@T4ji@I POSITIONS

@t4Ji@i POSITIONS

The BenMayInstitutefor CancerResearchandtheDepartmentof Surgeryat the Universityof Chicagoare seeking applicants for tenure-track positions at the Assistant or Associate Professor level with expertise in molecular oncology. Theidealcandidateswillbe an investigatorwiththe abilityto developan independentlyfundedresearchprogramin basic cancer biology, molecular genetics of cancers, or regulation of cell growth and differentiation. Candidates should havesufficientresearchexperienceto demonstratebothsignificantaccomplishmentsandoutstandingpotential. The faculty member is expected to take advantage of the extensive collaborative interactions available with members of the University genetics, biochemistry, immunology and molecular biology community.

The Ben May Institute for Cancer Research (BMICR) is a basic research unit that for 45 years has been committed to the studyof basicmechanismsof cancerandimmunology.TheDepartmentof Surgeryhas a stronghistoryof research in the field of oncology. The BMICR and Surgery are closely interfaced with the University of Chicago NCI designated Comprehensive Cancer Center, the University of Chicago Center for Molecular Oncology and the Gwen Knapp Center for Lupus and Immunology Research. Additionally, these departments are closely affiliated with degree granting Committees on Immunology and Cancer Biology. Letters of recommendation including curriculum vitae, bibliography, a brief statement of research interest and the names of three references should be sent to: Jeffrey Bluestone, Chair, Search Committee, University of Chicago, 5841S. Maryland Ave.,MC6027,Chicago,IL 60637. THE UNIVERSITY OF CHICAGO

Postdoctoral Research Fellowship Rapid Access to Intervention Development in Molecular Oncology â€œRAIDâ€• The Center for Molecular Medicine at the The NATIONALCANCERINSTITUTEis requesting applications for the University of Connecticut School of Medicine following initiative: Rapid Access to Intervention Development (RAID). invites applications for a postdoctoral fellow RAID will make available to academic investigators, on a competitive ship to (a) pursue novel approaches toward basis, the preclinical development contract resources of NCI â€˜s Developmental Therapeutics Program. The goal of RAID is the rapid understanding the role of the cyclin Dl onco movement of novel molecules and concepts from the laboratory to the gene in human neoplasia and in relevant ani clinic for proof-of-principle clinical trials. RAID will assist investigators ma! models, and (b) exploit this understanding who submit successftil applications by providing any (or all) of the for therapeutic purposes. preclinical development steps that may be obstacles to clinical translation. These may include. for example, production, bulk supply, A strong background in molecular biology is GMP manufacturing, formulation, and toxicology. Suitable agents for RAID will include small molecules, biologics, or vaccines. There are required, and experience in molecular oncol two receipt dates for proposals per year@February 1 and August 1. ogy is highly desirable. Current applications must be received by February 1, with all materials submitted directly to the office listed below. For information on process Review of applications will begin on January and procedure. visit the web site, http://dtp.nci.nih.gov. Inquiries are 1, 1999, and will continue until the position is encouraged. and the opportunity to clarify issues or questions is filled. Send curriculum vitae, statement of re welcome. As of this cycle of applications. academic investigators may search experience and interests, and names of have collaborations with small-business partners and still qualify for RAID funding. Please note that a maximum oftwo distinct proposals per three references to: investigator can be submitted per the application review date. Please Dr. Andrew Arnold contact Director, Center for Molecular Medicine RAID, Office of Associate Director University of Connecticut School of Medicine Developmental Therapeutics Program, NCI Executive Plaza North, Suite 843 263 Farmington Avenue 6130 Executive Blvd., Rockville, MD 20852 Farmington, CT 06030.1316 Tel: 301.496.8720; Fax: 301.402.0831 Email: [email protected]

