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Researchers Question Power of `Wonder Drug'

By Adam L. Berger

After nearly a decade of intense study, researchers at Harvard Medical School are beginning to understand how beta carotene, the simple chemical found in carrots, apricots and other vegetables, may hold the potential to stave off fatal diseases in humans.

These clinical scientists are now hypothesizing that this simple organic molecule may ward off cancer and heart disease by scooping up charged oxygen atoms, dangerous particles which wreak havoc as they roam through the body's circulatory system.

Many--but not all--of those scientists examining beta carotene have joined together on the Physicians' Health Study, a massive project involving as subjects 22,071 male physicians between 40 and 84 years old. The study was designed to test the effect of aspirin on heart disease and beta carotene on cancer.

Researchers cut short the aspirin half of the study in 1988, after preliminary data showed incontrovertably that aspirin has a beneficial effect on heart disease. Overseers of the study said they felt that to continue giving half of the subjects placebo pills instead of aspirin was unethical, as was withholding the clear scientific evidence of aspirin's positive benefits.

But for all their successes so far, leaders of the Physicians' Health Study are still coming up short on conclusive data about the mysterious vegetable extract beta carotene, composed of a backbone of carbon atoms flanked by two 6-atom carbon "rings."

"I must tell you," says Charles Hennekens, who heads the study, "the beta carotene aspect was supposed to end in December 1990." Lacking sufficient data, however, Hennekens and his colleagues have applied to the National Institutes of Health (NIH) for extended funding through 1996. Ninety-two percent of the physicians involvedas subjects in the study have agreed to continuetaking their pills, Hennekens says.

Meanwhile, clinical researchers around thecountry await the outcome of the Harvard study."We may have to be patient," says E. RobertGreenberg of Dartmouth College's Norris CottonCancer Center in Hanover, N.H. "You're talkingabout a process that may take decades."

"Wonder Drug"

In recent years, some of beta carotene'sproponents have heralded the chemical as a "wonderdrug," a biological police officer patrolling thebody and eliminating tumors and fatty buildupswherever they occur.

In particular, two compelling pieces ofscientific evidence point to beta carotene'santi-carcinogenic effect. For one, clinicalresearchers have shown that cancer victims have,in general, consumed less of the chemicalthroughout their lives: "You basically see thatthose individuals who have cancer report a dietlow in beta carotene," says Hennekens.

In addition, some clinicians have frozen bloodsamples from large samples of healthy subjects andseveral years later compared levels of betacarotene. Those who contracted cancer had,researchers found, a significantly lower level ofbeta carotene in their blood than the healthypopulation.

Promising though the chemical may look, Harvardscientists are not ready to claim victory yet.Researchers are quick to point out thatstatistical studies such as these only show that alow intake of beta carotene and a high risk ofcancer go together, but not necesarily that thechemical actually reduces risk.

Instead of a cure-all, scientists say, betacarotene might just be a "marker"--a biologicalred herring which does little for the human body,yet always shows up in a healthy diet high invegetables and fiber.

"The analogy I like to use is...the majority ofpeople with lung cancer have a yellow finger,"from smoking cigarettes, says Hennekens. "Bypreventing yellow finger, you're not going to doanything about [cancer]."

Conclusive proof of a link between betacarotene and cancer, says Hennekens, will comeabout only through the completion of a large-scalecomparison like the Physicians Health Trial, inwhich researchers carefully isolate the effect ofbeta carotene from all other substances with whichit naturally occurs.

Early Evidence

Already, a growing number of researchers atHarvard and elsewhere are trying to isolate theeffect on humans of beta carotene, first isolatedfrom carrots in 1910.

In 1981 and again in 1984, researchers foundthat the chemical may ward off breast cancer. Morerecent studies have pointed to the molecule'sbeneficial effect on ovarian and lung cancer.

And Micheline Mathews-Roth, an associateprofessor of medicine at the Medical School, saysthat she expects to publish a paper sometime in1991 directly linking beta carotene to theprevention of bladder cancer.

