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`BHHEER
`SBHBEH
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`GEOLGGY~GEOPHYS|CS
`LiERARY
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`AS 12/19/97 N 5340
`30261090693
`GEOLOGY GEOPHY LIB
`UNIV HISCONSIN
`1215 H DAYTON ST
`MADISON
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`1
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`

`0
`
`NIH Pl
`
`NEWS&COMMENT
`Apocalypse Not
`f All s
`0 G
`ans
`ne mm or
`Hes
`Universities Balk at OMB Funding Rules
`
`.,
`
`.
`..
`..
`1004
`
`1006
`
`1007
`
`1007
`
`1008
`
`1009
`
`
`
`Storm Aborts Antarctic Drilling Project
`
`Making the Most of a Short Life
`
`U.K. Science Funding: Academics Fear
`Research Cuts to Pay Overhead Costs
`
`RESEARCH NEWS
`
`
`
`The Dial-Up Sky
`Many Ways to Survey the Sky
`Amateur Sky Survey Keeps It Simple
`
`1010
`1011
`1012
`
`W
`
`AMERICAN
`ASSOCIATION FOR THE
`ADVANCEMENT OF
`SCIENCE
`
`”M“:
`
`_
`
`M
`
`‘
`
`FRONTIERS IN
`”/4 I
`g/gll CANCER RESEARCH
`NEWS
`From gencH Top to Bedside
`:rea’iment Marks Cancer Cells for Death
`
`omthe Bi°teCh Pharm! a Race t0
`Harvest New Cancer Cures
`
`Systems for Identifying New Drugs
`’fi‘fil’e Often FQUItV
`
`EARTICLES
`m
`Human Cancer Syndromes: Clues
`to the Origin and Nature of Cancer
`i‘ E- R- Fear?“
`,
`I
`I
`.
`_
`Grene‘tic Testgpg for Cancer RISk
`i3. .PonEer
`
`1036
`1037
`
`1039“.
`
`1041
`
`1043
`
`1050
`
`ISSN 0036—8075
`7 NOVEMBER 1997
`VOLUME 278
`NUMBER 5340
`
`
`
`1 004
`Cold water on climate-
`disease links
`
`
`
`
`
`1016& 1117
`Death on the forest edge
`
`X-rays Hint at Space Pirouette
`
`1012
`
`Fast-Forward Aging in a Mutant Mouse?
`
`1013
`
`NMR Maps Giant Molecules as
`They Fold and Flutter
`
`Death by Lethal Injection
`T. J. Silhavy
`
`1014
`
`Lining Up Proteins for NMR
`
`5 1015
`
`Ion Channels and the Locomotion
`S. Grillner
`
`Rain Forest Fragments Fare Poorly
`
`Geology: Growth, Death, and Climate
`Featured in Salt Lake City
`
`U 101 5 Quantum Nondemolition: Probing the
`Mystery of Quantum Mechanics
`S, R, Friberg
`
`1017
`
`V 1085
`
`fl 1087
`
`1088
`
`PERSPECTIVES
`
`
`
`POLICY FORUM
`
`
`
`An Environmental Rationale for
`
`1090
`
`Drilling Volcanoes
`J. C. Eichelberger
`
`1034 Retention of Endangered Chemicals
`D. J Wuebbles and J. M. Calm
`
`DEPARTMENTS
`
`
`
`I989
`995
`
`THIS WEEK IN SCIENCE
`EDITORIAL
`Cancer: What Should Be Done?
`J M Bishop
`LEI IERS
`997
`.
`..
`High Oiler the Permafrost: V. Winchester ' Restor-
`ing Ecosystems: W. Richter; J firemen and R.
`Hobbs; A. M. Shapiro; Response: A. P. Dobson, A
`D. Bradshaw, J. Baker 0 Rise in Asthma Cases: T:
`
`A. E. Platts~Mills and]. A. Woodfolk 0 Corrections
`and Clarifications
`SCIENCESCOPE
`1 003
`RANDOM SAMPLES
`1019
`W
`1 82
`BeogigrgngEngnt feviewed by R. A. Rettig . (1))at—
`.
