Biomedical subjects

Ichiro Kinoshita

Publications and source records attributed to Ichiro Kinoshita.

At least 19 recordsLinked to original sources

PubMed2025

Clinical utility of comprehensive genomic profiling test for colorectal cancer: a single institution prospective observational study.

PURPOSE: Next-generation sequencing (NGS) has revolutionized cancer treatment by enabling comprehensive cancer genomic profiling (CGP) to guide genotype-directed therapies. While several prospective trials have demonstrated varying outcomes with CGP in patients with advanced solid tumors, its clinical utility in colorectal cancer (CRC) remains to be evaluated. METHODS: We conducted a prospective observational study of CGP in our hospital between September 2019 and March 2024. Overall survival (OS) of the patients who received CGP-based therapy and those did not was compared, and genomic variables associated with OS were evaluated. RESULTS: A total of 100 patients with CRC underwent CGP using four platforms. The median patient age was 67 years, and most had a good performance status. The most frequent genomic alterations were TP53 (82%), APC (82%), and KRAS (55%). Actionable mutations such as ERBB2 amplification and BRAF V600E were identified in some patients, and 9% received CGP-based therapy, including immune checkpoint inhibitors for tumor mutational burden-high or microsatellite instability-high tumors. Patients receiving CGP-based therapy had longer OS from expert panel discussion (16.0 vs. 10.8 months) compared to those who did not. Alterations in TP53, SMAD4, and NF1 were associated with worse OS. Interestingly, PTEN mutations were linked to improved survival. TP53 alterations were more common in left-sided CRC. CONCLUSION: Although some patients with CRC received CGP-guided therapy, a statistically significant survival benefit was not observed. However, TP53 and SMAD4 mutations were identified as negative prognostic markers, indicating their potential as targets for future drug development.

Humans↗

PubMed2007

Increase in soluble CD138 in bronchoalveolar lavage fluid of multicentric Castleman's disease.

Multicentric Castleman's disease (MCD) is a rare and often incurable lymphoproliferative disorder. It is typically a systemic illness, but occasionally manifests primarily as a pulmonary parenchymal disease with massive infiltration of CD138 (syndecan-1)-positive plasma cells. This is the first report to demonstrate a marked elevation of soluble CD138, despite the absence of plasma cells, in BAL fluid in an MCD patient with pulmonary involvement. This finding suggests that the quantitative measurement of soluble CD138 in BAL fluid may reflect plasma cell infiltration and disease activity in the lungs of patients with MCD.

Biomarkers↗

PubMed2006

Non-responsiveness to gefitinib in a patient with lung adenocarcinoma having rare EGFR mutations S768I and V769L.

Mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) are associated with clinical responsiveness to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell lung cancers (NSCLCs). However, certain rare EGFR mutations including S768I are reported to confer less in vitro sensitivity to gefitinib, an EGFR-TKI, than major mutations such as exon 19 deletions and L858R and even the wild-type counterpart. Here, we report the first case of adenocarcinoma of the lung in which the patient had rare mutations S768I and V769L and was treated with gefitinib. Disease progressed during 6 weeks of treatment. This case suggests that in vitro sensitivity to gefitinib correlates with distinct clinical responsiveness to gefitinib in various types of EGFR mutations.

Adenocarcinoma↗

PubMed2006

Epithelioid sarcoma presenting as pulmonary cysts with cancer antigen 125 expression.

A 39-year-old Japanese woman presented with a swollen right hand and a right-sided pneumothorax. Chest CT revealed bilateral multiple pulmonary thin-walled cysts measuring<or=1 cm in diameter and small nodules. An initial skin biopsy led to a misdiagnosis of metastatic adenocarcinoma, as tumour cells were positive for cytokeratin, epithelial membrane antigen, carcinoembryonic antigen and cancer antigen 125. However, chemotherapy proved ineffective, and the skin biopsy was repeated. A final diagnosis of epithelioid sarcoma (ES) was made. Open lung biopsy showed that the pulmonary nodules represented metastases of ES. Although the pulmonary cyst walls did not contain tumour cells, bronchiolar wall adjacent to the cysts had been infiltrated by tumour cells. These findings suggested that pulmonary cysts, a rare form of pulmonary metastases from soft tissue sarcomas, had developed through a ball-valve effect of metastatic tumour in small airways. However, presence of cancer antigen 125 hindered obtaining a correct diagnosis of ES.

Adenocarcinoma↗

PubMed2005

E1AF/PEA3 activates the Rho/Rho-associated kinase pathway to increase the malignancy potential of non-small-cell lung cancer cells.

