An Official Journal ‘�

1�

of the !�American Association

for \Cancer Research

ClinicalCancerResearch

June 1998 #{149}Volume 4 Number 6pp. 1359-1582 #{149}ISSN 1078-0432

& riftwyIMPACT of BIOTECHNOLOGY on CANCER

PROGNOSIS #{149}DETECTION #{149}PREVENTION

Nice, France #{149}1998 #{149}4th lntemationah Symposium#{149} I

IMOLECULARBIOLOGY

Molecular studyof an en-vironmental carcinogen

E Bresnick PhD UMass

Tumor suppressorgenes & cell cycle

D Haber MD Mass General

Telomerase-diagnosticapplication

H Tahara MD Univ Hiroshima

Regulation of p53stability

Z Ronai PhD Mt Sinai NY

Stromal-epithelialinteractions

LWI( Chung PhD unwwgama

Genetic predisposition& therapy

G Thomas MD SMIoMaPa#{241}s

MOLECULARMECHANISMS

Tumor promotionpathways & inhibitors

H Fujiki MD ma Cancer hint

Genetic-epigeneticmultistage oncogenesis

H Yamasaki PhD �ec �

PAP1 mpdulatesIRCA1 tunchon

FJ Raushcer PhD Winter, Plulo

Disord�ers in cell cyclecontrol proteins

lB Weinstein MD Columbia Pns.b

p53-induced apoptosisTD llstyMD UC San Francisco

Mafr� mekilkp�leinases & inhibitors

P BouetMD PhD Shassbourg

COFACIORIALINFLUENCES

Environmental &

Viral effectsG de Th� MD Passsiwtaris

Endocrine r ulationrenhahon

M Gottordis MD Ugand

Nutrition-cancerrelationship

HO Adami MD Karolinska Inst

Helicobacter pylon &stomach cancer

D PaOi MD Careggi Fisr,nze

AIDS-assoc. tumorsH loochim MD binoxHUNY

MULTIFACTORIALDIAGNOSIS

Genetic analysis onelectronic microchips

M Nerenberg PhD Nqnogen

Genetic susceptibility& DNA adducts

H Bartsch PhD DkZHsidelberg

DNA methylation-chromosome aberr.

JM Trent PhD NCHGR Bethesda

Microsatellite analysisfor early detection

I Moo MD uix MDA

Prostate-precursorlesions & prognosis

DG Bostwick MD Mayo Clino

Predictive assessmentof multidrug resistance

P Sonneveld MD Rainerdarn

Gene therapy progressWH Fridman MD Curie Pars

Advances in genetherapy vectors

B Huber MD Glaxo/Matcame

Telomerase inhibitionTopoisomeraseinhibition

A Harstrick MD Essen

rancreas-farnesylfransferase inhibition

JB Gibbs Merck

Novel differentiationagents

S Waxman MD Mt SinM NY

RISKASSESSMENT

p53 in normal epithe-hum adjacent to h/n ca.

FX Bosch MD UrevHeidolbsrg

Telomerase in normalmucosa adjacent to ca.

NW Kim MD Geron

k-ms mutations in nor-mal tissue: lung cancer

I Minomoto MD Univ Kanawwa

DNA adducts in normaltissue adj. to breast ca.

DLI MD wxi.io.�

DNA in normal tissueadjacent to colon ca.

P Boaun MD Nsdssr Paris

LOH in normal tissue4 to breast cancer

SH Dair�, PhD San Francisco

Genetics of ghiomaprogression

P Kleihu.s MD IARC Lyon

Cell cycle inhibitorprotein p27

JM Slingerland MD �aronio

Prognostic oncogeneexpression

EMU Bems MD Roesmbm

Tumor angiogenesis& inhibitionCircadian rhythmchemotherapy

WJM Hrushesky MD �JbanyMed

Buotech. in cancerepidemiology studies

R Hayes MD N� Bethesda

NOVELIMMUNOTHERAPYNovel human infratumoral immunother.

