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Biomedical subjects

J L Mulshine

Publications and source records attributed to J L Mulshine.

At least 19 recordsLinked to original sources
PubMed2002

Lung cancer. 2: screening and early diagnosis of lung cancer.

Technical developments in spiral CT scanning mean that considerably smaller lung cancers can now be identified than with previous methods of detection. Only time will tell whether this enhanced capability will result in a reduction in the number of deaths from lung cancer. The implications and problems of screening for lung cancer are discussed. Screening implies a careful refinement of a range of clinical activities that must be routinely delivered in a carefully coordinated fashion to allow for the possibility of improved outcome. Critical analyses of the nuances of this process are essential if the field is to move forward.

Decision Making↗
PubMed2001

Five-lipoxygenase inhibitors can mediate apoptosis in human breast cancer cell lines through complex eicosanoid interactions.

Many arachidonic acid metabolites function in growth signaling for epithelial cells, and we previously reported the expression of the major arachidonic acid enzymes in human breast cancer cell lines. To evaluate the role of the 5-lipoxygenase (5-LO) pathway on breast cancer growth regulation, we exposed cells to insulinlike growth factor-1 or transferrin, which increased the levels of the 5-LO metabolite, 5(S)-hydrooxyeicosa-6E,8C,11Z,14Z-tetraenoic acid (5-HETE), by radioimmunoassay and high-performance liquid chromatography. Addition of 5-HETE to breast cancer cells resulted in growth stimulation, whereas selective biochemical inhibitors of 5-LO reduced the levels of 5-HETE and related metabolites. Application of 5-LO or 5-LO activating protein-directed inhibitors, but not a cyclooxygenase inhibitor, reduced growth, increased apoptosis, down-regulated bcl-2, up-regulated bax, and increased G1 arrest. Exposure of breast cancer cells to a 5-LO inhibitor up-regulated peroxisome proliferator-activated receptor (PPAR)a and PPARg expression, and these same cells were growth inhibited when exposed to relevant PPAR agonists. These results suggest that disruption of the 5-LO signaling pathway mediates growth arrest and apoptosis in breast cancer cells. Additional experiments suggest that this involves the interplay of several factors, including the loss of growth stimulation by 5-LO products, the induction of PPARg, and the potential activation of PPARg by interactions with shunted endoperoxides.

Apoptosis↗
PubMed2001

Expression of early lung cancer detection marker: hnRNP-A2/B1 and its relation to microsatellite alteration in non-small cell lung cancer.

We have reported that a mouse monoclonal antibody, 703D4, which recognizes heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP-A2/B1) can frequently detect lung cancer in exfoliated sputum epithelial cells 1-2 years earlier than routine chest X-ray or sputum cytomorphology. We along with others have shown that microsatellite alteration (MA) at selected loci can be recognized in sputum cells prior to clinical lung cancer. The present study was undertaken to determine how frequently the expression of hnRNP-A2/B1 message is associated with neoplastic clonal expansion as shown by MA in 41 cases of non-small cell lung cancer (NSCLC). We used Northern blotting to evaluate hnRNP-A2/B1 mRNA expression in lung tumor and remote noninvolved lung. We evaluated microsatellite instability (i.e. shifts; MI) or loss of heterozygosity (LOH) with a panel of 13 microsatellite markers at loci identified previously as susceptible in NSCLC. Of the 41 tumors, 25 (61%) over-expressed hnRNP-A2/B1 and 33 (80%) demonstrated MA in at least one of 13 loci (58% in at least two loci). The association between MA (one locus) and the overexpression of hnRNP-A2/B1 is statistically significant (P=0.0082), and those lung tumors with MA at two or more loci were significantly more likely to over-express hnRNP-A2/B1 mRNA (P=0.004). MA of loci on 3p were the only MA statistically associated with hnRNP-A2/B1 message overexpression (P=0.001). We conclude that lung tumor cells undergoing clonal expansion frequently upregulate hnRNP-A2/B1.

Adult↗
PubMed2001

Moving to the routine management of pre symptomatic lung cancer.

Lung cancer is the world's leading cause of cancer death. Since progress in the treatment of this cancer has been exceedingly slow, the upswing in tobacco consumption in many sectors becomes even more tragic. One area for cautious optimism is the recent pilot reports of improved early lung cancer detection using new spiral CT techniques from institutions in Japan and New York. The prospect of improved early detection in a major cancer raises a number of public health concerns and highlights the importance of critical validation of this proposed new tool. From experience with early detection-based management of other cancers, it is evident that the entire process of detection, case validation, intervention, monitoring and public education needs to be carefully developed. The International Association for the Study of Lung Cancer has worked with the National Cancer Institute over the last decade to nurture interest and expertise in conducting population-based management of early lung cancer. A distillation of this process up to the current time is reviewed in this manuscript.