`.
`items of Processes of Vertebrate Evolution, K. PadIan
`TECH-SIGHT: PRODUCTS
`114.?
`
`‘ AAAS Board of Directors
`
`Jane Lubchenco
`Robert D. Goldman
`Hetiring President, Chair
`Alice S, Huang
`Mildred 3. Dresselhaus
`Sheila Jasanoff
`M zegd‘g’r;enwood
`its/:23???- fin”
`'
`'
`,'
`.
`'
`PreSIdent-elect
`M'Chael J- NOVacek
`Anna 0- ROOSSVelt
`Jean E. Taylor
`
`
`William T. Golden
`I SCIENCE (ISSN 0036-8075) ls published weekly on Friday, except the last week in De-
`Treasurer
`cember, by the American Association tor the Advancement 01 Science, 1200 New York Avenue,
`Richard S. Nicholson
`NW, Washington, DC 20005. Periodicals Mall postage (publication No.484460) paid at Washington,
`DC, and additional mailing offices. Copyright © 1997 by the American Association for the Advance-
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`

`
`
`CANCER MODELS
`
`Systems for Identifying New
`Drugs Are Often Faulty
`
`emerging that some chemicals might have
`cancer-fighting effects. That evidence en—
`couraged many chemists to explore the anti-
`cancer potential of similar agents shelved in
`their laboratories. And after commercial in-
`terests decided against helping the academ-
`ics set up an efficient way to screen their
`chemicals, the NCI stepped in.
`The institute started by pulling together
`mouse models of three tumors: a leukemia,
`which affects blood cells; a sarcoma, which
`arises in bone, muscle, or connective tissue;
`and a carcinoma, the most common type of
`cancer, which arises in epithelial cells and
`includes such major killers as breast, colon,
`and lung cancers.
`Ini-
`tially, many of the agents
`tested in these models ap—
`peared to do well. How—
`ever, most worked against
`blood cancers such as leu—
`kemia and lymphoma, as
`opposed to the more com—
`mon solid tumors. And
`when tested in human can-
`
`
`
`
`
`
`
`
`
`NATUHEMEDICINE,SEPT.1997
`
`missed effective drugs. When Jacqueline
`Plowman’s team at NCI tested 12 antican-
`cer agents currently used in patients against
`48 human cancer cell lines transplanted in—
`dividually into mice, they found that 30 of
`the tumors did not show a significant re-
`sponse—defined as shrinking by at least
`50%—to any of the drugs.
`Researchers have not yet figured out why
`so many of the xenografts were insensitive to
`the drugs. But the NCI team says that the
`result means that drugs would have to be
`screened against six to 12 different xenografts
`to make sure that no active anticancer drugs
`were missed. That’s an expensive proposition,
`as the average assay costs about $1630 when
`performed by the government and $2900
`when done commercially. “I cannot get on
`my pulpit and say that the way we are doing
`this is the best way, because I don’t think
`there is a good way to do it,” says Sausville.
`To create better models of cancer devel-
`opment in humans, investigators are now
`drawing on the growing
`knowledge of human
`cancer—related gene mu—
`tations. They are geneti—
`cally altering mice so that
`they carry the same kinds
`of changes—either ab-
`normal
`activation of
`cancer-promoting onco—
`genes or loss of tumor—
`suppressor genes—that
`lead to cancer in humans.
`The hope is that the mice
`will develop tumors that
`behave the same way the
`human tumors do.
`So far,
`the results
`from these mouse models
`have been mixed, how—
`ever. One mutant mouse
`strain, for example, lacks
`a working APC gene, a
`tumor
`suppressor
`that
`leads to colon cancer
`when lost or inactivated.
