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AMERICAN y CANCER ? SOCIETY NATIONAL HOME OFFICE CLARK W. HEATH, JR.. MD Vice President Epidemiology ond Stdtistics August 4, 1994 Hasmukh C. Shah, Ph.D. Manager, Vinyl Chloride Panel Chemical Manufacturers Association 2501 M Street, N.W. Washington, DC 20037 Dear Dr. Shah: Thank you for your recent letter. The Time magazine chart is certainly misleading. It may well be that the American Cancer Society source they are citing is Cancer Facts and Figures 1994, in which case it is unfortunate that they ignore the word "possible". Cancer Facts and Figures is widely quoted and not infrequently quotations are not entirely accurate. We review the Cancer Facts and Figures text and update the numbers each year and shall certainly take your comments into consideration. There are, of course, many degrees of "possible" when considering risk factors, and in the instance of lymphoma I would think there is a distinctively lower possibility for vinyl chloride than for herbicides, neither being proven. The document is not meant, of course, to be an exhaustive treatise on all possible cause factors at each cancer site, but to provide brief overviews of major points. For no site other than liver (angiosarcoma) is vinyl chloride evidence conclusive, and even there it concerns only high, repeated, occupational exposures to vinyl chloride monomer (ideally, we should distinguish between monomer and polymer). Again, thanks for your letter and its attachments. Sincerely Clark W. Heath, Jr., M.D. cc: S. Montgomery A. Stone J. Laszlo, M.D. R&S 143296 1599 CLIFTON ROAD, N.E.. ATLANTA, GA 30329-4251 * 404-329-7686 * FAX 404-325-1467 CHBvUCAL manufacturbs association August 1, 1994 Clark Heath Jr., M.D. Vice-President for Epidemiology and Surveillance American Cancer Society 1599 Clifton Rd. NE Atlanta, GA 30329-4251 Dear Dr. Heath: 1 am writing this letter on behalf of the Chemical Manufacturers Association Vinyl Chloride Panel to express our concerns regarding a statement in the first full sentence of page fifteen of the ACS publication Cancer Facts and Figures 1994 (as well as in earlier issues). Referring to the risk factors associated with malignant lymphoma, this statement reads as follows: "Other possible risk factors include exposures to herbicides, industrial solvents, and vinyl chloride." We believe that a misunderstanding of this statement may have lead to the association of vinyl chloride exposure with risk of lymphoma in an article by J. Madeleine Nash in the April 25, 1994 issue of TINE magazine (page 60). A copy of this page is enclosed. The description in the table entitled "The Big Killers" implies, we believe, that vinyl chloride is a "proven" rather than a "possible" risk factor for malignant lymphoma. We are concerned that others may similarly misinterpret the statement appearing in Cancer Facts and Figures 1994. A large number of epidemiologic studies have been conducted on well-defined occupational cohorts with potential exposure to vinyl chloride. In some of these studies an elevation in lymphoma mortality was observed, but not in others. The largest and most recent such study, published by Wong et al. in 1991, did not observe any excess f lymphatic or hematopoietic cancer deaths, even among workers who were first exposed prior to 1950. In contrast, mortality due to cancer of the liver, with which vinyl chloride exposure is certainly causally associated, was most elevated in the subcohort of workers exposed prior to 1950. We believe that the epidemiologic evidence does not lead to an inference of a causal association between vinyl chloride exposure and malignant lymphoma. V Our view is consistent with that of Sir Richard Doll, who reviewed the evidence in 1988. We note that Doll refers to the studies by Tabershaw and Gaffey (1974) and Waxweiler et al. (1976) as having raised the possibility of an association between vinyl chloride and lymphoma. We hasten to point out that these were early studies conducted on workers who were eventually included in the much larger cohort studies by Wong et al. and referred to in this letter. 2501 M Street. NW, Washington, DC 20037 Telephone 202-887-1100 Fax 202-887-1237 R&S 143297 August 1, 1994 Pag 2 We respectfully request that the statement in Cancer Facts and Figures 1994 be amended to better reflect the current state of knowledge about the suspected association of vinyl chloride exposure with lymphoma. The suggested wording to be added is (underlined and in italics): "Other possible risk factors include exposures to herbicides, industrial solvents, and vinyl chloride, although the evidence supporting an association with vinyl chloride exposure Is limited An alternative to this change of wording would be to remove the specific reference to vinyl chloride from the statement. We note that vinyl chloride is not mentioned specifically as a possible risk fact r for cancer of the lung, although there is also equivocal epidemiologic evidence for an association between vinyl chloride exposure and this type of malignancy. We feel that our suggestion encompasses the current state of the evidence concerning vinyl chloride and lymphoma and would minimize