In addition, researchers have in recent monthsstumbled rather serendipitiously across a sideeffect of the chemical: its role in reducingmyocardial infarction, or heart failure.

J. Michael Gaziano, clinical fellow in medicineat the Medical School, presented the Harvardgroup's findings before an American HeartAssociation convention in Dallas last month. Thestudy was performed on 333 subjects--a subset ofthe full Physicians' Health Study--who alreadyshowed some signs of heart disease.

After six years, Gaziano and co-workers foundthat men taking a 50-milligram beta carotene pillevery other day (about 25 times the averageintake) were only half as likely as those takingplacebo pills to suffer a heart attack, an evenbetter result than the stunning 44 percentreduction achieved with aspirin.

For now, though, doctors aren't advising theirpatients to eat carrots until their stomach turnsand their skin becomes yellow. The study wasconducted on a sick population, Gaziano says, andbeta carotene's effects on healthy subjectsremains untested.

"Our message down at Dallas was primarily toresearchers," says Gaziano. "We're not at thestage where we can make thepublic."

Perhaps more importantly, researchers are waryof publicizing beta carotene's potential whilethousands of their subjects are still involved inthe study, either as controls or as beta carotenetakers.

"If we release more information about betacarotene, [the subjects] might start taking it,"and thus bias the study, Gaziano says. So on theadvice of the study's overseeing board, Hennekens,Gaziano and others will see no more data from thestudy until its completion, at least five yearsaway.

Scientific Theories

While they wait, however, research progressesapace on the molecule's chemical effects on humancells.

Scientists at Harvard and elsewhere haveproposed that beta carotene could hinder theoperation of low density lipoproteins (LDL), aform of cholesterol which is a prime suspect intumor growth.

Although they have no direct evidence,clinicians have seen oxidized LDL (LDL which hasabsorbed oxygen ions) devastate cells grown inpetri dishes, and they have suggested that itwould cause similar damage--perhaps even promotecancer growth--when shuttling through thecirculatory system of a human.

Oxidized LDL could be lethal in another manneras well: by attracting "foam cells" ormacrophages, which cause plaque to grow on arterywalls, the molecule may lead directly to heartdisease.

Through its ability to scavenge free oxygenions, beta carotene could undermine the dangerousoperation of the LDL molecules and thus reducecancer and heart disease risk.

For decades, chemists have known of themolecule's uncanny ability to grab onto chargedoxygen ions nearby. But only in the past decade orso have clinicians found a medical use for suchinformation.

One of the earliest to do so was Mathews-Roth,who legitimized beta carotene as a viable medicaldrug in the mid-1970s. Then working onprotoporphyria, an obscure disease which rendersits sufferers highly sensitive to light,Mathews-Roth stumbled across the organic moleculeas a treatment.

Protoporphyria victims suffer from a defectiveenzyme, which causes the protoporphyrin moleculeto seep into the subject's skin rather thanincoporating itself into the oxygen-carryinghemoglobin in the bloodstream, where it belongs.At the body's surface, the errant molecule reactswith oxygen in the air, causing severe itching andburning.

Mathews-Roth found that huge doses of betacarotene--up to 180 milligrams a day--can preventthe protoporphyria molecule from reacting withoxygen, and thus cures protoporphyria in all butthe most severe cases.

"The vast majority of people will be able to goout in the sun," says Mathews-Roth, whosetreatment won approval in 1975 from the Food andDrug Administration for her discovery.

Both Hennekens and Mathews-Roth admit that herprotoporphyria research was an important step inthe evolution of the Physicians' Health Study. Bydemonstrating that huge doses of beta carotene hadno adverse effects on the subjects (except for therather unfortunate consequence of turning theirskin yellowish-orange), she was able to sellHennekens on the safety of the drug in alarge-scale clinical trial.

"It had an important impact on our thinking,"recalls Hennekens. "The [subjects] didn't have anybiological abnormalities."

