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ANTICANCER VACCINE Based on hexasaccharide, potential vaccine moves from synthetic lab to clinical trial
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nother therapy for cancer patients sible with the total synthesis of globo Η could be on the way. A new vac- by a team led by Danishefsky (C&EN, icine preparation is being tested Aug. 7, 1995, page 31). The synthesis, this month on 24 patients with early met achieved through glycal assembly, made astatic prostate cancer at Memorial Sloan- sufficient quantities of globo Η available Kettering Cancer Center in New York for various studies. To prepare the vac cine, the synthesis team attached a han City. Blending synthetic chemistry, immu dle to the hexasaccharide portion of the nology, and medicine, teams from three antigen through which it can be linked laboratories at the center developed the to a carrier protein. vaccine [Angew. Chem., 109, 66 (1997)]. Mice treated with the globo Η hexasac They were led by Philip O. Livingston, charide bound to the carrier protein key head of the Laboratory for Tumor Vaccin- hole limpet hemocyanin in conjunction ology; Samuel J. Danishefsky, head of the with an immunological adjuvant produce Laboratory for Bioorganic Chemistry and chernis- f try professor at Columbia | University; and Kenneth ^ O.Lloyd, head of the Lab- | oratory for Tumor Anti- ° gen Immunochemistry. | The vaccine consists κ of a synthetically pre- ° pared, complex hexasac- -Q charide linked to a carri- | er protein. The oligosac charide is identical to the carbohydrate region of an antigen called globo H, which is found on var Danishefsky's total synthesis of globo Η allowed ious types of tumor cells. Livingston (right) to develop anticancer vaccine. It is by far the most com plex synthetically prepared oligosaccha large amounts of IgM antibodies and some ride to be incorporated in a carbohydrate- IgG antibodies. The next hurdle was to de based anticancer vaccine. termine whether these antibodies would Globo Η was first isolated from hu recognize the antigen when they encoun man breast cancer cells. It also is found tered it on tumor cells. As Livingston ex on prostate, colon, and pancreatic cancer plains, some other attempts at anticancer cells, says Livingston. If successful, the vac vaccines had to be abandoned when it cine could be used against a variety of could not be shown that the antibodies in cancers. duced by the vaccine did, in fact, recog The role of antibodies in cancer thera nize the antigen on tumor cells. py is well established, notes Livingston. That doesn't seem to be the case here. Antibodies recognize antigens on tumor Several lines of evidence show that the cells, marking the cells for destruction by vaccine-induced antibodies in mouse sera other parts of the immune system. Fur indeed also recognize globo H on tumor thermore, he explains, carbohydrates are cells. The researchers also demonstrate the most numerous antigens on the sur that binding of the anti-globo Η IgM to tu face of tumor cells, making them logical mor cells triggers a process called comple targets for vaccine development. ment fixation, which culminates in de Developing the vaccine became pos struction of the tumor cell. Says Livingston: 8 JANUARY 20, 1997 C&EN
"The synthetic globo Η in the vaccine is being perceived correctly by the immune system and is inducing the type of anticancer-cell response we had hoped for." The vaccine is not expected to give long-term immunity, such as that con ferred by polio vaccines and the like. Ac tivating the part of the immune system responsible for such an effect requires larger amounts of IgG antibodies than the vaccine is producing. That's not surprising to Harold J. Jen nings, head of vaccine design at the In stitute of Biological Sciences at the Na tional Research Council in Ottawa. Be cause globo Η is a self-antigen—a part of the body's "self' rather than an invad ing foreign matter—it induces mainly IgM antibodies. Rather than conferring long-lived im munity, this vaccine could be a powerful tool to use in recovery from treatment of cancer, says Jennings. After an operation to remove a tumor, the preparation could be used to recruit the human immune sys tem to destroy any remaining cancer cells, thus preventing recurrence of the cancer. "If the vaccine can remove the last of the cancer cells, it's a tremendous step for ward," Jennings says. "The globo Η accomplishment is only the first step in an evolving anticancer vaccine program," says Danishefsky. "The full force of synthetic chemistry is being brought to bear on the carbohy drate tumor antigen problem." Maureen Rouhi
Feds crack down on CFC smuggling Six federal agencies are combining forces to strike a blow against the smuggling of chlorofluorocarbons (CFCs) into the U.S. This beefed-up effort, part of the new National CFC Enforcement Initiative, has resulted in charges against or arrests of individuals and companies in Houston, Los Angeles, Miami, Philadelphia, San Di ego, and Savannah, Ga. CFC smuggling has intensified in the past few years as U.S. production is phased out and use of more expensive alternatives ris es (C&EN, Sept. 16, 1996, page 18). "The U.S. has experienced a flood of illegal im ports of CFCs—through fraudulent mark ings of containers, fraudulent paperwork, smuggling, and other means," explains En vironmental Protection Agency Adminis trator Carol M. Browner. U.S. Attorney General Janet Reno
