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Biomedical subjects

James L Mulshine

Publications and source records attributed to James L Mulshine.

At least 19 recordsLinked to original sources
PubMed2006

Ingenuity network-assisted transcription profiling: Identification of a new pharmacologic mechanism for MK886.

The small molecular inhibitor MK886 is known to block 5-lipoxygenase-activating protein ALOX5AP and shows antitumor activity in multiple human cell lines. The broad antitumor therapeutic window reported in vivo for MK886 in rodents supports further consideration of this structural class. Better understanding of the mode of action of the drug is important for application in humans to take place. Affymetrix microarray study was conducted to explore MK886 pharmacologic mechanism. Ingenuity Pathway Analysis software was applied to validate the results at the transcriptional level by putting them in the context of an experimental proteomic network. Genes most affected by MK886 included actin B and focal adhesion components. A subsequent National Cancer Institute-60 panel study, RT-PCR validation followed by confocal microscopy, and Western blotting also pointed to actin B down-regulation, filamentous actin loss, and disorganization of the transcription machinery. In agreement with these observations, MK886 was found to enhance the effect of UV radiation in H720 lung cancer cell line. In light of the modification of cytoskeleton and cell motility by lipid phosphoinositide 3-kinase products, MK886 interaction with actin B might be biologically important. The low toxicity of MK886 in vivo was modeled and explained by binding and transport by dietary lipids. The rate of lipid absorbance is generally higher for tumors, suggesting a promise of a targeted liposome-based delivery system for this drug. These results suggest a novel antitumor pharmacologic mechanism.

Actins↗
PubMed2006

Lung cancer screening.

Advances in imaging technology have ushered in a new era for lung cancer screening in high-risk individuals using computed tomographic (CT) scans. Although most published studies are nonrandomized observational cohorts of volunteers, the ability of CT scans to detect early stage lung cancer is undisputable. What is unresolved is the ability of spiral CT screening to affect lung cancer-related mortality. A large randomized trial sponsored by the National Cancer Institute to address this question is currently under way. Genomic and proteomic approaches promise to complement the ability of spiral CT to detect early lung cancer in the next few years. Currently, the decision to screen for lung cancer should involve a careful discussion with the individuals involved about the potential advantages, costs, and drawbacks of the approach.

Cost-Benefit Analysis↗
PubMed2005

Clinical issues in the management of early lung cancer.

Lung cancer is commonly diagnosed after metastatic spread, when therapies are rarely curative, providing an impetus for continued research directed at exploring approaches for cost-effective early lung cancer detection. Recently published pilot studies across three continents support a benefit of spiral computed tomography (CT) in detecting earlier stage non-small cell lung cancer. Improved resolution of early lung cancer is a result of significant changes in CT imaging hardware and software. The status and implications of these developments are reviewed. Many aspects of the management of screening for early lung cancer could be informed by optimizing the downstream clinical management of potential lung cancers identified by CT screening. The first and most critical issue is whether or not this improved detection rate is clearly associated with a reduction in lung cancer-related mortality. However, other related issues such as cost-benefit evaluations are also considered. If smaller, truly localized primary cancer can be routinely detected, then options for less morbid interventions would also be desirable. The rapid improvement in resolution and cost of spiral CT has provided a powerful impetus to reconsider the possibilities for achieving safe, economical, and meaningful early lung cancer detection.

Carcinoma, Non-Small-Cell Lung↗
PubMed2005

Inhibitors of the arachidonic acid pathway and peroxisome proliferator-activated receptor ligands have superadditive effects on lung cancer growth inhibition.

Arachidonic acid (AA) metabolizing enzymes and peroxisome proliferator-activated receptors (PPARs) have been shown to regulate the growth of epithelial cells. We have previously reported that exposure to the 5-lipoxygenase activating protein-directed inhibitor MK886 but not the cyclooxygenase inhibitor, indomethacin, reduced growth, increased apoptosis, and up-regulated PPARalpha and gamma expression in breast cancer cell lines. In the present study, we explore approaches to maximizing the proapoptotic effects of PPARgamma on lung cancer cell lines. Non-small-cell cancer cell line A549 revealed dose-dependent PPARgamma reporter activity after treatment with MK886. The addition of indomethacin in combination with MK886 further increases reporter activity. We also show increased growth inhibition and up-regulation of apoptosis after exposure to MK886 alone, or in combination with indomethacin and the PPAR ligand, 15-deoxy-Delta12,14-prostaglandin J2 compared with single drug exposures on the adenocarcinoma cell line A549 and small-cell cancer cell lines H345, N417, and H510. Real-time PCR analyses showed increased PPAR mRNA and retinoid X receptor (RXR)alpha mRNA expression after exposure to MK886 and indomethacin in a time-dependent fashion. The results suggest that the principal proapoptotic effect of these drugs may be mediated through the known antiproliferative effects of the PPARgamma-RXR interaction. We therefore explored a three-drug approach to attempt to maximize this effect. The combination of low-dose MK886, ciglitazone, and 13-cis-retinoic acid interacted at least in a superadditive fashion to inhibit the growth of lung cancer cell lines A549 and H1299, suggesting that targeting PPARgamma and AA action is a promising approach to lung cancer growth with a favorable therapeutic index.

