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Biomedical subjects

M A Morse

Publications and source records attributed to M A Morse.

At least 19 recordsLinked to original sources
PubMed2001

The p85 subunit of phosphoinositide 3-kinase is associated with beta-catenin in the cadherin-based adhesion complex.

Cell adhesion is fundamental to establishing and maintaining the discrete tissues in multicellular organisms. Adhesion must be sufficiently strong to preserve tissue architecture, whilst having the capacity to readily dissociate to permit fundamental processes, such as wound repair, to occur. However, very little is known about the signalling mechanisms involved in temporary down-regulation of cell adhesion to facilitate such processes. Cadherins are the principal mediators of cell-cell adhesion in a wide variety of tissues and species and form multi-protein complexes with cytosolic and cytoskeletal proteins to express their full adhesive capacity. In the present study we report that the p85 subunit of phosphoinositide 3-kinase (PI 3-kinase) is associated with the cadherin-based adhesion complex in human epithelial cells. The interaction of p85 with the complex is via beta-catenin. We also show that the interaction of p85 and beta-catenin is direct, involves the N-terminal Src homology domain 2 of p85 and is regulated by tyrosine phosphorylation. These data suggest that PI 3-kinase may play a role in the functional regulation of the cadherin-based adhesion complex.

Animals↗
PubMed2001

Chemoprevention of esophageal tumorigenesis by dietary administration of lyophilized black raspberries.

Fruit and vegetable consumption has consistently been associated with decreased risk of a number of aerodigestive tract cancers, including esophageal cancer. We have taken a "food-based" chemopreventive approach to evaluate the inhibitory potential of lyophilized black raspberries (LBRs) against N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in the F344 rat, during initiation and postinitiation phases of carcinogenesis. Anti-initiation studies included a 30-week tumorigenicity bioassay, quantification of DNA adducts, and NMBA metabolism study. Feeding 5 and 10% LBRs, for 2 weeks prior to NMBA treatment (0.25 mg/kg, weekly for 15 weeks) and throughout a 30-week bioassay, significantly reduced tumor multiplicity (39 and 49%, respectively). In a short-term bioassay, 5 and 10% LBRs inhibited formation of the promutagenic adduct O(6)-methylguanine (O(6)-meGua) by 73 and 80%, respectively, after a single dose of NMBA at 0.25 mg/kg. Feeding 5% LBRs also significantly inhibited adduct formation (64%) after NMBA administration at 0.50 mg/kg. The postinitiation inhibitory potential of berries was evaluated in a second bioassay with sacrifices at 15, 25, and 35 weeks. Administration of LBRs began after NMBA treatment (0.25 mg/kg, three times per week for 5 weeks). LBRs inhibited tumor progression as evidenced by significant reductions in the formation of preneoplastic esophageal lesions, decreased tumor incidence and multiplicity, and reduced cellular proliferation. At 25 weeks, both 5 and 10% LBRs significantly reduced tumor incidence (54 and 46%, respectively), tumor multiplicity (62 and 43%, respectively), proliferation rates, and preneoplastic lesion development. Yet, at 35 weeks, only 5% LBRs significantly reduced tumor incidence and multiplicity, proliferation indices and preneoplastic lesion formation. In conclusion, dietary administration of LBRs inhibited events associated with both the initiation and promotion/progression stages of carcinogenesis, which is promising considering the limited number of chemopreventives with this potential.

Animals↗
PubMed2001

Effects of dietary N-(4-hydroxyphenyl)retinamide on N-nitrosomethylbenzylamine metabolism and esophageal tumorigenesis in the Fischer 344 rat.

