. The Molecular Epidemiology Lab, an offshoot of the Lab Sciences Program, has just applied to the American Cancer Society for seed money of $1 million over five years. The lab will look for molecular markers of DNA damage in Hawaii's ethnic groups. Should they differ in each ethnic group, then these data will be compared with the dietary intake data that have shown fruit and vegetable constituents to be protective in these same groups. If the data correlate, they will further enhance the case for the diet/cancer hypothesis. Another outgrowth of the Lab Sciences Program is the Natural Products Screening Program, which is in search of agents that will both protect against and knock out cancer, according to Issell. CRCH has just begun to collaborate with Richard Moore and Greg Patterson of the University of Hawaii chemistry department. Reflecting on his work with the limu-make-o-Hana, Moore says, "I've always been more interested in plants. It was [mistakenly] called a plant; that was the initial stimulus to look at it." Now Moore is more heavily involved with plants, doing marine extract work that has received National Cancer Institute funding for the past four years. It is the only cytotoxic research in the world that is looking at blue-green algae. An indication of CRCH director Brian Issell's commitment to natural products research is the periwinkle he had planted in front of the center. Drugs for the treatment of the acute leukemia of childhood, Hodgkin's disease, and testicular cancer all come from the periwinkle. "I wanted everyone to know that," Issell says. "It has probably saved more years of life than any other plant." Issell, 47, comes to CRCH via New Zealand, where he began his cancer work in medical oncology while receiving his M.D. at the University of Otago Medical School. In 1978 he accepted a joint appointment with the State University of New York Upstate Medical Center at Syracuse and Bristol Laboratories to work on such drugs as cisplatin, which has proved successful in testicular cancer, and bleomycin, which is used for lymphomas. Issell went on to another joint appointment in 1984, this time with the Stanford Medical School and Cetus Corp., where he was recruited to work on the preclinical and clinical development of biological products, including interferon and interleukin-2 and various monoclonal antibody-based products. While on the Stanford faculty he was able to apply some of these new biologics to AIDS patients at San Francisco General Hospital. In 1988, after five years with Cetus and Stanford, Issell took the helm at the CRCH. --P.M. Although the Screening Program does not yet have a director, a job offer has been extended to a pharmaceutical industry applicant, and screening of about 150 extracts per week is already taking place, says Bertram. The current tests are enzyme assays, precursors to human cell line testing; the center hopes to eventually do about 500 enzyme assays and 30 cell line tests per week. Once the director is in place, Issell anticipates applying for both federal and private funding to jump the present $50,000 per year seed money to a budget of between $500,000 and $1 million per year. As far as Issell is concerned, this is an untapped area, and "the sky is the limit," he says. Chemist Moore expects that the 20 members of the university chemistry department who are already involved in natural product cancer research will eventually "find some connection" to CRCH. One area in which CRCH has always come up short is clinical trials. Even though the center is affiliated with the Southwest Oncology Group, the National Adjuvant Breast and Bowel Project, and the Pediatric Oncology Group, which enables local patients to access the latest experimental treatments from the mainland, CRCH has found that without a hospital it is unable to develop protocol studies that may be more suited to local needs. This is in the process of changing, however. In 1988 the center helped establish the Cancer Research Consortium to conduct clinical trials with Kuakini Medical Center, Queen's Medical Center, and Saint Francis Medical Center, all in Honolulu, with input from the University of Hawaii. The center is recruiting for two medical oncologist and four clinical lab positions, while each hospital will contribute its facilities and $200,000 per year, with the university chipping in $300,000 and the expertise of its faculty. This program is badly needed, says Bertram, because mainland drug protocols aren't always appropriate to Hawaii's ethnic mix. He points to a recent trial, in which "six out of six Japanese patients with colon cancer could not tolerate their drugs," as an example. Issell also plans to reach groups that find "Western medicine alie" and is looking at adding "traditional healers" to the team approach in the hope of increasing access to treatments and adherence to regimens. He would further like to investigate traditional Hawaiian plant and herb remedies. "We need to use proper documentation and scientific methods to see if some of this stuff works," he says. CRCH also has ties with the Japan National Cancer Institute (JNCI), particularly with regard to new drug developments, according to Bertram. He says that the Japanese use cancer drugs that are very different from those found in the United States and that there is a great deal of interest in determining whether it is "just cultural bias or [if the Japanese preference] has a real basis." Issell also wants to work more closely with JNCI in the area of stomach cancer, which is very high in Japan and Hawaii, and on breast cancer, which is increasing in Japan as it Westernizes and could be associated with dietary changes. Over the next decade Issell expects to develop ties with pharmaceutical companies as the center's Natural Product Screening Program grows and to move out into the community to implement what Issell calls "culturally sensitive" approaches to cancer control, but he says, essentially, we will be doing more of the same." He wants CRCH to concentrate on what it can do best and on what the state of Hawaii needs, such as work on stomach, breast, and gastrointestinal cancers, and he says the center won't branch into new areas just for the sake of growth. He worries about recruiting staff, saying "the biggest problem we have is the cost of living. "Researchers are excited about CRCH, but if they are beginning their careers, starting their families, and in the market for a home, they can be discouraged. Who signs on? "Those who are motivated and don't mind the decrease in the quality of life." Yet he expects the staff and budget to at least double and for the center to become more competitive in seeking both federal and private monies in the next 10 years. Confident about the center's future, he says, We don't want to be too diffuse; we want to be the world's experts in areas where we have an edge." Paul McCarthy is a freelance writer based in Hawaii.

Hawaiian Cancer Warriors Lead Research In Pacific

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