Cisplatin - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

CISPLATIN A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Cisplatin: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-00262-0 1. Cisplatin-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International, Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on cisplatin. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON CISPLATIN ................................................................................................. 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Cisplatin........................................................................................ 6 E-Journals: PubMed Central ....................................................................................................... 63 The National Library of Medicine: PubMed ................................................................................ 66 CHAPTER 2. NUTRITION AND CISPLATIN ..................................................................................... 107 Overview.................................................................................................................................... 107 Finding Nutrition Studies on Cisplatin .................................................................................... 107 Federal Resources on Nutrition ................................................................................................. 110 Additional Web Resources ......................................................................................................... 110 CHAPTER 3. ALTERNATIVE MEDICINE AND CISPLATIN ............................................................... 113 Overview.................................................................................................................................... 113 National Center for Complementary and Alternative Medicine................................................ 113 Additional Web Resources ......................................................................................................... 138 General References ..................................................................................................................... 140 CHAPTER 4. DISSERTATIONS ON CISPLATIN ................................................................................. 143 Overview.................................................................................................................................... 143 Dissertations on Cisplatin ......................................................................................................... 143 Keeping Current ........................................................................................................................ 144 CHAPTER 5. PATENTS ON CISPLATIN............................................................................................ 145 Overview.................................................................................................................................... 145 Patents on Cisplatin................................................................................................................... 145 Patent Applications on Cisplatin............................................................................................... 164 Keeping Current ........................................................................................................................ 175 CHAPTER 6. BOOKS ON CISPLATIN ............................................................................................... 177 Overview.................................................................................................................................... 177 Book Summaries: Federal Agencies............................................................................................ 177 Book Summaries: Online Booksellers......................................................................................... 178 Chapters on Cisplatin ................................................................................................................ 178 CHAPTER 7. PERIODICALS AND NEWS ON CISPLATIN.................................................................. 181 Overview.................................................................................................................................... 181 News Services and Press Releases.............................................................................................. 181 Academic Periodicals covering Cisplatin ................................................................................... 183 CHAPTER 8. RESEARCHING MEDICATIONS .................................................................................. 185 Overview.................................................................................................................................... 185 U.S. Pharmacopeia..................................................................................................................... 185 Commercial Databases ............................................................................................................... 186 Researching Orphan Drugs ....................................................................................................... 186 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 191 Overview.................................................................................................................................... 191 NIH Guidelines.......................................................................................................................... 191 NIH Databases........................................................................................................................... 193 Other Commercial Databases..................................................................................................... 195 APPENDIX B. PATIENT RESOURCES ............................................................................................... 197 Overview.................................................................................................................................... 197 Patient Guideline Sources.......................................................................................................... 197 Finding Associations.................................................................................................................. 199 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 201 Overview.................................................................................................................................... 201

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Preparation................................................................................................................................. 201 Finding a Local Medical Library................................................................................................ 201 Medical Libraries in the U.S. and Canada ................................................................................. 201 ONLINE GLOSSARIES................................................................................................................ 207 Online Dictionary Directories ................................................................................................... 207 CISPLATIN DICTIONARY ......................................................................................................... 209 INDEX .............................................................................................................................................. 287

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with cisplatin is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about cisplatin, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to cisplatin, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on cisplatin. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to cisplatin, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on cisplatin. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON CISPLATIN Overview In this chapter, we will show you how to locate peer-reviewed references and studies on cisplatin.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and cisplatin, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “cisplatin” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Metoclopramide: A Dopamine Receptor Antagonist Source: American Family Physician. 41(3): 919-924. March 1990. Summary: This article discusses metoclopramide, a dopamine receptor antagonist with unique properties of increasing lower esophageal sphincter pressure and increasing the rate of gastric emptying. These gastrointestinal motility actions are useful in the treatment of diabetic gastroparesis and severe gastroesophageal reflux and in postoperative situations involving visceral atony. The author covers the chemistry, pharmacology, clinical uses, adverse reactions, and drug interactions of metoclopramide. Metoclopramide is a useful adjunctive drug for intestinal intubation and radiologic examination. It has also been used intravenously to control the nausea and vomiting of intensive cancer chemotherapy, such as with cisplatin. Intravenous metoclopramide is generally not intended for long-term use. The most common adverse

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Cisplatin

reactions are restlessness, drowsiness, fatigue, and lassitude. 3 tables. 35 references. (AA-M). •