clinical research that are critical to addressing the current and looming crisis of cancer incidence, mortality, and health care costs.â€•In deter mining what it would take to expedite cancer research if adequate resources were made available, the Research Task Force gave serious CancerResearch consideration to key barriers that must be removed to accelerate progress against cancer, including those that contribute to the disproportionate effect of cancer on minority and medically underserved populations. The Research Task Force included leading scientists from the aca demic and private sectors, most of them members of the AACR. Thir teen subcommittees considered every aspect of cancer research, from the basic molecular biology of cancer to psychosocial research to unex plored opportunities in public-private partnerships. The findings of these subcommittees were then synthesized into the Report by Drs. Barker and Sigal. Dr. Barker, President and CEO of BIO-NOVA, Inc., is a leading member of the AACR, serving as Chairperson of its Public Education Committee since 1993. She is renowned for her effective leadership in public education, public policy, and science policy. For many years, she has worked actively to bring together scientists and consumer advocates in the fight against cancer. As a result of her vast knowledge in science and public issues, and her unflagging dedication, she has been very successful in forging synergistic relationships between these two impor tant sectors of the cancer community. Her unstinting passion about cancer and about the vital importance of research in accelerating pro gress against this disease has been the hallmark of her invaluable work in these areas. Dr. Sigal, President of Sigal Development, is a tireless advocate for cancer research. The eradication of cancer is a primary mission in Dr. The September 1, 1998, cover of Cancer Research featured THE Sigal's philanthropic and public pursuits. She founded and serves as MARCH. ..Coming Together To Conquer CancerTM, an historic advo Chairman of the Board of Friends of Cancer Research; this organization cacy event which took place on September 25â€”26,1998,at the National was formed to acknowledge the 25th Anniversary of the National Cancer Mall in Washington, DC, and in virtually every city and state around the Act and to emphasize the importance of cancer research in the conquest country. United in this unprecedented grassroots effort, hundreds of of this disease. She currently serves as President of the Creative Corn thousands of people participated in THE MARCH to express their grave munity Task Force for Cancer Research. She was a Presidential ap concern about cancer and its devastating effects on all Americans and, in pointee to the National Cancer Advisory Board from 1992-98, and she particular, to communicate to the Administration and to members of served as Chair of the Budget and Planning Committee of the Board for Congress that we must have the necessary resources NOW to address the over five years. Dr. Sigal is highly respected by cancer researchers for cancer crisis. The message was loud and clearâ€”cancer must become the her many years of leadership and her unwavering personal commitment Nation's No. 1 research and health care priority. By all accounts, this to the cure and prevention of cancer. She became an advocate for cancer event was very successful, and all those who actively contributed to the research when she lost her sister to breast cancer. In this regard, she intensive preparations for THE MARCH are to be congratulated for their shares the same tragic family loss as Dr. Barker, who has lost both a work. THE MARCH brought together cancer patients and cancer sur sister and a mother to breast cancer. vivors, researchers and physicians, and many others in the ongoing Drs. Barker and Sigal credit the strength of the Report to the dedi struggle against cancer, and it was in large part responsible for the cation of the individual members of the Research Task Force (whose largest dollar increase in funding (for FY 1999) ever given to the NIH names are listed in the Report) as well as to its Board of Directors, and the NC!. An upcoming special issue ofAACR News will be devoted including: John R. Durant, M.D.; Margaret Foti, Ph.D.; Phillip A. Sharp, to this amazing show of support from the community for more funding Ph.D.; and Ellen L. Stovall. We are all deeply grateful as well for the for cancer research. passion and moral support of the leadership of THE MARCH and its One of the most important initiatives of THE MARCH was the Chairman, Mr. Sidney Kimmel. preparation of The March Research Task Force Report. This Report was This Report can be distinguished from other blueprints for future commissioned by THE MARCH. Its release, the first post-rally initia cancer research in that The March Research Task Force was independent tive, should serve notice that this movement will not disappear just of any government or private agency concerns, and the Report represents because the speeches on the Mall are now over and the buses have the combined efforts of scientists, survivors, and private industry. It is returned home from the Capitol. This issue of Cancer Research contains also unique in its vision. It concludes, on the basis of the considered this seminal Report in its entirety (pages 5590â€”5627), and the cover deliberations of the Research Task Force, that significant reductions in appropriately highlights its publication and the two individuals who cancer incidence, mortality, and morbidity are possible in the next two spearheaded and directed this extraordinary effort, Research Task Force decades â€”butonly if the Nation is willing to make an annual investment Co-Chairpersons Anna D. Barker, Ph.D. (right), and Ellen V. Sigal, averaging $10 billion per year over the next five years. Such an ambi Ph.D. (left). Cancer Research is very proud to publish the Report and to tious commitment of resources should be made deliberately and swiftly, provide the opportunity for its widest dissemination to the cancer corn with confidence in the conclusions of the Research Task Force. Special munity. It is required reading for every cancer researcher, every member thanks are due to Drs. Barker and Sigal and to every member of this of Congress, and indeed every citizen whose life has been touched by prestigious group for defining the problems, identifying solutions, and cancer. challenging all of us to ensure that our efforts are focused on the goal of The March Research Task Force was formed more than a year ago, eradicating cancer. almost immediately after THE MARCH was conceived. It consisted of more than 160 of the Nation's leading cancer researchers and clinicians, cancer survivors, and advocates. The charge of the Research Task Force Webster K. Cavenee, Ph.D. was â€œtodistinguishthe exceptional opportunities and needs in basic and President, AACR

