Division Of Cancer Treatment Research Articles

Integrin β4 Regulates Migratory Behavior of Keratinocytes by Determining Laminin-332 Organization

Whether alpha6beta4 integrin regulates migration remains controversial. beta4 integrin-deficient (JEB) keratinocytes display aberrant migration in that they move in circles, a behavior that mirrors the circular arrays of laminin (LM)-332 in their matrix. In contrast, wild-type keratinocytes and JEB keratinocytes, induced to express beta4 integrin, assemble laminin-332 in linear tracks over which they migrate. Moreover, laminin-332-dependent migration of JEB keratinocytes along linear tracks is restored when cells are plated on wild-type keratinocyte matrix, whereas wild-type keratinocytes show rotation over circular arrays of laminn-332 in JEB keratinocyte matrix. The activities of Rac1 and the actin cytoskeleton-severing protein cofilin are low in JEB keratinocytes compared with wild-type cells but are rescued following expression of wild-type beta4 integrin in JEB cells. Additionally, in wild-type keratinocytes Rac1 is complexed with alpha6beta4 integrin. Moreover, Rac1 or cofilin inactivation induces wild-type keratinocytes to move in circles over rings of laminin-332 in their matrix. Together these data indicate that laminin-332 matrix organization is determined by the alpha6beta4 integrin/actin cytoskeleton via Rac1/cofilin signaling. Furthermore, our results imply that the organizational state of laminin-332 is a key determinant of the motility behavior of keratinocytes, an essential element of skin wound healing and the successful invasion of epidermal-derived tumor cells.

Sgt1p Is a Unique Co-chaperone That Acts as a Client Adaptor to Link Hsp90 to Skp1p

Sgt1p is a conserved, essential protein required for kinetochore assembly in both yeast and animal cells. Sgt1p has homology to both TPR and p23 domains, sequences often found in proteins that interact with and regulate the molecular chaperone, Hsp90. The presence of these domains and the recent findings that Sgt1p interacts with Hsp90 has led to the speculation that Sgt1p and Hsp90 form a co-chaperone complex. To test this possibility, we have used purified recombinant proteins to characterize the in vitro interactions between yeast Sgt1p and Hsp82p (an Hsp90 homologue in yeast). We show that Sgt1p interacts directly with Hsp82p via its p23 homology region in a nucleotide-dependent manner. However, Sgt1p binding does not alter the enzymatic activity of Hsp82p, suggesting that it is distinct from other co-chaperones. We find that Sgt1p can form a ternary chaperone complex with Hsp82p and Sti1p, a well characterized Hsp90 co-chaperone. Sgt1p interacts with its binding partner Skp1p through its TPR domains and links Skp1p to the core Hsp82p-Sti1p co-chaperone complex. The multidomain nature of Sgt1p and its ability to bridge the interaction between Skp1p and Hsp82p argue that Sgt1p acts as a "client adaptor" recruiting specific clients to Hsp82p co-chaperone complexes.

Phase II study of irofulven in recurrent or metastatic gastric cancer: A Cancer Therapeutic Research Group (CTRG) study

14105 Background: Cytotoxic chemotherapy has been widely used in patients (pts) with advanced or metastatic gastric cancer, but the reported high response rates in phase II settings have not been confirmed by randomized trials. Moreover, the therapeutic impact on survival has been modest. The purpose of this study was to evaluate Irofulven, a DNA interacting acylfulvene analog, as first line therapy for pts with recurrent or metastatic gastric cancer. Methods: The main eligibility criteria were: Histologically or cytologically confirmed disease; age > 18 yrs; ECOG ≤ 2; measurable disease; no prior chemotherapy for recurrent or metastatic disease; life expectancy > 3 months. Irofulven was given at 0.45 mg/kg i.v. over 30-min infusion (max. 50 mg), on Day 1 and 8, every 3 weeks. The primary endpoint was treatment response and toxicity; the secondary end-point was survival. A 2-stage phase II design was used. In the first stage, the target enrollment was 20, if ≤ 2 responses were observed, the study would be stopped and the treatment concluded to be ineffective; if ≥ 6 responses were observed, the study drug would be concluded to be active. Otherwise, another 15 pts would be entered into the second stage. Survival was constructed using the Kaplan-Meier method. All patients entering the trial were included in the survival analysis. Results: 23 pts were entered into the first stage. The median no. of cycles per pt was 2 (range: 1–6). 2 pts (9%) had ≥ 1 week delay in administration of subsequent cycle of chemotherapy. For the day 8 chemotherapy, 7 pts (30%) required dose reductions; 5 (22%) had dose omitted. 22% and 17% pts developed grade 3/4 anemia and neutropenia respectively. There was no grade 4 thrombocytopenia or neutropenic fever. Of the 20 evaluable pts, no responses was observed, 3 pts had stable disease after 2 cycles of treatment which was not confirmed by a further assessment. Median overall survival was 6.05 months (95% CI 4.55–9.39). Conclusions: Irofulven was tolerated at the described dose but showed no evidence of antitumor activity in patients with advanced gastric cancer. Acknowledgement: The study was sponsored by the Division of Cancer Treatment and Diagnosis, National Cancer Institute, U.S.A, and its collaborator MGI Pharma, Inc. No significant financial relationships to disclose.