BACKGROUND: 9-cis-Retinoic acid (9-cis-RA) and N-(4-hydroxyphenyl)retinamide (4-HPR) are effective chemopreventive agents against epithelial tumors in the oral cavity, breast, and prostate. We tested the inhibitory activity of these retinoids against N-nitrosomethylbenzylamine (NMBA)-induced tumorigenesis in the rat esophagus. METHODS: Male Fischer 344 rats were randomly assigned to receive diets either lacking or containing 9-cis-RA or 4-HPR for 1 week before tumor initiation with NMBA and then for the duration of the study. NMBA metabolism, O(6)-methylguanine adduct formation, and cytochrome P450 messenger RNA (mRNA) expression in the esophagi of the rats were studied to investigate the mechanisms by which dietary 4-HPR affects tumorigenesis. All statistical tests were two-sided. RESULTS: Dietary 4-HPR resulted in a dose-dependent and statistically significant enhancement (P<.05) of tumorigenesis in response to NMBA. In two different tumor bioassays, the mean tumor multiplicity for rats fed the highest concentration of dietary 4-HPR (0.8 g/kg diet) was increased by 5.9 tumors (95% confidence interval [CI] = 1.7 to 10.1 tumors) and 6.7 tumors (95% CI = 5.6 to 7.8 tumors) compared with the mean tumor multiplicity for rats that received the control diet lacking 4-HPR. Animals fed diets containing 9-cis-RA displayed no statistically significant increase in tumorigenesis. Compared with animals fed a diet lacking 4-HPR, animals fed 4-HPR had increased NMBA metabolism in esophageal explant cultures and had higher levels of O(6)-methylguanine DNA adducts and CYP2A3 mRNA in their esophagi. CONCLUSIONS: Dietary 4-HPR enhances tumorigenesis in response to NMBA in the rat esophagus by increasing tumor initiation events. Dietary 4-HPR may exert paradoxical effects at some sites, such as the aerodigestive tract, by modulating the bioactivation of carcinogens in target tissues.

Alitretinoin↗
PubMed2001

Monitoring and ensuring safety during clinical research.

Increased numbers of clinical trials, many of which are large, multicenter, and sometimes international, and the marked shift of funding for clinical trials to industry have made apparent the inadequacy of mechanisms for protecting human subjects that were developed when clinical research was generally carried out on a small scale at single institutions. To address concerns regarding the protection of human subjects, a group of professionals with expertise in various aspects of clinical trials was assembled in May 2000. Participants described and evaluated the mechanisms by which clinical trials are monitored, focusing on adverse event reporting and the processes by which various parties with oversight responsibilities interact in the course of these trials. In this article, we describe the manner in which adverse event reporting might function to enhance safety and the role of data monitoring committees in using aggregate data from these reports, outline the problems that now exist for institutional review boards as they are faced with multiple adverse event reports from clinical trials while conducting continuing review, and offer recommendations for improving the current approach.

Clinical Trials as Topic↗
PubMed2001

Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer.

Dysfunction in the physiological pathways of programmed cell death may promote proliferation of malignant cells, and correction of such defects may selectively induce apoptosis in cancer cells. We measured the levels of ceramide, a candidate lipid mediator of apoptosis, in human metastatic colorectal cancer and tested in vitro and in vivo effects of various ceramide analogues in inducing apoptosis in metastatic colon cancer. Human colon cancer showed a > 50% decrease in the cellular content of ceramide when compared with normal colon mucosa. Application of ceramide analogues and ceramidase inhibitors induced rapid cell death through activation of various proapoptotic molecules, such as caspases and release of cytochrome c. Ceramidase inhibition increases the ceramide content of tumor cells, resulting in maximum activation of the apoptotic cascade. Normal liver cells were completely resistant to inhibitors of ceramidases. Treatment of nude mice with B13, the most potent ceramidase inhibitor, completely prevented tumor growth using two different aggressive human colon cancer cell lines metastatic to the liver. Therefore, B13 and related analogues of ceramide and inhibitors of ceramidases offer a promising therapeutic strategy with selective toxicity toward malignant but not normal cells. These studies also suggest that the ceramide content in cancer cells might be involved in the pathogenesis of tumor growth in vitro and in vivo.