Angiogenesis in the Hollow Fiber Tumor Model Influences Drug Delivery to Tumor Cells: Implications for Anticancer Drug Screening Programs1

Roger M. Phillips,2Jennifer Pearce, Paul M. Loadman, Michael C. Bibby, Patricia A. Cooper, David J. Swaine, and John A. Double Clinical Oncology Unit, Universityof Bradford, Bradford, BD7 IDP, United Kingdom

Abstract unlikely that drug delivery problems would occur after an i.p. drug administration. Responses at the s.c. site after i.p. drug administration, The National Cancer Institute uses the hollow fiber assay as part of its however, may indicate that the new agent possesses both good bio screening program for anticancer drug discovery. Angiogenesis to hollow availability and pharmacological properties. Drug delivery to tumors fibers Implanted s.c. has not been reported, thereby raising concerns about the efficiency of drug delivery and Its subsequent effects on chemo is dependent on several factors, one of which is the presence of an sensitivity. By extending postimplantation times beyond the 6-day period established blood supply. Blood vessel development to hollow fibers presently used, extensive vascular networks develop, resulting in both implanted s.c. has not been reported previously, raising concerns increased delivery and chemosensitivity to doxorubicin. This study sug about the efficiency of drug delivery and the subsequent effects this gests that present protocols used to evaluate compounds may produce may have on chemosensitivity, bearing in mind the role that drug false negative results, and additional studies to determine the predictive C X T values play in determining chemosensitivity (9). Lack of value of the assay are required. activity at the s.c. site may, therefore, be caused by poor drug delivery as a result of lack of blood vessel development; if this is the case, the Introduction validity of the test system is called into question. Tumor cells in In the late 1980s, the Developmental Therapeutics Program of the hollow fibers should theoretically be able to induce an angiogenic NCI3 radically changed its approach to the large-scale, random response as the molecular weight cutoff point of the fiber walls is screening of compounds for anticancer activity (1). Instead of using large enough (Mr 500,000) to allow for appropriate growth factors to xenografts or syngeneic rodent tumor models as a front line screen, all pass through the fiber wall. Present protocols for using the hollow compounds submitted to the NC! are evaluated against a panel of fiber assay involve both short-term in vitro (1 day) and in vivo (6 day) well-characterized human tumor cell lines. Compounds are selected cultivation, which may be too short to enable angiogenesis to occur. for further evaluation if they possess disease-specific activity in vitro, The aims of this study, therefore, were: (a) to determine whether are COMPARE negative (i.e., have chemosensitivity fingerprints that hollow fibers implanted s.c. can develop a blood supply if postirn differfrom standardagents),or if activityin vitro is correlatedwith plantation times are extended beyond the 6-day period presently used; the expression of specific molecular targets in the cell line panel and (b) to determine what effect the presence or absence of a vascular (1â€”4).It was envisaged that the primary in vitro screen would have network has on both drug delivery and chernosensitivity in a murine such discriminative powers that only a few agents would need to be colon tumor model. evaluated against human tumor xenografts. This, however, has not Materials and Methods been the case (5), thereby creating a backlog of compounds