the possibility for the kind of misinterpretation we observed in the TIME magazine article. At the same time, we wish to point out that this letter was intended solely to address possible misinterpretations with respect to lymphoma and vinyl chloride. In no way do we acknowledge the existence of any association between exposure to herbicides or industrial solvents and the occurrence of malignant lymphoma. We trust that this letter and the attachments will serve to provide you with a comprehensive view of the evidence concerning the health effects of vinyl chloride exposure in humans. If you have any questions or would like more information, please contact me at (202) 887-1192. Sincerely Enclosures Hasmukh C. Shah, Ph.D. Manager, Vinyl Chloride Panel R&S 143298 August 1, 1994 Page 3 References Cited and Enclosed: American Cancer Society. Cancer Facts and Figures, 1994; 1-28. Doll R. Effects of exposure to vinyl chloride. An assessment of the evidence. Scand J Work Environ Health 1988;14:61-78. Nash JM. Stopping Cancer in its Tracks. TIME Magazine 1994; April 25: 54-61. Tabershaw IR and Gaffey WR. Mortality study of workers in the manufacture of vinyl chloride and its polymers. J Occup Med 1974;16:509-18. Waxweiler RJ et al. Neoplastic risk among workers exposed to vinyl chloride. Ann NY Acad Sci 1976;271:40-48. Wong 0 et al. An industry-wide epidemiologic study of vinyl chloride workers, 1942-1982. Am J Ind Med 1991;20:317-34. B&S 143299 4flt was like a tm s*lot^or measles or malfunctions. When she introduced a nor mal nm23 gene (nm stands for nonmetastatic) into highly malignant human breast cells, then injected these ceils into mice, their tendency to form metastases dropped as much as 90%. mumps. I do GUARDING THE MASTER 5WTTCH Until last week, p53, the subject of some 1,000 scien if \j/Az noteexxopectaainy side effects, except to feel tific papers in 1993 alone, was considered the most important cancer gene. The jour nal Science even named it Molecule of the Year. But now there is a new contender for notoriety--mtsi, as Alexander Kamb and his colleagues refer to the multiple tumor- faetter.W suppressor gene they have just discovered. "Multiple" refers to the fact that defects in this gene can cause many kinds of cancer; including melanoma, lung, breast and brain JACK SWEPS70N, 48. Pancreatic Cancer. On March 31 this Dallas dentist trav tumors. In fact, functional copies of mtsi eled to the National Cancer Institute in Bethesda, Maryland, to receive a new type of anticancer vaccine. Prepared by a team of researchers, including Dis. David Carbone and John Minna of the University ofTexas Southwestern Med* may be missing in more than 50% of all hu man cancers. What makes mtsi so significant is its dearrole in the cell-division cyde. Acell di ical Center, the vaccine was a synthetic version of a mutant protein fragment vides not at will but in response to specific found in Swepston's tumor. The hope is that the immune system will leam to signals, such as growth factors produced by recognize this target and destroy the cells that make it "I haven't felt a signifi cant improvement yet," he says, "but the doctors are tremendously excited." white blood cells rushing to repair a wound. These signals are picked up by re ceptors on the membrane of the cell and passed along--like batons in a high-speed enues of escape. Not all die myriad cells ulate newareas. Butwhile an embryonic cell relay--through the interior, all the way to a shed by tumors survive the turbulent voy stops proliferating and matures into adult master "on" switch positioned deep in the age through the bloodstream, notes exper tissue, the cancer ceilsjust keep dividing. nucleus. Not surprisingly, many onco imental oncologist Arm Chambers of die One reason forthe difference may lie in genes, induding one called ras, the first London Regional Cancer Centre in On a gene known as nm23, first identified by human cancer gene ever identified, are in tario. But those that do eventually slip Steeg in 1988. It seems to help mature cells volved in this type of signaling pathway. through blood-vessel walls with ease. Using stop dividing and arrange themselves in an But there are other molecules that deter a video camera attached to a microscopic orderly fashion. Steeg's research suggests mine whether the cell should heed these lens. Chambers has watched in wonder as that in cancer cells this crucial gene often signals. And the small protein produced by melanoma and breast-cancer cells, injected into mice, become lodged in capillary walls, then crawl out into the liver. Three days later, her camera resolves the spidery shapes of tiny metastatic growths. The les son, Chambers believes, is depressingiy THE BIG KILLERS EEssttiimmaatteess mm ttttiiee UU..SS.. 11999944 Canrtr Deaths ^suiv'va1 f.'o.v cases ta'-; P;st Factors clear. Cancer cells zip in and out of blood vessels so readily that, once angiogenesis occurs, they should be presumed to have al ready spread around the body. Metastasis is an event of awesome com plexity, one that requires multiple genes to cooperate as closely as musicians in an or chestra. Some ofthese genes code for chem ical solvents that enable the advancing