Amides↗
PubMed2001

Investigation of the enhancement of N-nitrosomethylbenzylamine-induced esophageal tumorigenesis by 6-phenylhexyl isothiocyanate.

Previous studies in our laboratory have shown that 6-phenylhexyl isothiocyanate (PHITC), enhances N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in F344 rats while the shorter chain analogs, phenylethyl isothiocyanate (PEITC), and 3-phenylpropyl isothiocyanate (PPITC), inhibit NMBA-induced esophageal tumorigenesis. To test the hypothesis that PHITC influences the promotional stage of esophageal tumorigenesis, groups of 22-27 rats were dosed with vehicle or NMBA three times a week for 5 week, and fed a modified AIN-76A diet containing PHITC at concentrations of 0.0, 1.0, and 2.5 micromol/g. At the 25th week, the rats were killed, esophagi harvested and tumors counted. In the groups that received NMBA+PHITC, apparent but statistically insignificant increases in tumor multiplicity of 32 and 42% were found in comparison to rats treated with NMBA alone. A higher frequency of dysplastic lesions was found in rats treated with NMBA+2.5 micromol/g PHITC (71%) when compared to rats treated with NMBA only (12%). To test whether PHITC increased cellular proliferation, we evaluated proliferating cell nuclear antigen (PCNA) expression by immunohistochemistry. While there were no significant increases in PCNA staining in rats treated with NMBA+PHITC compared to rats treated with NMBA only, rats treated with PHITC only had a significantly higher PCNA index compared to untreated controls. Expression of cyclin D1, another biomarker of proliferation, was analyzed by semi-quantitative reverse transcription-polymerase chain reaction. There were no significant increases in cyclin D1 expression in groups treated with NMBA+PHITC compared to the group treated with NMBA only. Thus, while the data suggest a promotional effect by PHITC as manifested by a significant increase in dysplastic leukoplakia by the high dose of PHITC and an increase in the PCNA index by PHITC alone, PHITC does not appear to have a significant effect on esophageal cell proliferation.

Animals↗
PubMed2001

Neoadjuvant chemoradiation for localized adenocarcinoma of the pancreas.

BACKGROUND: The use of neoadjuvant (preoperative) chemoradiotherapy (CRT) for pancreatic cancer has been advocated for its potential ability to optimize patient selection for surgical resection and to downstage locally advanced tumors. This article reports our experience with neoadjuvant CRT for localized pancreatic cancer. METHODS: Since 1995, 111 patients with radiographically localized, pathologically confirmed pancreatic adenocarcinoma have received neoadjuvant external beam radiation therapy (EBRT; median, 4500 cGy) with 5-flourouracil-based chemotherapy. Tumors were defined as potentially resectable (PR, n = 53) in the absence of arterial involvement and venous occlusion and locally advanced (LA, n = 58) with arterial involvement or venous occlusion by CT. RESULTS: Five patients (4.5%) were not restaged due to death (n = 3) or intolerance of therapy (n = 2). Twenty-one patients (19%) manifested distant metastatic disease on restaging CT. Twenty-eight patients with initially PR tumors (53%) and 11 patients with initially LA tumors (19%) were resected after CRT. Histologic examination revealed significant fibrosis in all resected specimens and two complete responses. Surgical margins were negative in 72%, and lymph nodes were negative in 70% of resected patients. Median survival in resected patients has not been reached at a median follow-up of 16 months. CONCLUSIONS: Neoadjuvant CRT provided an opportunity for patients with occult metastatic disease to avoid the morbidity of resection and resulted in tumor downstaging in a minority of patients with LA tumors. Survival after neoadjuvant CRT and resection appears to be at least comparable to survival after resection and adjuvant (postoperative) CRT.

Adenocarcinoma↗
PubMed2001

Direct detection of cellular immune responses to cancer vaccines.