I Iursz ScD MD �RV�l4if

Cytotoxic T lymphocytes and lL-2

N Restifo MD NG Bethesda

Dendritic cells inimmunotherapy

H Bohien MD Cologne

Breast-target-recognizing TIL

F Marincola MD Nd Bethesda

Clinical use ofantisense strategies

AM Gewirtz MD Univ Pennsylvanm

XenotherapyM Soulilou MD Univ Rennes

DEADLINE for ABSTRACTS - JULY 10, 1998http://www.cancerprev.org

Details from: HE Nieburgs MD #{149}Fax: 508-856-1567 #{149}Tel: 212-534-4991 #{149}e-mail: canprev@cancerprev.orgCorrespondence: Box 20, University of Massachusetts Medical Center, 55 Lake Ave N, Worcester, MA 01655 USA

Spax.orad by the lnsnrnorional Society For Pr.n.nMn Oncology in afficiel rslation. nrith The World Haahh Organization and The IntnrnoMnd Agency tsr Research on Cancn� and cosponsored by

The French N.tionol League AgoinstCancer, Curie Insbtu$n (Paris), Gustave Roussylnslitssn lYilinjivO, University at NM SOphiO-AntipOIiS F.cuhy ol Medicine, Center Antoina Locossognn, The talon Noticed Leogun Against Cancer,

N.tisn.l Insbtuln finr Research on Cancer (Gene.), Advanced BiOsachnOlogy Center (Ge...). Unrvnrssty dIll nies Collage of Mnthcina �Jrb.n.), UnMtrs�y of Massochu.ee. Madk,l Center (Macester), Massachusetts BiOsachnOlOgy Council

bA6i cS�1�t � �T LSPO � � Q �IGR

An Official Journalof theAmerican AssociationforCancer Research

Editor-in-ChiefJohn Mendelsohn

Growth factors, hormones, cell growth;

radiation therapy, surgery, subspecialty investigation

Deputy EditorWaun Ki HongClinical trials targeted at specific malignancies, chemoprevention

Publications Staff

Associate Director of Publications

Mary Anne Mennite

Manager, Editorial ServicesHeide M. Pusztay

Staff Editors

Michael J. BeveridgeKathleen C. AssenmacherPamela R. Arnold

Ronald M. VitaleCarolina Miranda

Staff Assistant

Mary Ellen Pining

Senior Editorial AssistantTheresa A. Griffith

Editorial AssistantsCecilia Gallo

Brenda Roberson

Marketing CoordinatorRobert B. O’Malley

Clinical pharmacology and pharmacokinetics,

drug metabolism, drug sensitivity and resistance,

drug interactions

Michael B. KastanCell cycle regulation, cell death

Paul SondelImmunotherapy and cytokines-preclinical, and

clinical trials

Beverly A. TeicherExperimental therapeutics, preclinical

pharmacology, combined modality regimens,

animal therapy models

Jeffrey M. TrentGenetics, cytogeneticsDavid Sidransky

Molecular pathogenesis, molecular correlates

Colleen M. Hubona, Executive Editor, Department of Educational Publishing Services-227, The University of Texas M.D.

Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030. Phone: (713) 792-6014; Fax: (713) 792-6016.

Accelerated mailing of all AACR journals to AACR members in Japan is supported by a generous grant from the

Banyu Pharmaceutical Company, Tsukuba, Japan. One-year subscriptions to Clinical Cancer Research are madeavailable to third-year hematology/oncology fellows in the United States through the generous support ofRh#{244}ne-Poulenc Rorer Oncology.