Extending the API TMA data exchange specification to single specimen and cutting edge matrix assembly (CEMA)

Context The AIDS and Cancer Specimen Resource (ACSR) sponsored by the National Cancer Institute (NCI) Division of Cancer Treatment and Diagnosis provides HIV/AIDS infected biologic samples, controls and de-identified clinical data to approved researchers. Researchers need clinical data for all specimens in a form that facilitates data integration. The Association for Pathology Informatics (API) Extensible Mark-up Language (XML) TMA Data Exchange Specification (DES) provides a common TMA data format. Design We used HTML, XML, XSLT, document type definitions (DTD), Windows host and java scripts with the TMA DES. We developed data elements that allowed us to specify single specimens (SS) and CEMA blocks and slides and placed them into the TMA DES element hierarchy. SS and CEMA common data elements (CDE) were added to the TMA DES DTD (renamed specimen DES or SDES DTD). Results The SS and CEMA data elements and their placement as optional CDEs in the SDES hierarchy have been defined. Data for 100 SS were exported from the ACSR database in the SDES format and validated with an enhanced DTD using independent validators. Researchers can encode SS, CEMA blocks and associated clinical data in the SDES format. Conclusions These SS and CEMA CDEs should be adopted by the API for optional use to allow others to export SS and CEMA data in a standard way. Such CDEs facilitate data exchange and integration and encourage development of software that benefits importers. Supported by NCI: U01 CA66531.

The tissue micro-array data exchange specification: a web based experience browsing imported data

BackgroundThe AIDS and Cancer Specimen Resource (ACSR) is an HIV/AIDS tissue bank consortium sponsored by the National Cancer Institute (NCI) Division of Cancer Treatment and Diagnosis (DCTD). The ACSR offers to approved researchers HIV infected biologic samples and uninfected control tissues including tissue cores in micro-arrays (TMA) accompanied by de-identified clinical data. Researchers interested in the type and quality of TMA tissue cores and the associated clinical data need an efficient method for viewing available TMA materials. Because each of the tissue samples within a TMA has separate data including a core tissue digital image and clinical data, an organized, standard approach to producing, navigating and publishing such data is necessary.The Association for Pathology Informatics (API) extensible mark-up language (XML) TMA data exchange specification (TMA DES) proposed in April 2003 provides a common format for TMA data. Exporting TMA data into the proposed format offers an opportunity to implement the API TMA DES. Using our public BrowseTMA tool, we created a web site that organizes and cross references TMA lists, digital "virtual slide" images, TMA DES export data, linked legends and clinical details for researchers.Microsoft Excel® and Microsoft Word® are used to convert tabular clinical data and produce an XML file in the TMA DES format. The BrowseTMA tool contains Extensible Stylesheet Language Transformation (XSLT) scripts that convert XML data into Hyper-Text Mark-up Language (HTML) web pages with hyperlinks automatically added to allow rapid navigation.ResultsBlock lists, virtual slide images, legends, clinical details and exports have been placed on the ACSR web site for 14 blocks with 1623 cores of 2.0, 1.0 and 0.6 mm sizes. Our virtual microscope can be used to view and annotate these TMA images. Researchers can readily navigate from TMA block lists to TMA legends and to clinical details for a selected tissue core.Exports for 11 blocks with 3812 cores from three other institutions were processed with the BrowseTMA tool. Fifty common data elements (CDE) from the TMA DES were used and 42 more created for site-specific data. Researchers can download TMA clinical data in the TMA DES format.ConclusionVirtual TMAs with clinical data can be viewed on the Internet by interested researchers using the BrowseTMA tool. We have organized our approach to producing, sorting, navigating and publishing TMA information to facilitate such review.We have converted Excel TMA data into TMA DES XML, and imported it and TMA DES XML from another institution into BrowseTMA to produce web pages that allow us to browse through the merged data. We proposed enhancements to the TMA DES as a result of this experience.We implemented improvements to the API TMA DES as a result of using exported data from several institutions. A document type definition was written for the API TMA DES (that optionally includes proposed enhancements). Independent validators can be used to check exports against the DTD (with or without the proposed enhancements). Linking tissue core images to readily navigable clinical data greatly improves the value of the TMA.