Disease Management↗
PubMed2001

Differential expression of the early lung cancer detection marker, heterogeneous nuclear ribonucleoprotein-A2/B1 (hnRNP-A2/B1) in normal breast and neoplastic breast cancer.

Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP-A2/B1) is highly expressed during critical stages of lung development and carcinogenesis. To determine if the expression of hnRNP-A2/B1 is an informative biomarker in breast carcinogenesis, we analyzed hnRNP-A2/B1 overexpression by immunohistochemistry in archived specimens. Expression was detected in 48/85 (56.5%) primary invasive breast cancers and 7/72 (9.7%) specimens of normal breast tissue. Northern analysis of breast cancer cells also demonstrated higher level of hnRNP-A2/B1 expression compared to normal or transformed breast cells. Expression of hnRNP-A2/B1 in breast cancer cells was decreased by exposure to retinoids coordinately with decreased cell growth. These results warrant further evaluation of hnRNP-A2/B1 as a marker of breast carcinogenesis.

Biomarkers, Tumor↗
PubMed2000

Considerations in developing successful, population-based molecular screening and prevention of lung cancer.

The current mortality rate for lung cancer exceeds 85%, as it has for the last 3 decades. This statistic reflects the utility of the major diagnostic tool that has been used during this period to diagnose lung cancer: the chest X-ray. The overwhelming majority of new cases of lung cancer that are detected with chest X-rays involve individuals who already have regional or distant metastatic disease. Because the systemic treatment of this disease has not improved greatly, patients with metastatic disease rarely are cured. This article reviews the issues involved with the development of sputum-based cellular diagnostics for early stage lung cancer. The biomarker, heterogeneous nuclear ribonucleoprotein A2/B1, is the lead marker for this approach. It has been used in several studies in independent cohorts that have suggested that its overexpression in bronchial epithelial cells is associated highly with the development of lung cancer. This marker is detectable 1 year or more prior to the detection of lung cancer by chest X-ray. Finding this early airway-confined phase of lung cancer may allow for the evolution of new management approaches for very early stage lung cancer. Research activities, such aerosolized chemoprevention, are discussed.

Biomarkers, Tumor↗
PubMed2000

Cyclooxygenase regulates human oropharyngeal carcinomas via the proinflammatory cytokine IL-6: a general role for inflammation?

High levels of prostaglandins are produced in human oropharyngeal carcinoma (OPC). Five human OPC cell lines tested expressed both isoforms of cyclooxygenases (COX). The pan-COX inhibitor ketorolac continuously and significantly decreased PGE(2) production and IL-6 and IL-8 levels in all OPC cell lines tested, but did not affect IL-1alpha, GM-CSF levels, or in vitro tumor cell growth. In contrast, ketorolac reduced OPC growth in vivo. The OPC cell lines used express the IL-6 receptor, and IL-6 stimulation of these cells causes transduction to occur via STAT3 pathway activation. Coincubation with OPC cell lines with conditioned medium from a TPA-exposed HL-60 cells stimulated growth proportional to the IL-6 levels measured in the conditioned medium. This growth effect was specifically inhibited by anti-IL-6 antibody. These results are consistent with cytokine products of inflammatory cells having paracrine growth effects on OPC. If chronic inflammation plays a role in promoting the development of OPC, this mechanism may also apply to other epithelial tumor systems modulated by COX activity.

Animals↗
PubMed2000

Phenotypically different cells with heterogeneous nuclear ribonucleoprotein A2/B1 overexpression show similar genetic alterations.