The evaluation of cancer immunotherapy is predicated on the hypothesis that markers of tumor antigen-specific T-cell immunity will cone-late with clinical efficacy. Establishing which candidate vaccines should enter large-scale clinical trials will necessitate optimal application of immunologic monitoring assays. Evidence suggests that available techniques are adequate for the direct detection of clinically significant antigen-specific T-cell responses from tissue specimens. To achieve this goal, it is important to have an understanding of individual methods and their limitations, to include appropriate control antigens in the monitoring strategy, and to incorporate statistical considerations into the design and analysis of such studies.

Cancer Vaccines↗
PubMed2001

Inhibition of N-nitrosomethylbenzylamine-induced tumorigenesis in the rat esophagus by dietary freeze-dried strawberries.

In the present study, we examined the ability of dietary freeze-dried strawberries to inhibit N-nitrosomethylbenzylamine (NMBA)-induced tumorigenesis in the rat esophagus. Initially, we conducted a bioassay to determine the effects of dietary freeze-dried strawberries on esophageal tumor development. Two weeks prior to NMBA treatment, animals were placed on a control diet or diets containing 5 and 10% freeze-dried strawberries. NMBA treatment was once per week for 15 weeks. At 30 weeks, 5 and 10% freeze-dried strawberries in the diet caused significant reductions in esophageal tumor multiplicity of 24 and 56%, respectively. Based on these results, we conducted studies to determine potential mechanisms by which freeze-dried strawberries inhibit tumorigenesis. In a short-term bioassay, we evaluated the effects of dietary freeze-dried strawberries on the formation of O6-methylguanine in the rat esophagus. Animals were placed on control diet or diets containing 5 and 10% freeze-dried strawberries for two weeks. At the end of this period, animals received a single subcutaneous dose of NMBA and were killed 24 h later. A significant decrease in O6-methylguanine levels was observed in the esophageal DNA of animals fed strawberries, suggesting that one or more components in strawberries influence the metabolism of NMBA to DNA-damaging species. Finally, in order to evaluate post-initiation effects, we conducted a study where freeze-dried strawberries were administered in the diet only following NMBA treatment. Animals were placed on control diet and dosed with NMBA three times per week for 5 weeks. Immediately following NMBA treatment, animals were placed on control diet or diets containing 5 and 10% freeze-dried strawberries. At 25 weeks, 5 and 10% freeze-dried strawberries in the diet significantly reduced tumor multiplicity by 38 and 31%, respectively. Our data suggest that dietary freeze-dried strawberries effectively inhibit NMBA-induced tumorigenesis in the rat esophagus.

Animals↗
PubMed2001

Molecular basis for cell tropism of CXCR4-dependent human immunodeficiency virus type 1 isolates.

Laboratory isolates of human immunodeficiency virus type 1 (HIV-1) that utilize CXCR4 as a coreceptor infect primary human macrophages inefficiently even though these express a low but detectable level of cell surface CXCR4. In contrast, infection of primary macrophages by primary CXCR4-tropic HIV-1 isolates is readily detectable. Here, we provide evidence suggesting that this difference in cell tropism results from a higher requirement for cell surface CXCR4 for infection by laboratory HIV-1 isolates. Transfected COS7 cells that express a high level of CD4 but a low level of CXCR4 were infected significantly more efficiently by two primary CXCR4-tropic HIV-1 isolates compared to the prototypic laboratory HIV-1 isolate IIIB. More importantly, overexpression of either wild-type or signaling-defective CXCR4 on primary macrophages dramatically enhanced the efficiency of infection by the laboratory HIV-1 isolate yet only modestly enhanced infection by either primary CXCR4-tropic virus. Overexpression of CD4 had, in contrast, only a limited effect on macrophage infection by the laboratory HIV-1, although infection by the primary isolates was markedly enhanced. We therefore conclude that the laboratory CXCR4-tropic HIV-1 isolate exhibits a significantly higher CXCR4 requirement for efficient infection than do the primary CXCR4-tropic isolates and that this difference can explain the poor ability of the laboratory HIV-1 isolate to replicate in primary macrophages. More generally, we propose that the cell tropisms displayed by different strains of HIV-1 in culture can largely be explained on the basis of differential requirements for cell surface CD4 and/or coreceptor expression levels.