awaiting evaluation against xenografts. Because of the cost associated with the Materials. Poly-Vinyl-Idene-Fluoride Spectra/Por Hollow fibers (internal use of xenografts to evaluate large numbers of compounds, the NC! diameter = 1 mm with a molecular weight cutoff point of M1500,000) were developed and introduced an intermediate screen through which corn purchased from Spectrum Medical, Inc. (Houston, TX). Doxorubicin, MTI', pounds must pass before full evaluation in xenograft tumor models and DMSO were purchased from Sigma (Poole, Dorset, United Kingdom). (6). The hollow fiber assay (7, 8) used by the NCI involves the Solvents for high-performance liquid chromatography analysis of doxorubicin short-term in vitro culture (1 day) oftumor cells inside biocompatable, were of analytical grade and were purchased from Fisher Scientific (Lough polyvinylidene fluoride fibers, followed by implantation into mice at borough, United Kingdom). All cell culture material was purchased from Life Technologies, Inc. (Paisley, United Kingdom). two anatomically separate sites (s.c. and i.p.). Drugs are administered Animals. Pure strain NMRI mice (6â€”8weeks of age) were obtained from i.p. (mice are treated daily for up to 4 days), fibers are removed 2 days B & K Universal, Ltd. (Hull, United Kingdom) and kept under 12 hourly later (total time in vivo is 6 days), and chemosensitivity is assessed cycles of light and darkness with access to a CRM pellet diet (Special Diet using a modified MU assay in vitro (8). Compounds are submitted Services, Witham, United Kingdom) and water ad libitum. All animal exper for more extensive in vivo evaluation in xenografts if they demon iments were conducted under appropriate animal licenses issued by the Home strata activity at both the s.c. and i.p. sites. Responses at the i.p. site Office (London, United Kingdom), and United Kingdom Coordinating Com might be expected to reflect in vitro chemosensitivity (although they mittee on Cancer Research guidelines were followed throughout (10). are unlikely to be identical as drug exposure parameters will be Cell Culture. MAC 15A cells were obtained from an ascitic murine differentdue to drug clearancefrom the peritonealcavity), as it is adenocarcinoma of the colon, as described elsewhere (9), and routinely main tamed as monolayer cultures in RPMI 1640 supplemented with FCS (10%), sodium pyruvate (2 mM),Penicillin/Streptomycin (50 IU ml'/50 @gml@), Received 8/24/98; accepted 10/19198. Thecostsof publicationofthisarticleweredefrayedinpartbythepaymentofpage and L-glutamine (2 mM) and buffered with HEPES (25 mM). Fibers were charges. This article must therefore be hereby marked advertisement in accordance with rehydrated, sterilized, and loaded with MAC l5A cells (1 X 106cells ml'), 18U.S.C.Section1734solelytoindicatethisfact. as described by Hollingshead et a!. (8). Fibers were transferred to a T-25 flask @ Supported by War on Cancer (Bradford, United Kingdom). containing growth medium and incubated at 37Â°Cfor a period of 14 days under 2 To whom requests for reprints should be addressed, at Clinical Oncology Unit, University of Bradford, Bradford, BD7 1DP, United Kingdom. constant agitation (80 rpm) on an orbital shaker, with daily changes of 3 The abbreviations used are: NCI, National Cancer Institute; MiT, 3-(4.5-dimethyl medium. Histological analysis of fibers after 14 days of culture in vitro thiazol-2yl)-2,5-diphenyltetrazolium bromide. demonstrated that fibers contain a central necrotic core (data not shown). 5263

Andrea Morrione, Barbara Valentinis, Shiwei Li, et al.

Cancer Res 1996;56:3165-3167.

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