cell to dissolve surrounding tissue. Others order up the production of adhesion molecules that like treads under a tank, move the cell forward. Why would genes do that? The an swer, notes Patricia Steeg of the National Cancer Institute, is that while the genes im Ndnay 11300 27,600 55% Smkinc portant to metastasis are abnormally turned on. they are not necessarily abnormal them Bladder 10,600 51,200 79% Smoking selves. A cancer cell, in many ways, is not that different from an embryonic cell on its wav to becoming a patch of skin or a bundle I stl i.5oo _________ unomdnw__________ ns46,000 83Tb forty menarcfte: aft mannose: obesity of nerves. Both embryonic and cancer cells j 7,925 29,600 53% Smoking: eicessive use of alcohol divide and form ill-defined clumps. Both get | up and move around. Both migrate and pop- I Skin Melanoma 6o/vn .9- aaa q a a/ Sunburn; fait comptmwi: etposur* to ,8UU 84Tb coat Ur. prtcb, creosote, arsenic, radium R&S 143300 (40 mil.. 4I`HII.25. I9V4 *** + *i(i(irjc + + + icirir1ric*4rir1c***1e*'k'k'k'k'k-k'k'k'k'k'k'kir-k'k-k'k-k-k1r'k'k'k'k'k'k,k1(iC'k'k'k'k1cic'k-k'k,k'k-k'Je`kirif'kir'k-kirir PRINTED BY . IJ073 763 2020 MCCREEDY, R L. 636-1824 94/05/20 13:23:52 ********-t*********************:fc*********^*****************************,*,i!ArTfr**** From: U246074 --S21VM To: U073763 --S08VRNA U075024 --S08VRNA MCCREEDY, RON R L HAYES, BILL W C Date and time U077399 --S08VRNA 05/20/94 12:54:35 BOND, GREGORY G G FROM: RAMLOW, JONATHAN M. SUBJECT: TIME MAGAZINE VCM/LYMPHOMA REFERENCE WE DISCUSSED THIS MATTER AT THE VINYL CHLORIDE PANEL RESEARCH COORDINATORS MEETING YESTERDAY AFTER GREG HAD TO LEAVE. WE ALL AGREED THAT THE BEST APPROACH TO THIS WOULD BE TO CORRESPOND WITH THE ACS TO BE SURE THAT THEY ARE AWARE OF THE RESULTS OF THE WONG ET AL. UPDATE OF THE INDUSTRY-WIDE VC/PVC COHORT AND OF THE INTERPRETATION OF THOSE RESULTS BY WONG ET AL. AND BY RICHARD DOLL. D. PENNEY OF VISTA IS GOING TO DRAFT A COVER LETTER TO ACS TO GO WITH A COPY OF WONG ET AL. AND DOLL'S 198 8 PAPER. CANCER FACTS AND FIGURES CLEARLY HAS VC IN A CATEGORY OF EXPOSURES THAT REALLY ARE ONLY HYPOTHETICALLY ASSOCIATED WITH LYMPHOMA. IN GENERAL, I PERCEIVE THAT ACS ATTEMPTS TO INCLUDE ONLY ESTABLISHED RISK FACTORS IN THE CAPSULE SUMMARIES FOR CANCER SITES, BUT THEY ALSO INCLUDE HYPOTHETICAL FACTORS FOR SITES ABOUT WHICH LITTLE IS KNOWN. I DON'T KNOW HOW THEY DECIDE WHAT TO INCLUDE AND WHAT NOT TO INCLUDE IN THE SUMMARIES. THE RESEARCH COORDINATORS GROUP WILL SEE PENNEY'S DRAFT WITHIN A COUPLE OF WEEKS. THEN WE WILL HAVE A CONFERENCE CALL TO FINALIZE IT. I WILL LET YOU KNOW WHAT COMES OUT OF THIS. JONATHAN RAMLOW R&S 143301 A Division of The Society of The Plastics Industry, Inc. May 4, 1994 TO: Ron McCreedy, Dow Frank Borrelli, Georgia Gulf Joe Ledvina, Vista RE: Time Magazine Article As you will recall, in the April 25 issue of Time Magazine the cover story on cancer included a chart of types of cancer with causes noted -- including vinyl chloride under lymphoma. The source of the information was given as the American Cancer Society. Enclosed is a copy of the ACS 1994 Facts and Figures report which ACS provided to Michelle McDonough of Edward Howard & Co. I have highlighted items on pages 14/15 and 20 where vinyl chloride is so noted. Let me know what action, if any, you think we at the VI need to take and whether you are aware of any action being considered by the Vinyl Chloride Research Panel at CMA. Meredith N. Scheck Assistant Director 65 Madison Avenue Morristown, NJ 07960 (201) 898-6699 Fax # (201) 898-6633 The ongtnal copy of toes document pnnted on recycled paper, r &S 143302 -I f 0 >' ' tfY J. MADELEINE NASH/CHICAGO K TKAI.TIIY AS A riHATK SLIPPING I-'HOM A COVK, the cancer cell severs the moorings (hat attach it to surrounding tissue. Slowly it extends one, two, three fingerlike probes and begins to creep. Then it detects the pulsating pres- ence of a nearby capillary and darts between the cells that compose the blood-vessel wall. It dives into the red river that courses through lung and liver, breast and brain. An hour or so later, it surfaces on some tran quil shore, settles down and--at the expense of its hap less neighbors--begins to prosper. Gradually the cancer cell invades the turfoccupied by its normal counterparts, killing-all those in its path. It tricks nearby cells into forming food-bearing blood ves sels, then compels them to churn out growth-spurring chemicals. To shield itself from patrolling immune cells, the cancer cell sprouts spiny armor like a sea urchin's. To expel the agents physicians send to kill it, the cancer cell deploys along its membrane a battery of tiny pumps. Is there a way to fight such a foe? Until now, medicine has tried to overwhelm the can cer cell with brute force, slicing it out with surgery, zap ping it with radiation or poisoning it with chemotherapy. All loo often, however, a few cells manage to survive the onslaught and germinate, sometimes years later, into tu mors that are impervious to treatment. The ability of the cancer cell to oulmanenver its attackers lias long been re flected in mortality statistics. Despite gains made against cancers such as childhood leukemia and Hodgkin's lymphoma, the overall death rate remains dismally high, litis year more than half a million Americans will succumb to cancer, making it the nation's second SCIENCE R&S 143303 I 1 R&S 143304 effectiveness or continuity. And another demonstration of how the AIG Companies provide the definitive response to risk. WORLD LEADERS IN INSURANCE AND FINANCIAL SERVICES. American International Group, Inc., Dept. A, 70 Pine Street, New York, NY 10270. . ON THE MARCH This breast-cancer cell spits out chemicals that dissolve surrounding tissue and slips through blood-vessel walls like a ghost. The disease thus can spread all over the body and become difficult to eradicate. -rmm I .'