Ototoxicity and Irradiation: Additional Etiologies of Hearing Loss in Adults Source: Journal of the American Academy of Audiology. 6(5): 351-357. September 1995. Summary: This article offers a brief review of the effects of the seven groups of substances and chemicals known to affect hearing and the vestibular system, followed by a more detailed discussion of cisplatin (cisplatinum). The authors provide an illustrative case study that exemplifies a recent finding of some recovery of hearing, following withdrawal of cisplatin chemotherapy. Some suggestions for reducing the potential for ototoxicity are also presented. The authors continue with a discussion of the effects of irradiation on hearing and the ear and they provide an illustrative case study. Included are some reported results from patients in the Ukraine who were exposed to excessive radiation as a result of the Chernobyl nuclear disaster. The authors also discuss the effects on the ear and vestibular system caused by the interaction between chemotherapy and irradiation treatment. The authors caution that due to recent successes of these treatments in fighting cancer, more patients with hearing loss triggered by these techniques will be seen in audiology clinics. 5 tables. 22 references. (AA-M).

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Prognostic Factors in Major Salivary Gland Cancer Source: Laryngoscope. 111(8): 1434-1439. August 2001. Contact: Available from Lippincott, Williams, and Wilkins. 530 Walnut Street, Philadelphia, PA 19106-3621. (215) 521-8300. Fax (215) 521-8902. Website: www.lww.com. Summary: This article reports on a study undertaken to identify features of major salivary gland cancers that are prognostic for disease free survival. The retrospective study included 78 patients with major salivary gland cancer (64 parotid and 14 submandibular, under the lower jaw, gland) who underwent surgery for definitive treatment from 1976 to 1996. A select group of patients also received adjuvant radiation (56 percent) and or chemotherapy (13 percent). Clinical and pathological risk factors were obtained from patients' charts and pathology reports. In this series, the 5 year disease free survival was 65 percent. Examining clinical and histologic features one at a time, the authors found poorer prognosis was associated with submandibular tumors compared with parotid, higher T stage, positive cervical (neck) nodes, perineural invasion, and high grade or adenoid cystic tumors. A multivariable analysis indicated that positive lymph nodes and perineural invasion were important histologic predictors of shorter disease free survival. Receipt of both adjuvant radiation and cisplatin based chemotherapy was an independent predictor of longer disease free survival. The authors conclude that the presence of positive lymph nodes and perineural invasion are important independent predictors of disease free survival. Adjuvant chemotherapy and radiation therapy may improve disease free survival. 2 figures. 5 tables. 23 references.

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Drug-Induced Hearing Loss: How It Can Be Prevented Source: Hearing Loss. 20(3): 14-18. May-June 1998. Contact: Available from Self Help for Hard of Hearing People, Inc. (SHHH). 7910 Woodmont Avenue, Suite 1200, Bethesda, MD 20814. Voice (301) 657-2248; TTY (301) 657-2249; Fax (301) 913-9413; E-mail: [email protected]; http://www.shhh.org.

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Summary: This article reviews drug-induced hearing loss and how it can be prevented. After an introductory section that outlines ototoxicity and other threats to hearing (from noise and heavy metals), the bulk of the article focuses on aminoglycoside antibiotics and their effect on hearing. Hearing loss is generally observed only when these drugs are administered over a long period of time. However, risk factors that can activate the ototoxic potential of these drugs include genetic predisposition, advanced age, impaired kidney function, poor nutrition, noise exposure, pre-existing disorders of hearing or balance, and administration of diuretics together with aminoglycosides. In addition, aminoglycoside-induced loss of balance may occur with or without accompanying hearing loss. Iron chelators (medications used to soak up excess iron in the bloodstream) have now been shown to prevent these toxic side effects of aminoglycosides. If clinical trials show that iron chelators work as well in humans as they do in animals, this research will lead to a safe and inexpensive way to eliminate the threat of hearing loss to future patients treated with antibiotics. The article concludes with a brief discussion of other ototoxic drugs, notably cisplatin, a drug used for cancer chemotherapy. 1 figure. 1 table. •