Immunocytochemical studies have revealed that overexpression of heterogeneous nuclear ribonucleoprotein (hnRNP) A2/ B1 in exfoliated epithelial cells is a potentially useful marker of early lung cancer. This study analyzed the correlation of hnRNP A2/B1 expression with molecular alterations in phenotypically different epithelial cells of paraffin-embedded pulmonary tissues. Sections from 20 human subjects were analyzed immunohistochemically for expression of hnRNP A2/B1. Normal-appearing, hyperplastic, and malignant epithelial cells with and without hnRNP A2/B1 expression (n = 78) were microdissected and assessed for microsatellite alterations (MA) and loss of heterozygosity (LOH) (n = 14 markers) as well as for clonality. Results showed that (1) hnRNP A2/B1 immunoreactive cells contained a significantly higher frequency of MA and LOH than did comparable cells that lacked detectable hnRNP A2/B1; (2) over 80% of MA and LOH seen in hnRNP A2/B1 immunoreactive normal-appearing and hyperplastic cells persisted in malignant cells; (3) preliminary analysis of methylation status of the androgen receptor gene in non-neoplastic cells was suggestive of hnRNP A2/B1-expressing cells being of clonal origin; and (4) cells with cytoplasmic hnRNP A2/B1 immunoreactivity had a 3-fold higher frequency of MA and LOH than did cells with nuclear hnRNP A2/B1 immunoreactivity. These findings suggest that phenotypically different respiratory epithelial cells with hnRNP A2/B1 overexpression might be clonally derived, and that the subcellular localization of hnRNP A2/B1 might be an important factor associated with tumor progression.

Cell Division↗
PubMed2000

Inhaled isotretinoin (13-cis retinoic acid) is an effective lung cancer chemopreventive agent in A/J mice at low doses: a pilot study.

In previously treated head-and-neck cancer patients, p.o. administered isotretinoin (13-cis retinoic acid) reduced the occurrence of second aerodigestive tumors, including lung tumors, but side effects made chronic therapy problematic. We reasoned that inhaled isotretinoin might provide sufficient drug to the target cells for efficacy while avoiding systemic toxicity, and we proceeded with the pilot study reported here. Male A/J mice were given single i.p. doses of urethane, a common experimental lung carcinogen, or benzo[a]pyrene (BaP) or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), putative major carcinogens in tobacco smoke. The following day, exposures to isotretinoin aerosols for 45 min daily at 1.3, 20.7, or 481 microg/l were initiated. After 2 weeks, the high dose caused severe toxicity on the snout skin, necessitating a reduction of dose frequency to twice a week. As a precaution, the mid dose was reduced to three exposures per week. The weekly total deposited doses after the dose frequency reductions were calculated to be 0.24, 1.6, and 24.9 mg/kg for the low, mid, and high doses, of which 16% was estimated to be deposited in the lungs. The weekly deposited pulmonary drug doses were calculated to be 0.01, 0.07, and 1.1% of a previously reported ineffective oral dose in urethane-treated A/J mice. After 10-16 weeks, mice were sacrificed to count areas of pulmonary hyperplasia and adenomas. For all carcinogens, the mice exposed to the high isotretinoin dose showed reductions of tumor multiplicity ranging from 56 to 80% (P < 0.005). The mid dose was associated with reductions of tumor multiplicity by 67 and 88% (P < 0.005) in BaP- and NNK-treated mice, respectively, and was tolerated until approximately 12 weeks, when both these and the high-dose mice began losing weight. The low-dose mice had nonsignificant reductions of 30% (P < 0.13) and 16% (P < 0.30) for BaP- and NNK-treated mice, respectively without any evidence of side effects. For BaP- and NNK-treated mice, numbers of hyperplastic areas directly correlated to dose level and inversely to tumor number, suggesting arrested progression. Inhaled mid-dose isotretinoin caused up-regulation of lung tissue nuclear retinoic acid receptors (RARs) relative to vehicle-exposed mice, RARalpha (3.9-fold vehicle), RARbeta (3.3-fold), and RARgamma (3.7-fold), suggesting that these receptors may be useful biomarkers of retinoid activity in this system. The encouraging results from this pilot study suggest that inhaled isotretinoin merits evaluation in people at high risk for lung cancer.

Administration, Inhalation↗
PubMed2000

Topical delivery of 13-cis-retinoic acid by inhalation up-regulates expression of rodent lung but not liver retinoic acid receptors.