How HHS Plans to Move Medical Innovations Forward: Summary of Task Force Report and Recommendations

How HHS Plans to Move Medical Innovations Forward: Summary of Task Force Report and Recommendations

The tissue microarray data exchange specification: A document type definition to validate and enhance XML data

BackgroundThe Association for Pathology Informatics (API) Extensible Mark-up Language (XML) TMA Data Exchange Specification (TMA DES) proposed in April 2003 provides a community-based, open source tool for sharing tissue microarray (TMA) data in a common format. Each tissue core within an array has separate data including digital images; therefore an organized, common approach to produce, navigate and publish such data facilitates viewing, sharing and merging TMA data from different laboratories. The AIDS and Cancer Specimen Resource (ACSR) is a HIV/AIDS tissue bank consortium sponsored by the National Cancer Institute (NCI) Division of Cancer Treatment and Diagnosis (DCTD). The ACSR offers HIV-related malignancies and uninfected control tissues in microarrays (TMA) accompanied by de-identified clinical data to approved researchers. Exporting our TMA data into the proposed API specified format offers an opportunity to evaluate the API specification in an applied setting and to explore its usefulness.ResultsA document type definition (DTD) that governs the allowed common data elements (CDE) in TMA DES export XML files was written, tested and evolved and is in routine use by the ACSR. This DTD defines TMA DES CDEs which are implemented in an external file that can be supplemented by internal DTD extensions for locally defined TMA data elements (LDE).ConclusionACSR implementation of the TMA DES demonstrated the utility of the specification and allowed application of a DTD to validate the language of the API specified XML elements and to identify possible enhancements within our TMA data management application. Improvements to the specification have additionally been suggested by our experience in importing other institution's exported TMA data. Enhancements to TMA DES to remove ambiguous situations and clarify the data should be considered. Better specified identifiers and hierarchical relationships will make automatic use of the data possible. Our tool can be used to reorder data and add identifiers; upgrading data for changes in the specification can be automatically accomplished. Using a DTD (optionally reflecting our proposed enhancements) can provide stronger validation of exported TMA data.

Isolation and Characterization of Griffithsin, a Novel HIV-inactivating Protein, from the Red Alga Griffithsia sp.

Griffithsin (GRFT), a novel anti-HIV protein, was isolated from an aqueous extract of the red alga Griffithsia sp. The 121-amino acid sequence of GRFT has been determined, and biologically active GRFT was subsequently produced by expression of a corresponding DNA sequence in Escherichia coli. Both native and recombinant GRFT displayed potent antiviral activity against laboratory strains and primary isolates of T- and M- tropic HIV-1 with EC50 values ranging from 0.043 to 0.63 nM. GRFT also aborted cell-to-cell fusion and transmission of HIV-1 infection at similar concentrations. High concentrations (e.g. 783 nM) of GRFT were not lethal to any tested host cell types. GRFT blocked CD4-dependent glycoprotein (gp) 120 binding to receptor-expressing cells and bound to viral coat glycoproteins (gp120, gp41, and gp160) in a glycosylation-dependent manner. GRFT preferentially inhibited gp120 binding of the monoclonal antibody (mAb) 2G12, which recognizes a carbohydrate-dependent motif, and the (mAb) 48d, which binds to CD4-induced epitope. In addition, GRFT moderately interfered with the binding of gp120 to sCD4. Further data showed that the binding of GRFT to soluble gp120 was inhibited by the monosaccharides glucose, mannose, and N-acetylglucosamine but not by galactose, xylose, fucose, N-acetylgalactosamine, or sialic acid-containing glycoproteins. Taken together these data suggest that GRFT is a new type of lectin that binds to various viral glycoproteins in a monosaccharide-dependent manner. GRFT could be a potential candidate microbicide to prevent the sexual transmission of HIV and AIDS.

Prostate-specific antigen doubling time as a surrogate marker for evaluation of oncologic drugs to treat prostate cancer.