Contradicting Evidence

Researchers are quick to point out that theirtheories are still speculative, and conclusiveproof is still at least half a decade away. Butalready, the much-heralded panacea has taken abeating from some investigators.

In one study published earlier this year,researchers at the Anderson Cancer Center inHouston found that beta carotene did not performas effectively as current treatments in reversingoral cancer.

Scott M. Lippman of the University of Texasgave the drug to one group of oral leukoplakiasufferers for a duration of three months, whileadministering to another group the proventreatment 13cRA. At the end of the study, none ofthe 13cRA group and half of the betacarotene group progressed to cancer. The resultswere published in The Journal of the NationalCancer Institute.

Within a few days of that announcement,Dartmouth researchers presented a study whichshows beta carotene was ineffective in treatingskin cancer after three to five years. E. RobertGreenberg of the Norris Cotton Cancer Centerauthored the study, which he published in TheNew England Journal of Medicine.

The skin is "a site that doesn't seem to beclosely related to dietary intake," Greenberg saidin a phone interview.

These two setbacks for the much-touted "carrotdrug" prompted the editorial board of the Journalof the National Cancer Institute to wonder intheir June issue: "Beta Carotene Didn't PreventCancer: What's Up, Doc?"

Not so quick, say Harvard researchers, whopoint out that the conditions of the two studieswere not general enough to make any conclusionsabout the drug's overall effect.

"In this sort of thing, you'll neverknow...whether it's because the stuff doesn'twork, or whether the stuff wasn't given for longenough and high enough doses," says Mathews-Roth.

Generally, diseases such as those studied inthe Hanover project go though a long promotionstage of 20 years or more, says Mathews-Roth,before the tumor erupts in full force in the body.Any test to measure a drug's effect on skincancer, she contends, whould require monitoringthe patient though both the promotion andinitiation stages, many more years thanGreenberg's study.

"It's wrong to say that beta carotene doesn'twork on skin cancer," says Mathews-Roth, whoseveral years ago found a positive correlationbetween beta carotene and skin cancer in ratswhich have been monitored from birth--indicatingthe opposite of Greenberg's study. "You can justsay it doesn't work under the conditions of thatstudy."

Greenberg's research has prompted Hennekens andhis Harvard colleagues to write a letter whichwill appear next week in The New EnglandJournal of Medicine critiquing the betacarotene study.

"You must have eight to 10 years of treatmentand follow-up," said Hennekens in a phoneinterview. And in the Journal letter, Hennekensand his colleagues take issue with the Greenbergstudy.

"Given the long latency of skin cancer, it isnot surprising that no effect of treatment...wasevident during five years of follow-up," wroteHennekens and his colleagues.

"[W]e believe that the finding of noassociation between beta carotene and skincancer...should not detract from the very stronghypothesis about beta carotene in thechemoprevention of cancer of other epithelialsites."

The Future

Hennekens, Gaziano and their colleagues canonly guess and dream about the outcome of theirstudy. They have decided to conduct the trialunder a "double-blind" standard, which means thatnot only are the subjects unaware of whether theyare taking placebos or the real thing, but so arethe investigators.

The only individuals who have access to all thedata are the members of the Data Monitoring Board,a group which has the power to decide to cut offthe study at any time if data from the studypoints strongly to one hypothesis, as they didwith aspirin two years ago.

Despite their ignorance, though, researchersare already looking past the study, anticipatingpopular reaction to the results. Hennekens fearsthat those who engage in high-riskactivities--smoking in particular--would take betacarotene instead of altering their lifestyle.

Clinical statistics show, says Hennekens, thattobacco raises the risk of cancer by 20 times,while beta carotene would only lower risk by 50percent at most. A smoker taking beta carotene,then, would face a risk 10 times higher than thenormal population.

"If you took beta carotene instead of stoppingsmoking, it would be a real shame," saysHennekens. "It should never be taken as analternative."Crimson File PhotoProfessors at the Medical School areparticipating in the Physicians' Health Study,which is testing more than 20,000 subjects to theeffects of beta carotene on cancer.

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