Clinical Cancer Research is published monthly, one volume per year, by the American Association for Cancer Research. Inc. (AACR). Except for members of the AACR. all subscriptions are payabkin advance to AACR. Subscription Office, P.O. Box I 1806. Birmingham. AL 35202 [Phone: (800) 633-4931 or (205) 995-1567; FAX: (205) 995.1588). to which all business communications, remittances(in United States cunency or its equivalent), and subscription orders should be sent. In Japan. send orders and inquiries to (sole agent): USACO Corporation. Tsutsumi Bldg.. 13.12, Shimbashi I-chore,Minato-ku, Tokyo 105. Japan; Tel. (03) 502-6471. Individuals who are not AACR members may subsciibe to volume 4 (1998) ofClinical CancerResearch at the rate of$120 U.SJ$160 foreign. ClinicalCancer Research is only available to institutions as a combined subscription with Cancer Research. The combined 1998 institutional subscription puce of S795 U.SJ5925 foreign includes $210 U.SJ$250foreign for a subscription to Clinical Cancer Research. (Foreign subscription cost includes cost of surface mail. For faster delivery, expedited mailing rates are available by contacting the AACR PublicationsDepartment.) Canadian subscribers should add 7% GST. Changes of address notification should be sent fA� days in advance and include both old and new addresses. Member subscribers should send addresschanges to: AACR Member Services, Public Ledger Bldg., Suite 826, 150 South Independence Mall wt�t, Philadelphia, PA 19106.3483. Nonmember subscribers should send changes of address to: AACR

Subscription Office. P.O. Box 1 1806, Bimsingham, AL 35202. Copies of the journal which are undeliverable because of address changes will be destroyed.

IIl�IiIIPhlUlIlUl�lI�IlI�lIl�llIllI11IUWNH3-’65X- 32 PA

ClinicalCancerResearchAmerican Association for

Cancer Research, Inc.

Executive Director andDirector of Publications

Margaret Foti

Administrative Staff

Director of Administration

Adam D. Blistein

ControllerJoan D. Ritchie

Manager, Meetings and Exhibits

Jeffrey M. Ruben

Meeting PlannerCarole L. Kanoff

Public Information Coordinator

Jenny Anne Horst-Martz

Assistant to the Executive Director

Ruth E. Fortson

Membership Development

CoordinatorRobin E. Felder

Administrative Assistant

Margaret A. Pickels

Systems SpecialistLydia I. Rodriguez

Secretary

Malika L. Wright

Editorial Assistant

Diana F. Certo

Office ClerkJames J. Waters

Data Entry Clerk

Robert A. Simms II

AACR Publications DepartmentPublic Ledger Building. Suite 826

150 South Independence Mall WestPhiladelphia. PA 19106-3483Phone: (215) 440-9300

FAX: (215) 440-9354

Senior EditorsBruce A. Chabner

Lance A. LiottaPathology, metastasis

Associate Editors

Martin D. AbeloffCarmen J. AllegraLaurence H. BakerCharles M. BalchBarthel BarlogieRobert C. Bast, Jr.

Cohn B. BeggJoseph R. Bertino

Ronald H. BlumGeorge J. BosiPaul A. Bunn, Jr.Michael A. CaligiunAlfred E. ChangPaul B. ChapmanMichaele C. ChristianCurt I. CivinRonald CrystalWilliam S. DaltonAlbert B. DeisserothPatricia K. DonahoeRoss C. DonehowerTimothy J. EberleinMerrill J. EgonnFrederick R. EilberRobert M. ElashoffPaul F. EngstromEric R. Fearon

Editorial Office

Isaiah J. FidlerRichard M. FoxMichael A. FriedmanZvi Y. FuksStephen L. GeorgeGiuseppe GiacconeLuca GianniAnna GiuhianoEli GhatsteinDavid W. Golde

Mark R. GreenJerome E. GroopmanWilliam N. HaitAdrian L. HarrisCurtis C. HarrisSandra J. HorningWilliam J. HoskinsJanet A. HoughtonStephen B. HowellDaniel C. IhdeJohn T. IsaacsRobert B. JenkinsDavid H. JohnsonV. Craig JordanBarton A. KamenS. B. KayeDavid P. Kelsen

David KhayatJohn M. KirkwoodDonald W. KufeSteven M. LarsonJohn S. LazoVictor A. Levin

Allen LichterMarc E. LippmanEdison T. LiuPatrick J. Loehrer, Sr.