Chemopreventive retinoids may be more effective if delivered to the lung epithelium by inhalation. 13-cis-Retinoic acid (13-cis-RA) was comparable to all-trans-retinoic acid (RA) in inducing transglutaminase II (TGase II) in cultured human cells. Inhaled 13-cis-RA had a significant stimulatory activity on TGase II in rat lung (P < 0.001) but not in liver tissue (P < 0.544). Furthermore, inhaled 13-cis-RA at daily deposited doses of 1.9 mg/kg/day up-regulated the expression of lung retinoic acid receptors (RARs) alpha, beta, and gamma at day 1 (RARalpha by 3.4-fold, RARbeta by 7.2-fold, and RARgamma by 9.7-fold) and at day 17 (RARalpha by 4.2-fold, RARbeta by 10.0-fold, and RARgamma by 12.9-fold). At a lower aerosol concentration, daily deposited doses of 0.6 mg/kg/day were also effective at 28 days. Lung RARalpha was induced by 4.7-fold, RARbeta by 8.0-fold, and RARgamma by 8.1-fold. Adjustment of dose by exposure duration was also effective; thus, inhalation of an aerosol concentration of 62.2 microg/liter, for durations from 5 to 240 min daily for 14 days, induced all RARs from 30.6- to 74-fold at the shortest exposure time. None of the animals exposed to 13-cis-RA aerosols showed RAR induction in livers. By contrast, a diet containing pharmacological RA (30 microg/g of diet) failed to induce RARs in SENCAR mouse lung, although it induced liver RARs (RARalpha, 21.8-fold; RARbeta, 13.5-fold; RARgamma, 12.5-fold); it also failed to induce lung TGase II. A striking increase of RARalpha expression was evident in the nuclei of hepatocytes. Pharmacological dietary RA stimulated RARalpha, RARbeta, and RARgamma as early as day 1 by 2-, 4-, and 2.1-fold, respectively, without effect on lung RARs. Therefore, 13-cis-RA delivered to lung tissue of rats is a potent stimulant of lung but not liver RARs. Conversely, dietary RA stimulates liver but not lung RARs. These data support the concept that epithelial delivery of chemopreventive retinoids to lung tissue is a more efficacious way to attain up-regulation of TGase II and the retinoid receptors and possibly to achieve chemoprevention.

Administration, Inhalation↗
PubMed2000

The early detection of occult lung cancer.

These sputum tests offer great promise in determining a molecular diagnosis of lung cancer far in advance of clinical presentation. Any or all of these tests could be incorporated into the routine management of individuals at risk for developing primary or second primary lung cancer; however, several issues must be considered before these tests are ready for clinical application. First, test performance characteristics must be confirmed in prospective trials. For several of these tests, those trials are currently underway. Second, management and intervention strategies appropriate to the stage at which lung cancer is diagnosed must be developed. The ability to detect lung cancer at the stage of clonal expansion, well in advance of malignant invasion of the basement membrane, suggests that noninvasive, chemoprevention might be appropriate in such cases. Preliminary studies of chemopreventive agents are now underway at the National Cancer Institute. Several of these agents could be delivered by inhaler to place a maximum dose directly on the transformed epithelium. Clinical trials are needed that evaluate combined diagnostic and therapeutic approaches for their impact on the incidence of clinical lung cancer. Finally, the larger public health issues of cost and accessibility of lung cancer screening must be considered before these advances in sputum and helical CT screening can reach their potential.

Gene Deletion↗
PubMed1999

Relationship of arachidonic acid metabolizing enzyme expression in epithelial cancer cell lines to the growth effect of selective biochemical inhibitors.

Arachidonic acid (AA) metabolizing enzymes are emerging as significant mediators of growth stimulation for epithelial cells. The relative contribution of the various family members of AA metabolizing enzymes to epithelial cancer cell growth is not known. To study this question, we first analyzed a series of epithelial cancer cells to establish the relative frequency of expression for the various enzymes. We analyzed the expression of five AA metabolizing enzymes as well as 5-lipoxygenase activating protein (FLAP) in a panel of human epithelial cancer cell lines (n = 20) using reverse transcription-PCR. From this analysis, we found that cyclooxygenase-1 (COX-1), 5-lipoxygenase (5-LOX), and FLAP were universally expressed in all cancer cell lines tested. For the remaining enzymes, the expression of COX-2, 12-LOX, and 15-LOX varied among cell lines, 60, 35, and 90%, respectively. Although the pattern of expression varied among the different cell types, all of the enzymes were expressed in all major cancer histologies. Using a panel of selective biochemical AA metabolizing enzyme inhibitors, we then evaluated the effect of these agents on cell lines with known expression status for the AA metabolizing enzymes. For the enzymes that were not universally expressed, growth inhibition by selective biochemical inhibitors did not closely correlate with the expression status of specific enzymes (P > 0.05). For the universally expressed enzymes, the LOX inhibitors were more potent growth inhibitors than the COX inhibitors. The frequent expression of the AA metabolizing enzymes suggests that AA metabolism pathway may be modulated in response to xenobiotic exposure during carcinogenesis. Although establishing a priori AA metabolizing enzyme status was not consistently informative about what AA metabolizing enzyme inhibition would be most growth inhibitory, the frequent inhibition of many epithelial cancers by these biochemical inhibitors opens a new avenue for cancer therapy and intervention in carcinogenesis.

5-Lipoxygenase-Activating Proteins↗