.& ' -'i . -JH. - ..v<- R&S 143305 1*:.: ^ ^ ERII ITS TRACKS w cells become malignant-and perhaps how to bring them under control < y-iy ' y; '' leading killer after cardiovascular disease. Yet despite the continuing casualties, there is reason to believe the war against cancer has reached a turning point. During the past two decades, a series of stunning discoveries has pried open the black box that governs the behavior of the cancer cell and revealed its innermost secrets. Now the insights gleaned from basic research are being translated into novel approaches to cancer therapy. It still looks difficult to eradicate malignant cells, but scientists are exploring ways to tame them, to make them behave and thus greatly prolong the lives of people with the disease. The new therapies cany the promise of being not only more effective than the current slashand-bum strategy but also much gentler to the patients who must endure the treat ment Exclaims Dr. Dennis Slamon, a ucla cancer specialist: "This is the most exciting time imaginable!" The excitement was running especial ly high last week, as encouraging news poured out of several labs all at once. From Thomas Jefferson University in Philadel phia came word that an experimental vac cine had given patients unusually long remissions from advanced melanoma, a deadly form of skin cancer. From Canada's McMaster University came a report identi fying a telltale enzyme found in cancer cells--but conspicuously absent from most normal cells. If cancer researchers can find a way to deactivate this enzyme, known as telomerase, they may at last have the mag- MALFUNCTION pressor gene that Alexander Kami) and his colleagues discovered may explain why these melanoma cells went astray. that A viral gene known to cause cancer in" chickens was practically a carbon copy, of a : normal gene found in animal and huqun cells. The virus had somehow stolen per fectly good gene and put it to bad use. Tnis finding helped lead to a general conclusion: ic bullet they have long been seeking. cells become cancerous because their nor Equally tantalizing was the article pub mal genetic machinery goes awry. The cul lished in Science by molecular biologist prits that initiate the damage can be virus Alexander Kamb and his colleagues at es, radiation, environmental poisons, de Myriad Genetics, a Salt Lake City, Utah, fective genes inherited from parents--or a biotech firm. A majority of cancer cells, combination of all of the above. they found, lack functioning copies of a gene that serves as a circuit breaker and shuts down the abnormal cell growth that causes malignancy. Already Kamb is dreaming up ways to fix this seemingly simple glitch. "The route to therapy," he says, "seems surprisingly clear." GOOD GENES GONE BAD The conceptual revolution that is just now sweeping into the clinic began in the 1960s, when re searchers started to realize that cancer is a disease of dna, the master molecule that encodes the genetic script of life. One of dna's most important jobs is to govern cell division, the process by which a cell makes a copy of itself and splits in two. Ordinari ly, cell division is tightly regulated, but a cancer cell divides uncontrollably, pushing into surrounding tissue. A pivotal discovery came in 1976, when Drs. J. Michael Bishop and Harold Varmus at the University of California, San Francis co, made a startling observation. They saw 56 TIME. APRIL 25,199-1 R&S 143306 .' By last week researchers had found make are minor and quickly repaired by Johns Hopkins and Boston's Dana-Farber perhaps 100 cancer genes, at least three proteins that serve as miniature mechanics. Cancer Institute have identified four new dozen of them important in human tu- Occasionally, though, cells with defects in genes associated with a form of early onset i mors. Some, known as oncogenes, turn on their dna will continue to divide, eventual colon cancer known to afflict particular cell division, whereas others, called tumor- ly forming small growths. The more cell- families. These genes are carried by as | suppressor genes, are responsible for division cycles an organism undergoes, the many as 1 in every 200 Americans, maldng j switching the process off. In their normal more likely it is to accumulate colonies of them the most common cause of cancer S form, both kinds of genes work as a team, abnormal cells, each the offspring of a sin susceptibility yet discovered. In their nor 0 enabling the body to perform such vital gle progenitor. By the time humans reach mal