CFCs until 2006. According to Justice De partment figures, CFCs can be purchased for $2 per lb in Mexico and sold to users in the U.S. for about $20 per lb. Because these are illicit purchases, buyers evade the $5.80-per-lb excise tax the U.S. charg es on CFC sales. Other nations that may be sources of the smuggled CFCs include In dia, China, and Russia. In addition to Justice and EPA, the oth er federal agencies taking part in the CFC enforcement initiative are the U.S. Cus toms Service, the Internal Revenue Ser vice, the State Department, and the Feder al Bureau of Investigation. William Brooks, a Justice Department spokesman, says the group will vigorously pursue smugglers as long as the problem persists. David Hanson Reno: shutting down CFC black market
vows, "We will shut down this black market, and we will not let [smugglers] endanger our ecosystem and our chil dren for a few dollars." In 1987, the U.S. and 159 other nations signed the Montreal Protocol on Substanc es That Deplete the Ozone Layer, agreeing to phase out production of ozone-deplet ing substances. One result of that agree ment is the provisions in the 1990 Clean Air Act that prohibit shipment of CFCs into the U.S. after Jan. 1, 1996. Invoking that law, the government has brought charges against more than a dozen individuals and companies and has arrested the individuals. The biggest case involved an attempt to smuggle 28 1-ton cylinders of CFCs into the U.S. through the Port of Los Angeles. In another case, a Pennsylvania company netted more than $ 1 million in ill-gotten gains from its smuggling of 1.5 million lb of CFC refrig erant during 1994 and 1995. Prior to these charges, U.S. enforce ment actions had resulted in the seizure of only about 1.5 million lb of illegal CFCs over the past three years. However, officials estimate that 20 million lb of CFCs entered the U.S. illegally last year. Most of the gas is smuggled in 30-lb cyl inders that are sold to unsuspecting auto mobile dealers and service stations that use it to recharge the air-conditioning systems in cars. It is still legal for licensed distributors to sell CFCs in the U.S. The U.S. has stockpiled an approximately two-year supply of the chemicals. Mexico is a prime source for these compounds because the Montreal proto col allows some developing countries, such as Mexico, to continue to produce
Endocrine disrupter screens on the way New findings reported last week may con tribute substantially to the creation of tests for detecting chemicals that disrupt hor mone systems. These chemicals have the potential to shape the development of the fetal reproductive system, and the Envi ronmental Protection Agency, by law, must develop a screening and testing pro gram for them by August 1998. Scientists led by toxicologist Michael D. Shelby at the National Institute of Environ mental Healtli Sciences report that a set of three existing tests, when used in combina tion, provides a rapid assessment of a chem ical's potential to mimic the hormone es trogen [Environ. Health Perspect, 104, 1296 (1996)]. When the three tests are run at the same time, results can be obtained in three to five weeks at a cost of about $15,000, Shelby says. Conventional cancer bioassays using animals can take one to two years and cost $1 million to $2 million. "Shelby's tests are on target," says Gary E. Timm, senior technical adviser in EPA's Chemical Control Division, and they could help speed the development of a testing regime for endocrine disrupters. In the trio of tests, one determines whether a chemical can bind to an estro gen receptor site. Another detects wheth er a chemical activates estrogen-respon sive genes in a cell line. And the third ex amines whether the chemical causes the proliferation of estrogen-responsive uter ine tissue in female lab mice. Shelby and colleagues used this com bination of assays on 10 chemicals that have known or suspected estrogenic ac
tivity, including 17P-estradiol, diethylstilbestrol (DES), tamoxifen, methoxychlor, nonylphenol, ο,ρ-ΌΌΎ, and kepone. "The results are consistent with what is known about the estrogenic activities of the chemicals studied," says Shelby. Although Shelby's set of tests may turn out to be useful, it would probably consti tute only one component of a screening regime, Timm explains. EPA and its adviso ry committee have decided that in addi tion to estrogens, tests need to be devel oped to detect chemicals that act as antiestrogens, androgens, antiandrogens, and thyroid hormones. EPA and its advisers have also decided that these tests need to be able to screen for effects in both humans and wildlife. Shelby's battery of tests would probably detect chemicals that have estrogen-like activity in mammals, but might miss some estrogen mimics in birds and fish, Timm cautions. Another research group, headed by John A. McLachlan of Tulane-Xavier Cen ter for Bioenvironmental Research, New Orleans, has found that some combina tions of hormone-dismpting chemicals act synergistically [Environ. Health Perspect, 104, 1318 (1996)]. This may mean that any testing program that is developed will need to account for such interactions. The Tulane researchers base their con clusion on lab studies on how chemi cals—alone and in combination—interfere with alligators' sex hormones. These stud ies show how DDT and dicofol caused major reproductive problems among alli gators in Florida's Lake Apopaka (C&EN, May 13, 1996, page 28). Bette Hileman
Tagging explosives: Safety and cost dominate debate The National Research Council committee organized to evaluate the value of tagging explosives as a counterterrorism measure held its first public healing last week in Washington, D.C. The panel heard from in dustrial and special interest groups, compa nies with commercial or potential tagging technologies, and law enforcement agents. The breadth of interest in the hearings underscores the complexity of the com mittee's task. "The issues are complicated at many levels," said committee chair woman Marye Anne Fox, vice president for research and chemistry professor at JANUARY 20, 1997 C&EN 9