Acetophenones↗
PubMed2005

New developments in lung cancer screening.

Lung cancer is the most lethal cancer in our society. Late diagnosis of this disease is a major problem and so recent favorable reports with spiral computed tomography screening of high-risk populations have rekindled interest in improving early lung cancer detections. The process of lung cancer screening is a complicated process that involves many component activities. Interest to date has heavily focused on the initial case identification, but more recent reports have suggested that the issues with case work-up and surgical management also bear closer consideration. Given the dynamic nature of spiral computed tomography scan development and the remarkable improvements in imaging resolution over the last decade, there is an urgent need for research to establish optimal clinical management of early lung cancer detected in a screening setting.

Humans↗
PubMed2005

cDNA expression profiling reveals elevated gene expression in cell clusters overlying focally disrupted myoepithelial cell layers: implications for breast tumor invasion.

BACKGROUND: Our previous studies revealed that a subset of mammary ductal carcinoma in situ (DCIS) contained focally disrupted myoepithelial (ME) cell layers that were predominantly overlain by estrogen receptor (ER) negative cells, which showed a substantially higher rate of cell proliferation and genetic alterations than adjacent ER positive cells within the same duct. This study attempted to assess whether these cells also had a different expression profile on tumor progression related genes. DESIGN: Consecutive sections were made from frozen tissues of 30 DCIS with focally disrupted ME cell layers and associated ER negative cell clusters. ER negative and adjacent ER positive cells within the same duct were microdissected for RNA extraction and amplification. Amplified RNA was converted to biotin-labeled cDNAs and interrogated with 'Cancer PathwayFinder' arrays. RESULTS: Cells within each or among ER negative clusters were immunohistochemically and morphologically similar, whereas they differed substantially from adjacent cells within the same duct. Of 20-paired informative ER negative and positive cells, 15 genes were differentially expressed. Of which, 11(73.3%) were higher in ER negative, 2 (13.3%) were higher in ER positive, and 2 (13.3%) were equal in these cells (p <0.01). Of 11 up-regulated genes in ER negative cells, 8 indirectly or directly promote proliferation and progression, and 3 promote apoptosis. CONCLUSION: ER negative cell clusters showed a significantly higher expressing frequency of multiple tumor progression related genes than their adjacent ER positive counterparts, suggesting that they are likely to be biologically more aggressive and have a greater potential for invasion.

Breast Neoplasms↗
PubMed2005

A subset of in situ breast tumor cell clusters lacks expression of proliferation and progression related markers but shows signs of stromal and vascular invasion.

BACKGROUND: Our previous studies in pre-invasive mammary tumors revealed that estrogen receptor negative cell clusters (ER NCC) overlying focally disrupted myoepithelial (ME) cell layers showed a significantly higher rate of genetic abnormalities and cell proliferation than adjacent cells without ME cell layer disruptions. A subset of these ER NCC, however, completely lacked expression of Ki-67, a most commonly used marker for cell proliferation. The purpose of this study was to further elucidate the immunohistochemical and morphological profiles of these ER NCC. METHODS: Fifteen cases with such ER NCC were selected from our previous studies and assessed with a panel of commonly used biomarkers for cell proliferation, tumor progression, and normal stem cells. RESULTS: Immunohistochemically, in addition to Ki-67 and ER, these ER NCC completely lacked expression of all other proliferation and progression related markers that were distinctly expressed in adjacent cells within the same duct but overlying the non-disrupted ME cell layer. These ER NCC also lacked expression of all normal stem cell-related markers tested. These cell clusters, however, showed a higher and atypical expression of c-erb-B2, compared to their adjacent counterparts. Morphologically, these ER NCC were generally arranged as triangle shaped structures penetrating into the stroma, similar to micro-invasive lesions. About 15% of these ER NCC appeared to directly spread into blood vessel-like structures. These ER NCC and their possible derivatives within the stroma and blood vessels-like structures shared the same morphologic and immunohistochemical features. No comparable ER positive cell clusters were identified in any of the cases. CONCLUSIONS: These findings suggest that these ER NCC and their possible derivatives are likely regulated by yet to be defined molecules and mechanisms, and they are unlikely to respond to currently available anti-mitotic agents.