Dan L. LongoMichael T. LotzeMaurie MarkmanWilliam P. McGuire HI

Roland MertelsmannFrank L. Meyskens, Jr.John D. MinnaBruce MinskyMonica MorrowJames L. MulshineSharon B. MurphyCharles E. MyersLarry NortonRichard J. O’ReillyRobert F. OzolsIra PastanWilliam P. Peters

Herbert M. Pinedo

Philip A. PizzoWilliam K. Plunkett

Jerome B. Posner

Derek RaghavanMark J. Ratain

John C. Reed

Ralph A. Reisfeld

Jerome Ritz

Jack A. Roth

Eric B. RowinskyEdward A. Sausville

Howard I. Scher

Richard L. Schilsky

Richard M. Simon

John F. Smyth

Jeffrey A. SosmanMichael B. Sporn

Louise C. StrongMasaaki Terada

Daniel D. Von HoffRaymond P. Warrell, Jr.

Jane WeeksRalph R. WeichselbaumTheresa L. Whiteside

Leonard A. Zwelling

i�i�

Notice to Members of the American Association for Cancer Research (AACR)

Officers for 1998 -1999

President: Webster K. Cavenee, Ludwig Institute for Cancer Research, La Jolla, CA 92093-0660

President-Elect: Daniel D. Von Hoff, Institute for Drug Development, San Antonio, TX 78245

Treasurer: Bayard D. Clarkson, Memorial Sloan-Kettering Cancer Center, New York, NY 10021

Executive Director: Margaret Foti, AACR, Public Ledger Bldg., Suite 826, Philadelphia, PA 19106-3483

Annual Dues

The annual dues of active members of the AACR are $175, $50 of which may be applied to a subscription to Clinical CancerResearch. Corresponding members of the Association will be charged an appropriate fee to offset periodicals postage costs. Payment

of dues and changes of address of members of the Association should be sent promptly to Margaret Foti, Executive Director, AACR,

Public Ledger Bldg., Suite 826, 150 South Independence Mall West, Philadelphia, PA 19106-3483; Phone: (215) 440-9300; FAX:(215) 440-9313.

Submission of Manuscripts

Clinical Cancer Research, a journal of the American Associationfor Cancer Research, publishes original articles describing clinicalresearch on the cellular and molecular characterization, prevention,

diagnosis, and therapy of human cancer. Its focus is on innovativeclinical research and translational research which bridges the labo-ratory and the clinic. Clinical Cancer Research is especially inter-

ested in clinical trials evaluating new treatments for cancer; researchon molecular abnormalities that predict incidence, response to ther-

apy, and outcome; and laboratory studies of new drugs and biolog-

ical agents that will lead to clinical trials in patients. All submissionsundergo peer review. Papers should be sent directly to an appropri-ate Senior Editor or to the Editor-in-Chief for review. See “Instruc-tions for Authors” (page ii of this issue) for complete mailingaddresses of the Editor-in-Chief, Deputy Editor, and Senior Editors.

Back Issues and Single Copy Sales of the Journal

Copies of back stock of the journal may be ordered fromAACR Subscription Office, P.O. Box 11806, Birmingham, AL35202 [Phone: (800) 633-4931 or (205) 995-1567; FAX: (205)995-1588]. As long as supplies permit, single copies will be

sold by this company at $25.00/copy. Orders outside the U.S.

add $3/copy to offset postage costs.