Ototoxicity: Mechanisms, Protective Agents, and Monitoring Source: Current Opinion in Otolaryngology and Head and Neck Surgery. 8(5): 436-440. October 2000. Contact: Available from Lippincott Williams and Wilkins. 12107 Insurance Way, Hagerstown, MD 21740. (800) 637-3030. Fax (301) 824-7390. Website: www.lww.com. Summary: This article reviews recent progress in determining the mechanisms of ototoxicity (toxic effects of drugs on the ear) but also in finding otoprotective agents. For aminoglycosides, new dosing protocols and protective agents, including growth factors and salicylates, show promise for eventually reducing ototoxicity. Further evidence of genetic susceptibility has been published. For chemotherapeutic (cancer drugs, in the majority) agents, further evidence of oxidative damage and ion channel blockade mechanisms reinforces earlier work. Protective agents for cisplatin induced ototoxity have been further investigated and include antioxidants and metal binders. Protection has been demonstrated not only for the organ of Corti but also for the stria vascularis. For audiologic monitoring of ototoxicity, new methods of collecting and interpreting high frequency audiometry, auditory brainstem responses (ABR), and otoacoustic emissions (OAEs) have been proposed to enhance early detection. High frequency audiometry has also been proposed to monitor industrial solvent exposure. 24 references (6 annotated).

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Ototoxicity and Antineoplastic Drugs Source: Current Opinion in Otolaryngology and Head and Neck Surgery. 7(5): 239-243. October 1999. Summary: This article reviews recent research dealing with the ototoxicity (ear or hearing damage) of chemotherapeutic agents. Recent experimental studies suggest that platinum based chemotherapy may damage the cochlea through the generation of reactive oxygen species. These reactive compounds could then cause extensive damage to the hair cells of the cochlea. New risk factors have been identified in patients receiving chemotherapy with cisplatin and or carboplatin. The author notes that previous noise exposure may also result in an increased risk for cisplatin ototoxicity. The author also reviews future strategies to reduce of prevent hearing loss from these chemotherapeutic agents. 15 references (6 annotated).

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Federally Funded Research on Cisplatin The U.S. Government supports a variety of research studies relating to cisplatin. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to cisplatin. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore cisplatin. The following is typical of the type of information found when searching the CRISP database for cisplatin: •

Project Title: ADENOVIRUS BASED P53 GENE THERAPY FOR OVARIAN CANCER Principal Investigator & Institution: Mathis, J Michael.; Cell Biology and Anatomy; Louisiana State Univ Hsc Shreveport P. O. Box 33932 Shreveport, La 71103 Timing: Fiscal Year 2002; Project Start 08-DEC-1998; Project End 30-NOV-2003 Summary: (Applicant's Abstract) The goal of this application is to develop a preclinical therapeutic model of ovarian cancer involving an adenovirus-based vector encoding the human p53 tumor suppressor gene. This application involves the introduction of a gene that has direct tumor cytotoxicity or indirect tumor growth inhibitory function (through a phenomenon termed the "bystander effect"), or potentially both. The applicant has demonstrated the efficacy of gene therapy in vivo using an adenovirus vector for the transfer of biologically active p53 into ovarian cancer cells. The goal of this project is to further define the following five aspects of adenovirus-based p53 gene therapy in the treatment of ovarian cancer. First, while p53 gene therapy has shown efficacy in a microscopic disease model, the applicant plans to determine whether this treatment will be effective in the presence of larger tumor volumes that more closely model human ovarian cancer. Second, because mutant p53 protein can inhibit wild type p53 function, he plans to investigate the role of specific endogenous p53 mutations on the response to adenovirus-based p53 gene therapy. These results may allow him to predict patient response to p53 gene therapy. Third, he will determine the mechanisms by which p53 acts to inhibit tumor growth in G2. It is well documented that introduction of cancer cell lines with wild-type p53 results in a G1 arrest. However, he has recently observed that certain cells arrest at the G2/M checkpoint. The arrest of cells during DNA synthesis and replication after DNA damage is thought to provide the cell with sufficient time to repair the damage before progression through the cell cycle. Fourth, because p53 has been shown to re-sensitize chemo- resistant cells to alkylating agents, he plans to determine the effectiveness of adenovirus-based p53 gene therapy alone or in combination with cisplatin therapy. Finally, some data suggest that wild-type p53 regulates a balance of potent angiogenic and anti- angiogenic factors. Thus, he plans to

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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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investigate the bystander effect of adenovirus-based p53 gene therapy on tumor angiogenesis. In this application, he intends to take the first steps toward the translation of promising preliminary data on an adenovirus-based cancer gene therapeutic model system into practical and scientifically based human trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTICANCER DICTYOSTELIUM