With more than 230,000 new cases each year in the United States, prostate cancer is the most common cancer diagnosed among American men [(1)][1] . Prostate cancer is expected to account for nearly 30,000 deaths in the United States in 2004 and consequently represents the second most common cause of

Workshop on partial breast irradiation: state of the art and the science, Bethesda, MD, December 8-10, 2002.

Breast conserving surgery followed by radiation therapy has been accepted as an alternative to mastectomy in the management of patients with early-stage breast cancer. Over the past decade there has been increasing interest in a variety of radiation techniques designed to treat only the portion of the breast deemed to be at high risk for local recurrence (partial-breast irradiation [PBI]) and to shorten the duration of treatment (accelerated partial-breast irradiation [APBI]). To consider issues regarding the equivalency of the various radiation therapy approaches and to address future needs for research, quality assurance, and training, the National Cancer Institute, Division of Cancer Treatment and Diagnosis, Radiation Research Program, hosted a Workshop on PBI in December 2002. Although 5- to 7-year outcome data on patients treated with PBI and APBI are now becoming available, many issues remain unresolved, including clinical and pathologic selection criteria, radiation dose and fractionation and how they relate to the standard fractionation for whole breast irradiation, appropriate target volume, local control within the untreated ipsilateral breast tissue, and overall survival. This Workshop report defines the issues in relation to PBI and APBI, recommends parameters for consideration in clinical trials and for reporting of results, serves to enhance dialogue among the advocates of the various radiation techniques, and emphasizes the importance of education and training in regard to results of PBI and APBI as they become emerging clinical treatments.

Clinical research in neutron capture therapy

A 1.5-day workshop to assess the current state of the science in neutron capture therapy (NCT) was convened at the request of the Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute and the U.S. Department of Energy. The topics were primarily clinical with physics, chemistry, and biology relevant to the immediate trials discussed. The morning of the first day was directed toward updates on epithermal neutron sources, the chemistry of medicinal boron compounds, and preclinical studies. In the afternoon, participants from Europe, Asia, and North America were invited to present their clinical experience with NCT. The participants then separated into breakout sessions. The following morning session included presentations and discussions of each breakout session. These are presented below. NCT was first proposed in 1936, just 4 years after the neutron itself was discovered. NCT is a unique form of radiotherapy that carries a potential for a significant improvement in therapeutic gain. The classification of neutrons into energy categories is somewhat arbitrary, but for the present purpose “thermal neutrons” have an energy 1 eV, “epithermal neutrons” have an energy between 1 eV and 10 KeV, and “fast neutrons” may be considered, for therapeutic purposes, to be in the megavoltage range. NCT is a form of binary therapy, similar to photodynamic therapy, in which neither the thermal neutrons nor the boron carrier molecule has significant cytotoxic effect but produces highly radiobiologically effective particles when the two interact. This is in contrast to the more familiar “fast neutrons,” which are highly radiobiologically effective by themselves. These reactions between a neutron carrier molecule such as boron-10 (B-10) and thermal neutrons produce He-4 and Li-7 ions of very high linear energy transfer (LET) but very short ( 10 m) range. This therapy was first studied in glioblastoma in 1951 using crude thermal neutron beams and B-10–enriched boric acid. Since then, NCT has been studied in several countries, usually with glioblastoma. The difficulties with NCT were, and continue to be, difficulty in finding appropriate neutron beams, a scarcity of suitable boron carrier agents, uncertain dosimetry, and a lack of rigorous and reproducible clinical trials. This workshop was convened to address these issues. These issues were divided into three broad topics: carrier agent development, preclinical studies, and clinical studies.