Cancer Research, Inc., since these articles are considered to be inthe public domain. In the case of articles supported by federalgrants or contracts, copyright transfer to the American Associationfor Cancer Research, Inc., is required. The federal government

may retain a nonexclusive license to publish or republish such

material.The Journal will routinely allow authors (or others with the

permission of the authors) to include select parts of a copy-

righted article in reviews, books, or subsequent papers, upon

written request to the AACR Director of Publications. Requests

to reproduce an article in its entirety will be considered on anindividual basis and permission may be granted contingent upon

payment ofan appropriate copyright fee. All reproduction requestsmust include a brief description of intended use and a stamped,

self-addressed envelope. Third parties should obtain the approvalof the authors before corresponding with the AACR.

Those who wish to photocopy articles should contact theAACR Publications Department [Phone: (2 15) 440-9300;FAX: (215) 440-9354].

No responsibility is accepted by the Editors, by the Amer-ican Association for Cancer Research, Inc., or by CadmusJournal Services for the opinions expressed by contributorsor for the content of the advertisements.

Advertisements

Advertisement insertion orders and copy must be received onemonth prior to the date of issue in which the advertisement is

to be published. The journal is mailed on approximately the 1stday of the month of issue. Inquiries about advertising should bedirected to: M. J. Mrvica Associates, Inc., 2 West Taunton

Ave., Berlin, NJ 08009 [Telephone: (609) 768-9360; FAX:

(609) 753-0064].

Copyright and Permissions

Authors who wish to publish in Clinical Cancer Research mustformally transfer copyright to the proprietor of the journal, the

American Association for Cancer Research, Inc. It is under-stood by this transfer that the authors relinquish all exclusiverights of copyright ownership, including the rights of reproduc-

tion, derivation, distribution, sale, and display.Authors who prepared their articles as part of their official

duties as employees of the U.S. Federal Government are notrequired to transfer copyright to the American Association for

Clinical Cancer Research is abstracted and/or indexed in

Cancer Lit, Chemical Abstracts, Current Contents/Clinical

Medicine, and Index MedicusIMEDLINE.

Clinical Cancer Research (ISSN 1078-0432) is published monthlyby the American Association for Cancer Research, Inc., PublicLedger Bldg., Suite 826, 150 South Independence Mall West,Philadelphia, PA I 9106-3483 for $50 annually for members and

$120 for individual nonmembers. Clinical Cancer Research is

only available to institutions as a combined subscription with

Cancer Research. The combined 1998 institutional subscriptionprice of $795 includes $210 for a subscription to Clinical CancerResearch. Periodicals postage paid at Philadelphia, PA and addi-

tional mailing offices. POSTMASTER: Send address changes toAACR Subscription Office, P.O. Box 1 1806, Birmingham, AL

35202. Copyright 1998 by the American Association for CancerResearch, Inc. Printed on acid-free paper in the U.S.A.

ANTI-CANCER PROTEINS AND DRUGS:

STRUCTURE, Fui�c’noN AND DESIGN

A New York Academy of Sciences Conference

November 6-9, 1 998 at The Rockefeller University

Researchers working on tumor suppressor genes and on

anti-cancer drugs, including Robert Weinberg and Frank

McCormick, will discuss the therapeutic potential of

these discoveries and will focus on cutting-edge anti-cancer

protein/drug research issues. This conference is designed

to promote a comprehensive understanding and

cooperation between industrial and academic researchers,

in order to facilitate the design and creation of more

effective anti-cancer molecules for the treatment of cancers.

Sessions: #{149}Nuclear Proteins #{149}Cytoplasmic Proteins

#{149}Extracellular Proteins #{149}Anti-Cancer Drugs

#{149}DNA or Peptide Delivery/Targeting

Call for Abstracts: July 31 , 1998 submission deadline.

For program, abstract and registration information contact:

New York Academy of Sciences

Science & Technology Meetings

2 E. 63rd St., New York, NY 10021

T: 212.838.0230, ext. 324

F: 212.838.5640

E: conference@nyas.org

http://www.nyas.org

Rapid Access to Intervention Development

“RAID”Ihe NATIONAL CANCER INSTITUTE announces a nc�

initiative: Rapid Access to Intervention Development (RAID).