`This mouse seems to do
`well at re—creating the
`early signs of colon can-
`cer. But in the later stages
`of the disease, the type of
`mutations in the tumors
`
`Screening potential anticancer drugs sounds
`easy. Just take a candidate drug, add it to a
`tumor type of choice, and then monitor
`whether the agent kills the cells or inhibits
`cancer growth. Too bad it hasn’t been that
`simple. Even as investigators try to develop a
`new generation of more effective and less
`toxic anticancer drugs that directly target
`the gene changes propelling cells toward un—
`controllable division (see p. 1036), they face
`a long—standing problem: sifting through po—
`tential anticancer agents to find ones
`promising enough to make human clinical
`trials worthwhile.
`Indeed, since formal screening began in
`1955, many thousands of drugs have shown
`activity in either cell or animal models, but
`only 39 that are used exclusively for che—
`motherapy, as opposed to supportive care,
`have won approval from the US. Food and
`Drug Administration. “The fundamental
`problem in drug discovery for cancer is that
`the model systems are not predictive at
`all," says Alan Oliff, executive director for
`cancer research at Merck Research Labora—
`tories in West Point, Pennsylvania.
`Pharmaceutical companies often test drug
`candidates in animals carrying transplanted
`human tumors, a model called a xenograft.
`But not only have very few of the drugs
`that showed anticancer activity in xeno—
`grafts made it into the clinic, a recent study
`conducted at the National Cancer Institute
`(NCI) also suggests that the xenograft mod-
`els miss effective drugs. The animals appar-
`ently do not handle the drugs exactly the way
`the human body does. And attempts to use
`human cells in culture don’t seem to be faring
`any better, partly because cell culture pro—
`vides no information about whether a drug
`will make it to the tumor sites.
`
`The pressure is on to do better. So re—
`searchers are now trying to exploit recent dis—
`coveries about the subtle genetic and cellular
`changes that lead a cell toward cancer to cre—
`ate cultured cells or animal models that accu-
`rately reproduce these changes. “The real
`challenge for the 19905 is how to maximize
`our screening systems so that we are using the
`biological information that has accumulated,”
`says Edward Sausville, associate director of the
`division of cancer treatment and diagnosis for
`the developmental therapeutics program at
`the NCI. “In short, we need to find faithful
`representations of carcinogenesis.”
`The first efforts to do so date back to the
`end of World War II, when hints began
`
`
`
`Not a matched pair. In the
`clonogenic assay (top), tumor cells
`with (+/+) and without (—/—) the p21
`gene responded similarly to radia—
`tion. But in mice, the p21—tumors
`often shrank, while those having
`the gene never did.
`
`cer patients, most of these
`compounds failed to live up
`to their early promise.
`Researchers blamed the
`failures on the fact that
`the drugs were being tested
`against mouse, not human,
`tumors, and beginning in
`1975, NCI
`researchers
`came up with the xenograft
`models, in which investiga—
`tors implant human tumors
`underneath the skin of mice
`with faulty immune sys-
`tems. Because the animals
`can’t reject the foreign tis—
`sue,
`the tumors usually
`grow unchecked, unless
`stopped by an effective
`drug. But the results of
`xenograft screening turned
`out to be not much better than those obtained
`with the original models, mainly because the
`xenograft tumors don’t behave like naturally
`occurring tumors in humans—they don’t
`spread to other tissues, for example. Thus,
`drugs tested in the xenografts appeared effec—
`tive but worked poorly in humans. “We had
`basically discovered compounds that were
`good mouse drugs rather than good human
`drugs," says Sausville.
`The xenograft models may also have
`
`begin to diverge from those in human colon
`cancer, and the disease manifests itself differ—
`ently as well. It spares the liver, for example,
`unlike the human cancer.