LACK OF RETROPERITONEAL LYMPHADENOPATHY PREDICTS SURVIVAL OF PATIENTS WITH METASTATIC RENAL CELL CARCINOMA

Patients with metastatic renal cell carcinoma have a reported 5-year survival of 0% to 20%. The ability to predict which patients would benefit from nephrectomy and interleukin-2 (IL-2) therapy before any treatment is initiated would be useful for maximizing the advantage of therapy and improving the quality of life. A retrospective analysis of the x-rays and charts of patients treated at the National Institutes of Health Surgery Branch between 1985 and 1996, who presented with metastatic renal cancer beyond the locoregional area and the primary tumor in place, was performed. Preoperative computerized tomography or magnetic resonance imaging, or radiological reports if no scans were available, were used to obtain an estimate of the volume of retroperitoneal lymphadenopathy. Operative notes were used to evaluate whether all lymphadenopathy was resected or disease left in situ, or if any extrarenal resection, including venacavotomy, was performed. Mean survival rate was calculated from the time of nephrectomy to the time of death or last clinical followup. If patients received IL-2 therapy, the response to treatment was recorded. Mean survival and response rate for IL-2 were compared among patients in 3 separate analyses. Patients without preoperatively detected lymphadenopathy were compared with those with at least 1 cm.3 retroperitoneal lymphadenopathy. Also, the patients who had detectable lymphadenopathy were divided into subgroups consisting of all resected, incompletely resected, unresectable and unknown if all disease was resected. Each subgroup was compared with patients without detectable preoperative lymphadenopathy. Patients with less than were compared to those with greater than 50 cm.3 retroperitoneal lymphadenopathy. Patients undergoing extrarenal resection at nephrectomy (complex surgery) due to direct invasion of the tumor into another intra-abdominal organ were compared with those undergoing radical nephrectomy alone, regardless of lymph node status. Statistical analysis was done with the Mantel-Cox test for comparison of survival on Kaplan-Meier curves and with Fisher's exact test for response rates for IL-2. A total of 154 patients with metastatic renal cell carcinoma underwent cytoreductive nephrectomy as preparation for IL-2 based regimens. There were 82 patients with metastatic renal cell carcinoma and no preoperative retroperitoneal lymphadenopathy who survived longer (median 14.7 months) than the 72 with lymphadenopathy (median 8.5, p = 0.0004). Patients with incompletely resected, unresectable or an unknown volume resected had decreased survival compared to those with no retroperitoneal lymphadenopathy. A multivariate analysis of survival was performed evaluating the known prognostic indicators, performance status and tumor burden, as represented by the number of organs involved with metastases, and the new prognostic factor, lymphadenopathy. Lymphadenopathy was more closely associated with survival than performance status, and appeared to be a new prognostic variable. Patients with and without retroperitoneal lymphadenopathy at initial presentation had similar rates for treatment with IL-2 (54% for both groups). Of the 82 patients with no lymphadenopathy 11 (13%) had long-term survival greater than 5 years. Of the 6 complete responses to IL-2, 5 occurred in this group. Only 1 other patient with incompletely resected retroperitoneal lymphadenopathy survived longer than 5 years. No significant difference in survival was seen between patients who did or did not undergo complex surgery. Patients who presented with metastatic renal cancer and retroperitoneal lymphadenopathy had a shorter survival than those with no detectable retroperitoneal lymphadenopathy. It is warranted to continue to perform complex extrarenal resection during nephrectomy since no significant difference in the response rate for IL-2 or mean survival compared with those of patients undergoing nephrectomy alone is currently detectable.

Training the next generation of imaging scientists and clinicians

Biomedical imaging is changing rapidly, and research in the field increasingly requires a multidisciplinary, molecular bio­ logic orientation. There is a critical need for imaging scien­ tists with training in molecular biology, engineering, com­ puter sciences, and related fields. The Biomedical Imaging Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute (NCI) does not sponsor or ad­ minister training grants directly, but it collaborates with the NCI Training Branch. The intent of this collaboration is to fa­ cilitate research training for the next generation of academic imaging experts and scientific investigators. During the past decade, the rapid development of molecu­ lar biologic techniques has revolutionized our basic under­ standing of human disease. In association with the develop­ ment of basic molecular biologic technologies there has been important development and evolution of computer, engineer­ ing, and analytical technologies. These developments have had a tremendous impact on the imaging sciences. Molecular, metabolic, and functional imaging allow clinicians and re­ searchers to study relevant cellular or molecular processes in vivo. These newly developed techniques allow visualization and quantitation of clinically relevant physiologic variables such as blood flow, oxygen consumption, glucose metabo­ lism, proliferative activity, or tissue hypoxia as they take

The Importance of ATP Binding and Hydrolysis by Hsp90 in Formation and Function of Protein Heterocomplexes