RAID ��ill make available to academic investigators. on a corn-

petitive basis. the preclinical development contract resources of

NCI’s l)evelopmental Therapeutics Program. The goal of RAID

is the rapid movement of novel molecules and concepts from the

laboratory to the clinic for proof-of-principle clinical trials.

RAID will assist investigators who submit successful applica-

tions by providing any (or all) of the preclinical development

steps that may be obstacles to clinical translation. These may

include, for example, production, bulk supply, GMP manufac-

turing, formulation, and toxicology. Suitable agents for RAID

�vill include small molecules, biologics. or vaccines. The first

group of proposals will be received by August 1. 1998

Thereafter. there will be two receipt dates per year. 1-ebruary 1.

and August 1. with all materials submitted directlv to the office

listed below. For information on process and procedure. visit the

web site, http://epnws I .ncifcrf.gov:2345/dis3d/raidfin.html.

Inquiries are encouraged, and the opportunity to clarit�’ issues or

questions is welcome. Please contact:

RAID, Office of Associate Director

Developmental Therapeutics Program, NCI

Executive Plaza North, Suite 843

6130 Executive Blvd., Rockville, MD 20852Tel: 301.496.8720; Fax: 301.402.0831

Email: sausville(�dtpax2.ncifcrf.govNsw� Aof Sciences

A New ResourceKit from theNational CancerInstitute

order this aU(1 other

materials, call the

Cancer Inkrmat ion Service.

a prograni of the

I\ational Cancer Inst it Ut P at

1 -800-4-CANCER(1 -800-422-6237)

People u’it/i TT}’ equipment.

dial 1-500- 332- S(i 1.5

AACR SPECIAL CONFERENCE IN CANCER RESEARCH

Cellular Targets of Viral Carcinogenesis

September 24-28, 1998Marriott’ s Laguna Cliffs Resort

Dana Point, CaliforniaCONFERENCE CHAIRPERSONS

Thea D. Tlsty I San Francisco, CAEileen P. White / Piscataway, NJDon Ganem / San Francisco, CA

Carol Prives I New York, NY

TENTATIVE SCIENTIFIC PROGRAM

Cell CycleJean Y. J. Wang I La Jolla, CAWilliam Kaelin / Boston, MAKaren H. Vousden I Frederick, MDThomas E. Shenk I Princeton, NJ

Signal TransductionDaniel C. DiMaio / New Haven, CTElliott Kieff/ Boston, MA

ApoptosisEileen P. White / Piscataway, NJAnne E. Griep I Madison, WIPhilip E. Branton I Montreal, Canada

Genomic InstabilityCarol Prives I New York, NYThea D. Tlsty / San Francisco, CAMichael R. Botchan I Berkeley, CA

Evasion of Host Cell DefensesGrant McFadden / London, CanadaMarshall S. Horwitz I Bronx, NYRobert H. Silverman / Cleveland, OH

Cell ProliferationKarl Munger I Boston, MAElizabeth Moran / Philadelphia, PADon Ganem / San Francisco, CA

Animal ModelsFrancis V. Chisari I La Jolla, CALisa M. Coussens I San Francisco, CADouglas Hanahan / San Francisco, CA

Therapeutic OpportunitiesPramod K. Srivastava I Farmington, CTDavid H. Kim / Richmond, CA

Additional Speakers to be Announced

Applicants are encouraged to submitabstracts for poster presentation.Selected proffered papers will also bescheduled for oral presentations.

Application deadline: July 13, 1998

Information and Application Forms

Amencan Association for Cancer ResearchPublic Ledger Building, Suite 826150 South Independence Mall WestPhiladelphia, PA 19106-348321 5-440-9300 21 5-440-931 3 (FAX)e-mail: aacr©aacr.orgAACR Website: http://www.aacr.org