Animals↗
PubMed2001

Surrogate markers of response to cancer immunotherapy.

Clinically effective cancer immunotherapy has been sought for more than 100 years and has been recently applied most successfully in strategies that passively deliver immune effectors such as monoclonal antibodies (anti-CD20 for lymphoma and anti-HER2/neu for breast cancer), donor lymphocyte infusions in chronic myelongenous leukemia and non-myeloablative allogeneic peripheral blood progenitor transplants for renal cell carcinoma. There is mounting enthusiasm for strategies employing active stimulation of antitumour immune responses. These include vaccines based on tumour antigen proteins and peptides, autologous, allogeneic or gene-modified tumour cells, dendritic cells and antigen-encoding viral vector constructs. Indeed, randomised Phase III clinical trials of autologous tumour cell vaccines for colorectal cancer demonstrated an improvement in disease free survival and a trend toward improved overall survival [1]. Despite these preliminary successes, it is clear that the many strategies under development cannot all be evaluated for survival benefit in large clinical trials that require many years, patients and resources to complete. This highlights the need to develop intermediate markers to help prioritise which agents to test in prospective randomised Phase III trials.

Biomarkers↗
PubMed2001

Technology evaluation: BLP-25, Biomira Inc.

Biomira is developing the MUC-1 peptide-based vaccine BLP-25 for the potential treatment of cancer. It is in phase II trials for non-small cell lung cancer (NSCLC) [335997], [353448], [384703]. The MUC-1 mucin secreted by cancer cells has been shown to decrease the activity of certain immune response cells, including killer T-cells, and can inhibit the immune T-cell response by > 70%. BLP-25 is designed to target an immune response to the MUC-1 mucin that is shown by > 90% of common solid tumors. The introduction of IL-2 reverses the T-cell suppression caused by MUC-1 mucin, and enhances the cellular immune response > 100-fold. Biomira has been incorporating IL-2 into a liposomal delivery system for BLP-25 [274576]. In late 1998, Biomira entered into a research collaboration with Axis Genetics. The collaboration will assess the further potential of therapeutic cancer vaccines against MUC-1. Each company has developed a vaccine targeting the MUC-1 peptide and Biomira will be evaluating Axis's vaccine in preclinical trials [313395]. In December 1996, Biomira signed a licensing agreement whereby it was granted the rights to use Dana-Farber Cancer Institute's two US patents relating to MUC-1 (based on pioneering work at the Institute on the identification of cell-surface molecules that are characteristic of cancer cells) for peptide-based cancer vaccines [228101].

Amino Acid Sequence↗
PubMed2001

Monitoring cellular immune responses to cancer immunotherapy.

Many clinical trials are testing the feasibility of stimulating the immune system to treat cancer. Although the efficacy of this approach will ultimately be determined by clinically relevant endpoints, detection of the magnitude and activity of the immune response is an important intermediate point in the development of these strategies. Assays that predict clinically relevant endpoints are particularly desirable for helping to determine which strategies should ultimately be tested in larger randomized clinical trials. In this review, we will discuss these cellular immunological assays and the current status of their role in clinical trials of immunotherapy.

Animals↗
PubMed2001

Technology evaluation: VEGF165 gene therapy, Valentis Inc.