The chaperone hsp90 is capable of binding and hydrolyzing ATP. Using information on a related ATPase, DNA gyrase B, we selected three conserved residues in hsp90's ATP-binding domain for mutation. Two of these mutations eliminate nucleotide binding, while the third retains nucleotide binding but is apparently deficient in ATP hydrolysis. We first analyzed how these mutations affect hsp90's binding to the co-chaperones p23 and Hop, and to the hydrophobic resin, phenyl-Sepharose. These experiments showed that ATP's effects, specifically, increased affinity for p23 and decreased affinity for Hop and phenyl-Sepharose, are brought on by ATP binding alone. We also tested the ability of hsp90 mutants to assist hsp70, hsp40, and Hop in the refolding of denatured firefly luciferase. While hsp90 is capable of participating in this process in a nucleotide-independent manner, the ability to hydrolyze ATP markedly potentiates hsp90's effect. Finally, we assembled progesterone receptor heterocomplexes with hsp70, hsp40, Hop, p23, and wild type or mutant hsp90. While neither ATP binding nor hydrolysis was necessary to bind hsp90 to the receptor, mature complexes containing p23 and capable of hormone binding were only obtained with wild type hsp90.

Bombesin receptor structure and expression in human lung carcinoma cell lines: Fathi Z, Way JW, Coijay MH, Viallet J, Sausville EA, Battey JF. Laboratoy of Biological Chemistry, Division of Cancer Treatment, National Cancer Institute, Bethesda, MD 20892. J Cell Biochem 1996;62 Suppl. 24:237–246

Bombesin receptor structure and expression in human lung carcinoma cell lines: Fathi Z, Way JW, Coijay MH, Viallet J, Sausville EA, Battey JF. Laboratoy of Biological Chemistry, Division of Cancer Treatment, National Cancer Institute, Bethesda, MD 20892. J Cell Biochem 1996;62 Suppl. 24:237–246

CHANGES IN SKELETAL IMAGES INDUCED BY GRANULOCYTE- COLONY- STIMULATING FACTOR (G-CSF)

Dept. of Nuclear Medicine1, Clinical Center, and Medical Branch2, Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda MD.

The clinical development of paclitaxel: a successful collaboration of academia, industry and the National Cancer Institute.

The successful development of paclitaxel as an important new antineoplastic agent with the potential to have an impact on a number of human cancers was possible as a result of significant contributions from individuals and groups with diverse areas of interest and expertise. The advancement of paclitaxel through the preclinical and clinical evaluation which ultimately led to its approval, as well as surmounting the regulatory hurdles which were faced required the close collaboration of individual investigators at academic institutions, the pharmaceutical industry (Bristol-Myers Squibb) and the National Cancer Institute. The latter stages of this developmental effort can be viewed as a prime example of the potential of the Cooperative Research and Development Agreement (CRADA) mechanism to bring novel therapies to patients with serious illnesses in a timely fashion. It is also tangible evidence of the vision and perseverance of a number of members of the Division of Cancer Treatment (DCT) under the direction of Dr. Bruce Chabner, in whose honor this symposium is given.

Cytokines in the treatment of advanced melanoma

Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, MD 20854, USA

Patient treatment on a compassionate basis: documentation of high adverse drug reaction rate.

The special exception mechanism was established by the Division of Cancer Treatment (DCT), National Cancer Institute (NCI), for the provision of anticancer drugs not yet approved by the Food and Drug Administration (FDA) to patients on a compassionate basis. Strict guidelines have been established for the distribution of drugs through this mechanism and for the reporting of adverse drug reactions (ADRs) with investigational drugs. These guidelines have been used to format the data base which is maintained on all ADRs submitted by investigators. In this paper, the incidence of ADRs with the eleven investigational drugs most frequently administered on special exception protocols was determined for a twelve month time period, January 1, 1985 through December 31, 1985. On special exception protocols, the overall incidence rate of ADRs was significantly greater than that seen on research protocols for the time period. For three drugs, Methyl-G, DBD, and AMSA, the ADR incidence rate was seven to fifteen-fold greater on special exception protocols than on research protocols. In an analysis of all ADRs submitted to the FDA for the twelve months time period, no difference was found in the frequency of distribution of either types of adverse effects or the causal assessments of ADRs on special exception and research protocols.

Expression of CYP1A1 gene in patients with lung cancer: Evidence for cigarette smoke-induced gene expression in normal lung tissue and for altered gene regulation in primary pulmonary carcinomas : McLemore TL, Adelberg S, Liu MC et al. Program Development Research Group, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, MD. J Natl Cancer Inst 1990 82;1333–1339

Expression of CYP1A1 gene in patients with lung cancer: Evidence for cigarette smoke-induced gene expression in normal lung tissue and for altered gene regulation in primary pulmonary carcinomas : McLemore TL, Adelberg S, Liu MC et al. Program Development Research Group, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, MD. J Natl Cancer Inst 1990 82;1333–1339