`Other new mouse models have fared even
`worse. Take the one in which the retina-
`blastoma (RB) tumor—suppressor gene was
`knocked out. In humans, loss of RB leads to a
`cancer in the retina of the eye. But when the
`gene is inactivated in mice, the rodents get
`pituitary gland tumors. And BRCAI knock-
`1041
`
`www.5ciencemag.org 0 SCIENCE - VOL. 278 0 7 NOVEMBER 1997
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`
`
`outs—which are supposed to simulate human
`breast and ovarian cancer—don’t get any tu—
`mors at all. “One might expect that these
`animals would also mimic human symptoms,
`not just the genetic mutations,” says molecu-
`lar biologist Tyler Jacks of the Massachusetts
`Institute of Technology. “In fact, that is usu—
`ally the exception, not the rule."
`Why gene knockouts in mice have effects
`so different from those of the corresponding
`mutations in humans is unclear. One possibil-
`ity is that in mice, other genes can compensate
`for a missing gene, such as BRCAI. Another,
`says Jacks,
`is that “the genetic wiring for
`growth control in mice and hu—
`mans is subtly different.”
`The limitations of animal
`
`models have spurred the NCI,
`among others, to test drug can—
`didates in cultures of human
`cells. The institute now relies
`
`Colon
`Brain
`
`on a panel of 60 human tumor
`cell lines, including samples of
`all the major human malignan—
`cies. Drugs to be tested are fed to
`subsets of the panel, based on
`tumor cell type, and their cell—
`killing activity is monitored.
`Over the last 7 years,
`the
`panel has been used to screen
`almost 63,000 compounds, and
`5000 have exhibited tumor cell—killing ac—
`tivity. But that has created another dilemma,
`because so many compounds show antitumor
`cell activity in culture, and the cost of bring-
`ing them all to clinical trials—where most
`don’t work anyway—would be daunting. As
`Sausville asks: “How do you prioritize so
`many compounds for clinical trials?” For
`that, the NCI uses a computer database to
`sift through past antitumor agents and look
`for only those compounds with novel mecha—
`nisms of action. Computer screening has
`whittled the number of promising agents
`down to about 1200, according to Sausville.
`Those compounds are then tested in what
`is known as a hollow fiber model, in which
`tiny tubes filled with tumor cells are im-
`planted into mice in a variety of sites. By
`monitoring the tumor cell—killing effects of
`drugs on the implants, researchers can test
`which drugs actually make it to the tumor sites
`when the drugs are administered in different
`ways: intravenously versus orally, for example.
`Sausville cautions, however, that it’s still too
`early to tell how predictive these screens are,
`because only a few of the drugs tested have
`gone far enough to show efficacy in humans.
`Both drug screeners and doctors also use
`another cell culture method, the so-called
`clonogenic assay, to sift through potential
`anticancer drugs. They grow cell lines or a
`patient’s tumor cells in petri dishes or cul—
`ture flasks and monitor the cells’ responses
`to various anticancer treatments. But clono—
`
`Lung, non—small cell
`Lung, small cell
`Breast
`Melanoma
`Ovarian
`Prostate
`Renal
`
`Radiation, like many of the drugs used to
`treat cancer, works by damaging the cells’
`DNA. This either brings cell replication to a
`halt or triggers a process known as apoptosis in
`which the cells essentially commit suicide.
`Waldman wanted to see how 1721, one of the
`genes involved in sensing the DNA damage
`and halting cell replication, influences that
`response to radiation.
`In the mouse xenograft assay, Waldman
`and his colleagues found that the radiation
`cured 40% of the tumors composed of cells
`lacking p21, while tumors made of cells carry-
`ing the gene were never cured. But this differ—
`ence was not apparent in the clonogenic as—
`say, where the radiation appeared to thwart
`the growth of both dispersed tumor cell types.
`“We showed this gross difference in sensitivity
`in real tumors in mice and in the clonogenic
`assay,” Waldman says.