Valentis Inc, formerly GeneMedicine, is developing a vascular endothelial growth factor (VEGF165) non-viral gene therapy using its proprietary PINC polymer for plasmid condensation. Two physician-initiated phase II angioplasty trials are ongoing, one for treating peripheral vascular disease and one for treating coronary artery disease [281714], [347153]. In February 2000, the trials were expected to be completed in the fourth quarter of 2000 [356225]; however, in October 2000, it was reported that the trial for peripheral vascular disease would be completed in the first quarter of 2001 [385232]. In March 2000, Valentis initiated a trial incorporating Valentis's DOTMA-based cationic lipid gene delivery system and the VEGF165 gene with Eurogene's local collar-reservoir delivery device. The trial is designed to demonstrate that the VEGF165 gene, delivered locally to the outside surface of a blood vessel, will transfect and express in the smooth muscle cells of the vessel wall [360683]. In March 1999, Valentis was awarded with a Phase II SBIR grant of $686,260. The aim of grant was to advance the development of non-viral gene therapies for ischemia. Specifically, Valentis intended to select an optimal promoter to be used with the VEGF expression plasmid. Valentis also intended to evaluate the gene therapy system in a rabbit ischemia model and complete the necessary preclinical studies for submission of an IND [318137].

Angioplasty↗
PubMed2001

Assays for monitoring cellular immune responses to active immunotherapy of cancer.

Numerous cancer immunotherapy strategies are currently being tested in clinical trials. Although clinical efficacy will be the final test of these approaches, the long and complicated developmental pathway for these agents necessitates evaluating immunological responses as intermediate markers of the most likely candidates for success. This has emphasized the need for assays that accurately detect and quantitate T cell-mediated, antigen-specific immune responses. This review evaluates the currently used in vivo and in vitro methods of assessing T-cell number and function, including delayed-type hypersensitivity, tetramer analysis, ELISPOT, flow cytometry-based analysis of cytokine expression, and PCR-based detection of T-cell receptor gene usage or cytokine production. We provide examples of how each has been used to monitor recent clinical trials and a discussion of how well each correlates with clinical outcome.

Cytokines↗
PubMed2001

Technology evaluation: CEA-TRICOM, Therion Biologics Corp.

Therion Biologics, the NCI and Aventis Pasteur are investigating CEA-TRICOM, a recombinant, pox virus-based vaccine that incorporates a triple dose of costimulatory molecules as well as the carcinoembryonic antigen (CEA) tumor antigen, for the potential treatment of colorectal cancer. CEA-TRICOM is designed to stimulate and strengthen the body's immune system to kill colorectal cancer cells. CEA-TRICOM is administered in a priming and boosting protocol using two unique pox virus vectors, rV-CEA-TRICOM (recombinant vaccinia vector) and rF-CEA-TRICOM (recombinant fowlpox vector). The TRICOM component of both rV-CEA-TRICOM and rF-CEA-TRICOM comprises three costimulatory molecule transgenes (B7-1, ICAM-1 and LFA-3) [414643], [414645], known to elicit strong cellular immune responses necessary for complete tumor destruction. In preclinical studies conducted by the NCI and Therion, researchers have demonstrated that this combination of three costimulatory molecules dramatically boosts the immune response to eradicate cancer in murine models [399610], [414631]. In February 2001, Therion Biologics and the NCI initiated a phase I trial of CEA-TRICOM [399610]. The phase I trial of CEA-TRICOM is designed to demonstrate proof-of-principle for using multiple costimulatory molecules in conjunction with a tumor antigen to improve the strength of cellular immune responses. It is a multistage, dose-escalation study that will assess the safety and immunologic effects of CEA-TRICOM in up to 42 patients who have advanced metastatic colorectal cancer. Subjects will receive rF-CEA-TRICOM alone, rV-CEA-TRICOM followed by booster vaccinations with rF-CEA-TRICOM or rV-CEA-TRICOM followed by rF-CEA-TRICOM and GM-CSF adjuvant. The primary measure of immune response will be the level of CEA-specific T-cells stimulated by vaccination, with levels of CEA-expressing tumor cells in the blood used as a potential secondary measure of treatment effect [399610].

Carcinoembryonic Antigen↗