form, these biological versions ofcom tasks as replacing dead cells or repairing middle adulthood, then, their bodies con puterized spelling checkers produce pro 1 defective ones. But mutations in the chem- tain millions ofcells that have taken at least teins that scoot along strands ofreplicating 5 ical makeup ofthese genes, whether inher- one step toward cancer. dna, searching for tiny typos. When a pro S ited or acquired later in life, can disrupt tein finds an error in one of the words these finely tuned checks and balances. A ven so, cancer is hardly in spelled out by dna's four-letter chemical l cell containing a faulty oncogene is often evitable. For example, 50% of alphabet, it flashes an alarm. A person i i likened to a car with a stuck accelerator, a Americans will develop at least born with only one good copy of any of E| cell with a damaged tumor-suppressor 0 gene to a car with no brakes. 1 Scientists have thus stripped away canjj cer's mystery and revealed the malignant cell for what it is: not an intrinsically evil i villain but an ordinary machine that has broken down in very specific, and poteii- one precancerous polyp in then- these genes is fine, until some cell in his or colon at some point, but only a her colon loses or mutates its backup copy. fraction of such polyps will devel Without a spelling checker, mutation piles op into aggressive tumors. Why? upon mutation, telescoping the time it Usually it takes so long for colon takes for cancer to develop. cancer to unfold that most people end up dying of other causes. Indeed, contrBaEryNtToOUT OF SHAPE Cancer-causing mu - s tially reparable, ways. They have Studied popular perception, getting cancer istnaotiot ants can occur quite by accident But the life history ofa cancer cell and found er- all easy. To begin with, a cell must acccuhmrounic exposure to carcinogens--chemi fj rant genes at almost every step of the way, late mutations not in just one or two genes cals whose by-products bind to dna and from the initial formation ofatumortothe but in several. In the case of colon cancer, damage it-greatly accelerate the rate at advanced stages of metastasis, the lethal Dr. Bert Vogelstein and his colleagues at which dividing cells make errors. Proven spread of the disease through the body. Baltimore's Johns Hopkins Oncology Cen carcinogens include asbestos, benzene and ter have shown that a cell must sustain some ingredients of cigarette smoke. Many FATAL FLAWS Cancer is not a modem dis damage to at least three tumor-suppressor carcinogens, it turns out, are not blunder- ease. Some of our apelike ancestors un genes and one oncogene. The first muta busses but leave highly individualized fin doubtedly suffered from it; so did the tion spurs the growth of the cell, triggering gerprints in the dna they touch. At the Na- - dinosaurs. In fact, says Robert Weinberg, a the formation of a benign polyp. Later tional Cancer Institute, Dr. Curtis Harris, a molecular biologist at the Massachusetts changes cause the polyp to expand and be molecular epidemiologist, has been exam Institute of Technology, "it is a risk all mul come increasingly irregular in shape. By ining cells from liver- and lung-cancer ticellular organisms run." Each time a hu the time a cell in this growing mass suffers bents, searching for mutabons in a tunBt- man cell divides, it must replicate its DNA, a final, fateful hit to its dna, many decades suppressor gene known as p53 (p stands fpr a biochemical manuscript some 3 billion may have gone by. the protein the gene makes and 53 for the characters long. In the course of transcrib Clearly, however, some people are at a proteinjs molecular weight). Smokers who ing such a lengthy document, even a skilled much higher risk of developing cancer develop lung cancer, Harris has found, typist could be expected to make mistakes, than others, and at an earlier age. For show bny alteradons in the p53 gene that and cells, like typists, occasionally err. them, heredity plays a major role. Over the differ from those in nonsmokers. They also More often than not, the mistakes they past five months, competing teams at vary from the changes found in Chinese Malignant tumor X i. x 0. 4 - ,'X"\*> - . * r-----1--- v. -fOr' t , ' -- j - . 'tv*' Metastasis !I i X & xA:-. \.-f.X x.. -X New blood vessels ^ Chemotherapy X tv;' -*>,> 1 ^^ , > V t. Xv "y X X x" 'XX , - ' Resistant tumor ...x X X' 't . '__________ -- Resistant cell * /tX' / Dead cells ^ 2 Defects m these genes, 3 More >: 4 The malignant rate s ) producing e cnemicaltljaf preventsr?X57 eitheri iimnhiewruiteoduvoir wcauuosveud bvyj .t.>. mutuuwtaJutivoMnosminaayj bi/liowoduvveossjgettsofrMoUnMtMfoVrkmUi'nHgig.* NneewwrMapipiullaMriiietcsothueignigi groivyipirIInHtWo thptec',;n,:_ ; cells,, ugiid, yuii|{uipic radiatBioon, chemicals or --> cause t.h..e..c..e.l.ls.........funtor, prwf.t.M...g..I.t..w..H..h..m..i.t.r.ie..n..ls...T..h.is a.lso Ba-tes a mut.e..f.c..r.U...