DRUG

RESISTANCE

STUDIES

USING

Principal Investigator & Institution: Alexander, Stephen; Associate Professor; Biological Sciences; University of Missouri Columbia 310 Jesse Hall Columbia, Mo 65211 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: Human tumors frequently develop resistance to many of the widely used chemotherapeutic agents. Many different mechanisms have been proposed for the molecular basis of this resistance. Studies on drug resistance in tumor cells have often focused on the mechanism of action of the drug, and looked for resistance due to altered drug concentration in the cell, different models of drug inactivation or altered damage repair. As such, other pathways that may be involved with the cellular cytotoxic response to individual drugs have been overlooked. We propose to use the cellular slime mold Dictyostelium discoideum in an unbiased approach to identify novel molecular targets that can be modulated to increase sensitivity of tumor cells to chemotherapeutic drugs. The genes and pathways of Dictyostelium are highly conserved with those of humans, and molecular genetic methods are well developed for this organism. Our preliminary system on cisplatin resistance resulted in the identification of 6 genes. Significantly, none of these had been previously associated with cisplatin, and each represents a potential new target for therapy. The goal of the present study is to demonstrate the general utility of this system and to show that it can be applied to the understanding of resistance to other drugs. We have focused on four classes of DNA damaging drugs that damage DNA by different mechanisms. These include: both intra- and inter-strand crosslinkers, monoalkylators, and oxygen radicals. We will 1) create a comprehensive Dictyostelium insertional mutant library, 2) isolate mutants resistant to drugs of each of the four classes and identify the cognate genes, and 3) test the mutants for cross-resistance to the other drugs. These studies will identify new mechanisms for drug resistance and new targets for chemotherapeutic intervention which can subsequently be validated in human cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTIOXIDANT INVOLVEMENT IN NOISE INDUCED HEARING LOSS Principal Investigator & Institution: Henderson, Donald; Professor and Chairman; State University of New York at Buffalo Suite 211 Ub Commons Buffalo, Ny 14228 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2002 Summary: This research focuses on the relation between the cochlea's antioxidant system and resistance to noise or carboplatin. The project is a logical extension of previous research in our lab that showed (1) the ear could acquire resistance to noise by prior exposure to benign moderate level noise; (2) the antioxidant enzymes catalase, glutathione reductase and gamma-glutamyl cysteine synthtase (GCS) are increased in concentration in both stria and organ of Corti after prophylactic noise exposures; (3) the degree of temporary and permanent hearing loss as well as hair loss from exposures to a traumatic noise could be reduced by prior treatment of R- phenylisopropyladenoisine

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(R-PIA). Collectively, these results suggest that high level noise exposures produce hearing loss by the mechanism of reactive oxygen intermediates (ROI) cytotoxicity and that prophylactic noise exposures, as well as intervention by R-PIA, can reduce both the effects of noise and cisplatin (Ryback et al., 1995). The proposed set of experiments has four specific aims: (1) What is the relation between glutathione related enzymes (specifically GCS), and susceptibility to noise? (2) Can the susceptibility to noiseinduced hearing loss be decreased with drugs that up-regulate GCS or increased with drugs that suppress GCS? (3) What is the normal anatomical distribution of glutathione (GSH) and does it change with exposure to noise? (4) Is the otoxicity of carboplatin influenced by drugs that up-regulate or down- regulate the antioxidant system? These experiments will be conducted on chinchillas. Hearing functions will be measured by evoked potentials and otoacoustic emissions. GCS levels will be assessed by our collaborator Dr. Howard Steinman at Albert Einstein College of Medicine. Cochlear analysis will include cell counts from surface preparations and confocal studies of GSH distribution. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: APOPTOTIC PATHWAY DEFECTS IN NEUROBLASTOMA Principal Investigator & Institution: Kidd, Vincent J.; Professor; St. Jude Children's Research Hospital Memphis, Tn 381052794 Timing: Fiscal Year 2003; Project Start 15-JUL-1995; Project End 31-DEC-2007 Summary: (provided by applicant): Late stage neuroblastoma tumors, particularly those with amplified MYCN genes, have a poor prognosis, primarily due to their ability to survive treatment with multiple chemotherapeutic agents/irradiation. The continuing goal of this research program is to understand how genetic alterations, such as MYCN gene amplification and chromosome lp36 loss-of-heterozygosity (LOH), contribute to this tumor phenotype. During the last funding period we found that a critical apoptotic signaling molecule, caspase-8, is preferentially silenced by methylation in >60% of the stage 4 neuroblastoma patient tumors with simplified MYCN, whereas