Biomarkers, Tumor↗
PubMed2005

Current issues in lung cancer screening.

Despite improvements in drug therapy, late-stage lung cancer remains routinely incurable. The field of screening for early lung cancer is a challenging, fast-moving, cross-disciplinary area, not without controversy. The ideal situation is one in which we approach screening proactively to allow it to mature as a public health strategy. Spiral CT screening for lung cancer is a new and promising approach to thoracic imaging; it allows for a much more rapid and comprehensive evaluation of a structure than the original CT scan. In this review we will discuss issues inherent to the lung cancer screening process, including the value of smoking cessation strategies, the challenge with the rapid pace of developments in the field, cost concerns, consideration of biases in trial design (overdiagnosis, for example), overtreatment, and radiation risk. We discuss recommendations from several organizations, such as the US Preventive Services Task Force and the American Cancer Society.

Humans↗
PubMed2004

Randomized, double-blind, placebo-controlled phase IIb trial of the cyclooxygenase inhibitor ketorolac as an oral rinse in oropharyngeal leukoplakia.

PURPOSE: Nonselective cyclooxygenase (COX) inhibitors have been reported to decrease the frequency of upper aerodigestive cancers. Ketorolac tromethamine oral rinse has been shown to resolve another COX-dependent process, periodontal disease, without incurring gastrointestinal side effects. This trial evaluated if a topically delivered oral rinse containing ketorolac was as safe as and more effective than oral rinse alone in reducing the area of oral leukoplakia. EXPERIMENTAL DESIGN: 57 patients were randomized (2:1 ratio) in a double-blind, placebo-controlled study of ketorolac (10 ml of a 0.1% ketorolac rinse solution; n = 38) or placebo (10 ml of rinse solution; n = 19) given twice daily for 30 s over 90 days. Primary end point was evaluated visually obtaining bidimensional measurement of the size of leukoplakia lesion(s) at entry and at 90 days. Secondary end point was histological assessment of the leukoplakia as sampled by serial punch biopsy and independently reviewed by three pathologists. RESULTS: The patients included 67% males, 11% non-Caucasian, and 86% used tobacco with no significant differences between the two arms. Both rinses were well tolerated with good compliance, and there was no significant difference in adverse events (P = 0.27). Major response rate (complete response and partial response) was 30% for ketorolac and 32% for the placebo arm. There was no significant difference in change in histology between the two arms. CONCLUSION: Local delivery of a COX-containing oral rinse was well tolerated but produced no significant reduction in the extent of leukoplakia compared with the placebo. However, the favorable response rate to placebo arm remains unexplained and additional investigation of the tissue penetration with ketorolac is warranted.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

Epithelial-directed drug delivery: influence of formulation and delivery devices.

Technology to deliver drugs reliable throughout the entire respiratory tract has greatly improved in part because of asthma- and infectious disease-related applications. Recent improvements with spiral CT technology applied to detect early lung cancer in high risk populations have also enhanced the prospect of finding locally confined primary lung cancers. In this setting, the need to safely and economically manage the local regional phase of early lung cancer is assuming great strategic importance. At the same time the growing knowledge regarding the molecular and biochemical events driving the progression of lung cancer is allowing the development of targeted drug that may be useful in arresting lung cancer progression. The questions considered in this forum is whether improvements in these areas are sufficiently mature to allow application of local regional drug delivery with targeted drug agents to improve the management of early lung cancer.

Antineoplastic Agents↗
PubMed2004

Lung cancer screening with spiral CT: toward a working strategy.

Given that there is no validated test for early lung cancer detection, the current standard approach to lung cancer detection is to wait for signs or symptoms to develop. In that setting, newly detected lung cancer is generally rapidly fatal resulting in over 157,000 deaths annually. Sole dependence on tobacco control is an insufficient public health response to lung cancer, since most newly diagnosed individuals are either former smokers or never smokers. Finding a more effective way to diagnose premetastatic lung cancer would be a crucial step toward an improved lung cancer-related mortality rate. Based on studies of breast cancer screening, we know that achieving optimal benefit from early cancer detection also involves defining the most effective, efficient, and safest approach to the clinical management of screen-identified lung cancer. In this review, we consider how to build on the successes of other cancer screening efforts to detect and manage early lung cancer. This involves outlining the specific elements for lung cancer that could make a screening program safe, affordable, and effective. We also explore the current standards of early lung cancer management and target areas where potential pitfalls and opportunities for improvement exist.

Cost-Benefit Analysis↗