-.v../- b iwfenfit t-wt umi viruseess,,eventually let the cell "" tobecome X ` malignarrtcrilstobreakayrayfromtherraintumormassand -ri*;^and^wlnfciihew'.turiw^ts)fe^<iancer r grow innttonaRtuimmowr. " maslingn^anntt * tm.altn nthar norf* , Where tfieV Start flew CanCerS. ..'"will teV*''4""'''*' V TIME, APRIL 25 199-1 R&s 143307 57 ... t n r liver-cancer patients. In the latter group, Samuel Broder, director of the National aflatoxin, a fungal contaminant of food, is Cancer Institute, "it must contain within the carcinogen, and it alters dna in an ex its cells the knowledge that they have to quisitely precise way, substituting in a sin die. But the cancer cell divides at all cost gle location a T (thymine) for a G (guanine) It's forgotten how to die." in dna's four-letter chemical alphabet. The tumor-suppressor gene p53 is of How can such a small mistake--the ten described as "the guardian of the equivalent of changing the spelling of genome" because it keeps watch over dna Smith to Smyth--have such an impact? during cell division. When damage occurs, Each three-letter "word" of a gene "sen p53 commands other genes to bring cell di tence" spells out the instructions for pro vision to a halt If repairs are made, then ducing 1 of 20 amino acids, compounds p53 allows the cell cycle to contiriue! Butin that in turn link to form proteins, A change some cases, if the damage is too serious to in just one letter can result in the substitu be patched, p53 activates other genes that tion of one amino acid for another. The cause the cell to self-destruct Mutations in new amino acid will be larger, smaller, stiffer or more elastic than the correct one. In ways radical and subtle, it will affect the shape of the protein and its activity. For if a cell is like a fac tory, then a protein is a cog in a machine that may have as many as 50 components. "If one of them develops a kink in its structure" says Harris, "then the machine doesn't fit together as well." Kinks in proteins that form the nuclear matrix--a dynamic scaffold to which dna is at tached-may be particularly di abolical. Tlie reason cancer cells typically have a swollen and misshapen nucleus, be lieves Johns Hopkins molecular biologist Donald Coffey, is that the proteins that form the nu clear matrix are misaligned in some fashion. Inside the matrix, notes Coffey, 50,000 to 100,000 loops of dna are coiled like a Slinky, but the length of the loops, and where they begin and end, varies from tissue to tissue. The genes closest to the matrix are those that a particular cell intends to have turned on. IMMORTALITY on chromosome tips act as molecular clocks. Calvin Harley has found how cancer cells stop the ticktock. Genes meant to stay inactive are much far ther away. The conclusion is inescapable: a p53, which have been detected in more mutation in a gene that changes the archi than 50% of all human cancers, are thus ex tecture of the nuclear matrix could wreak tremely dangerous. In laboratory cultures, havoc by turning the wrong genes on or off. some cancer cells that possess mutant ver sions ofp53 do not die when challenged by YEARNINGS FOR IMMORTALITY Normal antitumor agents, while those that have cells do not live forever. Under certain cir normal p53 genes go belly-up. cumstances, cells are actually programmed Healthy cells apparently have a precise to die. One of the most fascinating features; system for ensuring their mortality; short of early development, for example, is the strips of dna known as telomeres seem to explosive proliferation of certain types of- provide a molecular clock. When .a cell is cells, followed by mass suicide. .Human fyoung, it has more than a thousand telo embryos start with paddles for hands; it is meres strung along the ends of chromo cell death that gives them fingers. Neurons somes like beads in a necklace. Each time also expire by the billions as the brain re a cell divides, 10 to 20 telomeres are lost, fines its circuitry during development. In and the necklace grows shorter. Eventual adults, the cell-death program serves as a ly, after many cell divisions, the necklace stem disciplinarian. Cells that become ir becomes so short that the cell fails an in reparably damaged are expected to fall on ternal health check designed to keep old, their swords for the greater good of the or possibly damaged cells from reproducing. ganism. "For an animal to live," says Dr. Result: cell division stops, the cell begins to age rapidly, and eventually it dies. Canoer cells, in contrast, haveleamed to stop the ticking of the telomere clock. According to research published last week in the Pro ceedings of the National Academy of Sci ences by Calvin Harley and colleagues at McMaster University in Hamilton, On tario, malignant cells foil the clock by pro ducing an enzyme--telomerase--that pro tects the length of the telomere chains in essence, telomerase makes the cancer cell immortal. A CALL FOR BLOOD Perhaps the most crit ical stage in the life of a tumor comes after , it expands to about a million > cells. At this point, it is "much 5 smaller than a BB," says Dr. Ju? dah Folkman of Harvard Medl ical School. This tiny mass-- * known as a carcinoma in situ, iLliterallycancer in place-is maMignant, but not yet dangerous. | <Why? Because die cells at the | center of the tumor are too far | from the bloodstream to obtain l essential nutrients, they are less r vigorous. Like a society with > zero population growth, a carcil