`He suggests that the different responses in
`the two systems have to do with the fact that
`a subset of p21 mutants die in response to
`radiation, while cells with the normal gene
`merely arrest cell division. Either way, the
`dispersed tumor cells in the clonogenic assay
`will fail to grow. However, in the xenograft
`tumors, which consist of many cells in a solid
`mass, the arrested, but nonetheless living,
`p21+ tumor cells may release substances that
`encourage the growth of any nearby tumor
`cells that escaped the effects of the radiation.
`But tumor cells lacking the p21 gene die, and
`because dead cells cannot “feed” neighboring
`
`genic assays have their problems, too. Some-
`times they don‘t work because the cells sim—
`ply fail to divide in culture. And the results
`cannot tell a researcher how anticancer drugs
`will act in the body.
`What’s more, new results from Bert Vo—
`gelstein’s group at Johns Hopkins University
`School of Medicine add another question
`mark about the assay’s predictive ability. Todd
`Waldman, a postdoc in the Vogelstein labo—
`ratory, found that xenografts and clonogenic
`assays deliver very different messages about
`how cancer cells lacking a particular gene,
`p21, respond to DNA—crippling agents.
`
`TESTING THE XENOG RAFT ASSAY
`Cell
`Lines
`Tested
`(0
`
`% of Tumors Responding to Drugs
`Minimal Response Significant Response
`( < 40% shrinkage)
`( > 50% shrinkage)
`
`mmwmmwxlh
`
`tumor cells, the entire tumor may shrink.
`The finding indicates that the clonogenic
`assay can’t always predict how a tumor will
`respond to a drug in an animal. Still, by link-
`ing the different responses in two models to
`the presence or absence of a specific gene
`system, the Waldman team’s results help
`clarify why tumor cells might respond dif—
`ferently in culture and in animals. Indeed,
`the general idea that a tumor’s drug sensi—
`tivity may be linked to the genetic muta—
`tions it carries has led others to try to use cells
`with comparable mutations to identify better
`chemotherapeutic agents.
`Leland Hartwell, Stephen
`Friend, and their colleagues at
`the Fred Hutchinson Cancer Re-
`
`search Center in Seattle are pio—
`neering one such effort. They are
`building on previous work in
`which Hartwell’s team discov-
`
`ered a series of yeast genes, called
`checkpoint genes,
`that
`nor—
`mally stop cells from progressing
`through the cell cycle and divid—
`ing if they have abnormalities
`such as unrepaired DNA dam-
`age. Because mutations in check-
`point and other cell cycle—
`related genes have been linked
`to human cancers, looking for
`drugs that restore normal growth control in
`mutated yeast might be one way to find new
`cancer therapies (see Article on p. 1064).
`The NCI is taking a similar tack. They are
`looking to see if they can reclassify the cells
`in their panel, which was set up based on
`tissue type—breast cancer versus colon can—
`cer, for example—according to the types of
`genetic defects the cells carry. To enable
`drugs that counteract specific defects to be
`prescribed most effectively, researchers are
`also developing technologies for analyzing
`the gene defects in each patient’s tumors.
`That way, if drugs that correct specific de—
`fects can be identified, they could then be
`matched to each individual’s tumor cell
`
`makeup. “This would be so valuable," says
`Homer Pearce, vice president of cancer re—
`search and clinical investigation at Eli Lilly
`and Co. in Indianapolis. “It would help to
`identify patients that have the greatest chance
`of benefiting from therapy, while minimiz-
`ing the number that would be exposed to a
`treatment that would not work.”
`
`Indeed, Merck’s Oliff says, “the future of
`cancer drug screening is turning almost ex-
`clusively toward defining molecular targets.”
`If the approach works, drug developers would
`finally have an easy way to identify promis—
`ing cancer drugs, and cancer patients might
`have an array of new treatments.
`—Trisha Gura
`
`Trisha Gum is a writer in Cleveland, Ohio.
`
`1 042
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`SCIENCE 0 VOL. 278 - 7NOVEMBER 1997 - www.5ciencemag.org
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