noma in situ adds about as many | new cells as it loses old ones. | Months, years, even d$cf ,ades may pass. Then an omi- transition ,occurs. -Some S bells in the tumor begin sgcjret\ ing chemicals that attrRfet en dothelial cells--the key COmpo nents of blood vessels. These cells form capillaries that grow into the tumor. They also pump out molecular messengers called growth factors that stimulate the tumor to divide more quickly. What triggers blood-vessel formation, or angiogenesis, as the process is known? A major factor, scientists believe, is a sudden drop in the cancer cell's production of thrombospondin, a protein that inhibits the growth of new blood vessels. In the normal adult, angiogenesis is not only a rare event, but one cells stiive to prevent, save for special circumstances like wound healing. For'blood vessels invading joints can cause arthritis, and thdse invading the retina of the eyecfoicaUse blindness. To preventsujh damageTcells keep blood ves sels- at bay^-by>,pumping|.put throm bospondin. At a recent scientific confer ence, Noel Bouck, a molecular biologist from Northwestern University Medical School, stunned her colleagues by present ing preliminary data suggesting that thrombospondin production may be regu lated by that ubiquitous gene, p53. PULLING UP STAKES Angiogenesis is the harbinger of metastasis. The same vessels that feed the tumor also provide it with av- 58 TIME, APRIL'S. 1994 R&S 143308 malfunctions. When she introduced a nor mal nm23 gene (nm stands for non metastatic) into highly malignant human breast cells, then injected these cells into mice, their tendency to form metastases dropped as much as 90%. GUARDING THE MASTER SWITCH Until last week, p53, the subject ofsome 1,000 scien tific papers in 1993 alone, was considered the most important cancer gene. The jour nal Science even named it Molecule of the Year. But now there is a new contender for notoriety-MTSi, as Alexander Kamb and his colleagues refer to the multiple tumor- suppressor gene they have just discovered. "Multiple" refers to the fact that defects in this gene can cause many kinds of cancer, including melanoma, lung, breast and brain JACK SWEPSTON, 48. Pa 2*-eied.to theNafionaieaiicerS ^tviJe'oTMi Dallas de ' tumors. In fact, functional copies of mtsi may be missing in more than 50% of all hu man cancers. What makes mtsi so significant is its t1 i^l^Jenter, wBl^yStiietioy^btfiof a mutant clear role in the cell-division cycle. A cell di vides not at will but in response to specific signals, such as growth factors produced by white blood cells rushing to repair a ;' cant impfovementyetT1i6sa^J<TOt't}ic!H6eti wound. These signals are picked up by re ceptors on the membrane of the cell and passed along--like batons in a high-speed enues of escape. Not all the myriad cells ulate new areas. Butwhile an embryonic cell relay-through the interior, all the way to-a shed by tumors survive the turbulent voy stops proliferating and matures into adult master "on" switch positioned deep in the age through the bloodstream, notes exper tissue, the cancer cells just keep dividing. nucleus. Not surprisingly, many onco imental oncologist Ann Chambers of the One reason for the difference may lie in genes, including one called ras, thetfirst London Regional Cancer Centre in On a gene known as nm23, first identified by human cancer gene ever identified,'^ in tario. But those that do eventually slip Steeg in 1988, It seems to help mature cells volved in this type of signaling pathway. through blood-vessel walls with ease. Using stop dividing and arrange themselves in an But there are other molecules that deter a video camera attached to a microscopic orderly fashion. Steeg's research suggests mine whether the cell should heed these lens, Chambers has watched in wonder as that in cancer cells this crucial gene often signals. And the small protein produced by melanoma and breast-cancer cells, injected into mice, become lodged in capillary walls, then crawl out into the liver. Three THE BIG KILLERS days later, her camera resolves the spidery shapes of tiny metastatic growths. The les son, Chambers believes, is depressingly Estimate in the U.S , 1394 Cs'Ce: ,va; , F'-rr -c clear. Cancer cells zip in and out of blood vessels so readily that, once angiogenesis occurs, they should be presumed to have al ready spread around the body. Metastasis is an event of awesome com plexity, one that requires multiple genes to cooperate as closely as musicians in an or chestra. Some ofthese genes code for chem ical solvents that enable the advancing cell to dissolve surrounding tissue. Others order up the production of adhesion molecules that, like treads under a tank, move the cell forward. Why would genes do that? The an swer, notes Patricia Steeg of the National Cancer Institute, is that while the genes im portant to metastasis are abnormally turned on, they are not necessarily abnormal them selves. A cancer cell, in many ways, is not that different from an embryonic cell on its way to becoming a patch of skin or a bundle of nerves. Both embryonic and cancer cells 7,925 29,600 53%.' Sroiasg;essiofsiiaSeS,- divide and form ill-defined dumps. Both get v' Skln Melanoma . ' : up and move around. Both migrate and pop Wfefawicinfoottody 900 32 000 ^ 84% Sur^.m; (air comtfmon; exposure to J... I', R&S 143309 60 TTMF APRTT 25 ' MTSI appears to be among the most impor tant inhibitors of cell division. Last year re searchers at New York's Cold Spring Har jjv 1 ^ \V'T" .: v? > j-1 . ftThey will bor Laboratory discovered that a protein they called pl6 stifled an enzyme that is a growth promoter. Last week it became clear that pl6 and the mtsi protein are one and the same. IS have surgical J*- ' . .. M options not Vvv: available to TARGETS FOR CANCER FIGHTERS Theo retically, any gene that goes awry in a can : V.: 0; 1 y//% me. For that cer cell offers a way to attack the problem. But those that directly influence a cell's de :,4- reason I decid cision to divide are spurring particular in terest. The protein made by the mtsi gene ed they would seems exceptionally promising, for it has characteristics suggesting it may be easily fashioned into a drug, which then might be able to stop tumor cells in their tracks. "In |v > be tested. I'm ,V p-kr a real advo terms of therapeutic potential," declares Kamb, "mtsi may be the most important cate for early tumor-suppressor gene yet discovered." Still, as pharmaceutical companies well know, many surprises can pop up on f rWfWfjwf detection.?^ the way to developing a new drug, and oth er approaches to cancer therapy may win }\[((((({ {{((lUUft, out in the end. Among the possibilities are anticancer vaccines designed to stimulate ^'paralegal the immune system to combat tumors. frejitanv Currently being tested in the U.S. and ;jhbv.o.-- Canada is a vaccine that spurs an assault on the weirdly configured carbohydrates that protrude horn tumor cells like spikes on a medieval ball and chain. At the meeting of the American Society for Cancer Research last week. Dr. David Berd of Thomas Jef ferson University presented the most en couraging evidence to date that the vaccine strategy may work. Berd told ofinoculating because the process is so rare in normal future already exists. "After all, we don't 47 melanoma patients with a vaccine made cells. Clinical trials have begun on several cure diseases like diabetes and hyperten of their own tumor cells inactivated by ra compounds that interfere with angiogene sion," says Dr. Lance Liotta, the National diation. Three years later, 60% remained sis. One such compound comes from a fun Cancer Institute's leading metastasis ex- tumor-free, compared with 20% in the un gus that was accidentally discovered in pert."We control them. Why can't we look vaccinated control group. The approach 1989 when it contaminated cultures of en at cancer that way?" .. works best, apparently, in patients who dothelial cells in Judah Folkman's Harvard By this reasoning, even metastatic have tumors small enough to be surgically laboratory, dramatically curtailing their cancer may eventually be brought to heel. *t removed but whose disease shows signs of growth. This drug, says Folkman, is aimed Squeezed into a tiny cubicle day after day spread. ; '. . ,. not at curing cancer but at prolonging the at the National Cancer Institute, Patricia The discovery announced last week period of time colonies of tumor cells Steeg stares at colonies of aggressive that cancer cells rely>on the^nzyme telo- missed rational therapy remain in breast-cancer cells that have shut down merasefos^aKvebpensup^a difierenfab treading. "Suppose we pro- the protective nm23 gene. Soon she will tack strategy. The leaded or ihlV'Research team, Calvin Harley, has'takep a leave from. McMaster University fo^^work'aL pefon Ckirp. inhfenloPark, CalifoTMa,;Thhcom- paay hhyiag to *-**"*'*<- theacbdn'trfteloini ejqrlalnslhnl^^^ can inhibit talon tumor to die aftefA fewldduftin loir ! of dormancy for 10 years, squirt over these colonies newly identi andthenanof gr 10 years," muses Folk- fied antitumor compounds. Among them s're beginning to corn- she hopes to find one, maybe niore, that life span." interferes with metastatic growth. A total iost significant : of 14 of these compouhds are already sit- ijwhatjoins ^fingin a freezer in her lab--white.Crystals _,$r?fSrthis ither, it is the seis- 4oK"fatet csltutsutbeersli.keIfsthneosweflafakeilstoinhtahveeboanttoemf they collectively repre- fect, Steeg has a.list of more than 30 fcresearchers speak not of: others that might. Like many cancer re telomerase and tjj^nonm ,, Kr cell but of tricking searchers, she conveys, through her own sperm) don't, says Harley, ^gives us hope yi perhaps of old age, personal enthusiasm, a sense that an im that we may be able to develop a drug with as othercells do. They also talk ofretning in mense psychological barrier has been out serious side eFects^^;r, * the cancerqdl.even rehabilitating it, a task breached. No, Steeg has not yet found a The formation of blood vessels in a tu that demands the development of less tox drug that cures cancer or even controls it. mor through angiogenesis- is Another ic drugs that can be tolerated over a life- But, she exclaims, "I'm beginning to like promising target for an anHcancef drug- ; tbne,Thb model for cancer therapy of the the odds." .I . TIME.APRtl.25,19<M R&S 143310 61