E1AF/PEA3, an Ets family transcription factor, is frequently overexpressed in non-small-cell lung cancers (NSCLCs). Overexpression of E1AF increases motility and invasion of VMRC-LCD and NCI-H226 NSCLC cells, which lack endogenous E1AF expression, and the effect is synergistically increased by hepatocyte growth factor (HGF). The small GTPase Rho/Rho-associated kinase (ROCK) pathway is also involved in motility and invasion. To determine the role of the Rho/ROCK pathway in malignant phenotypes induced by E1AF, we analyzed VMRC-LCD cells transfected with an E1AF expression vector (LCD-E1AF cells) or with empty vector (LCD-vector cells). LCD-E1AF cells had more GTP-bound (active) Rho than LCD-vector cells and Rho activation was synergistically increased by HGF. The Rho activation by E1AF and HGF was also shown in NCI-H226 cells. Phosphorylation of myosin light chain (MLC), a downstream effector of ROCK signaling, was higher in LCD-E1AF cells than in LCD-vector cells, especially under HGF treatment. A specific ROCK inhibitor, Y27632, strongly suppressed MLC phosphorylation, cell motility, and invasion. In nude mice implanted s.c. and intrapulmonarily, LCD-E1AF cells made more local tumors than LCD-vector cells (six of six versus one of seven mice and four of seven versus one of seven mice, respectively). Three of the four mice with lung tumors from LCD-E1AF cells had lymph node metastases whereas the mouse with LCD-vector tumors did not. LCD-E1AF tumors showed higher MLC phosphorylation than LCD-vector tumors. These results suggest that E1AF activates the Rho/ROCK pathway in an HGF-enhanced manner and its activation is important in E1AF-induced motility and invasion as well as tumorigenesis and metastasis in NSCLC cells.

Adenovirus E1A Proteins↗

PubMed2005

Expression of N-acetylglucosaminyltransferase V in the development of human esophageal cancers: immunohistochemical data from carcinomas and nearby noncancerous lesions.

OBJECTIVE: N-Acetylglucosaminyltransferase V (GnT-V) is a key enzyme in the formation of branching asparagine-linked oligosaccharides and is linked to tumor invasion and metastasis in colon and breast cancers. In normal esophageal epithelium, beta1,6-branched asparagine-linked oligosaccharides synthesized by GnT-V are seen in the basal cell layers but not in the superficial cell layers, and its presence has been shown in invasive esophageal cancers. However, neither GnT-V expression nor its clinical significance has been previously examined in human normal, premalignant and malignant esophageal tissues. METHODS: GnT-V expression was studied by immunohistochemistry using a specific monoclonal antibody in 121 surgically resected specimens of esophageal squamous cell carcinomas (SCCs) and adjacent tissues, and was analyzed statistically in relation to various characteristics. RESULTS: GnT-V expression was observed in none (0%) of the 19 normal epithelial tissues, 1 (2%) of the 43 hyperplastic tissues, 30 (54%) of the 56 mildly dysplastic tissues, 27 (63%) of the 43 moderately dysplastic tissues, 21 (44%) of the 48 in situ SCCs and 29 (26%) of the 110 invasive SCCs (p<0.005). GnT-V expression was observed significantly more frequently in mildly and moderately dysplastic tissues when compared with normal epithelial and hyperplastic tissues (p<0.005), and its frequency was decreased in in situ and invasive SCCs (p<0.005). GnT-V expression was frequently observed in SCCs of small size and without distant metastasis or lymph node metastasis. CONCLUSIONS: Increased expression of GnT-V is associated with the early event of esophageal tumorigenesis.

Adult↗

PubMed2005

Susceptibility to oxygen desaturation during bronchoscopy in elderly patients with pulmonary fibrosis.

BACKGROUND: Fiber-optic flexible bronchoscopy (FFB) is a frequently performed procedure for the diagnosis and treatment of pulmonary disorders. However, hypoxemia occasionally occurs during FFB. OBJECTIVES: We attempted to examine the causes of arterial oxygen desaturation during FFB. METHODS: We studied 336 patients who underwent FFB without intervention between June 1, 2001 and September 30, 2002. Arterial oxygen saturation (SpO2) was continuously monitored using oximetry with a recording system. We analyzed the relationship between a reduction in SpO2 during FFB and various clinical parameters or background lung diseases. RESULTS: Of the 336 patients, 73 (22%) had an episode of oxygen desaturation (SpO2 <90% over 10 s). Of patients over 80 years old, 55% had an episode of oxygen desaturation, which was significantly higher than 27% observed in the patients of 80 and less than 80 years old (p < 0.05). Patients with pulmonary fibrosis had a higher risk of desaturation (55%) compared to patients with other complications or patients without any complication (p < 0.05). Multivariable analysis revealed that both age and pulmonary fibrosis were independent predictors of oxygen desaturation. However, the majority of the patients (94%) did not require routine oxygen supplementation. CONCLUSION: Although FFB is safe and does not require oxygen supplementation in most cases, age over 80 years and pulmonary fibrosis are high risk factors for significant oxygen desaturation during FFB.

Adult↗

PubMed2005

Cyclin A is a c-Jun target gene and is necessary for c-Jun-induced anchorage-independent growth in RAT1a cells.

Overexpression of c-Jun enables Rat1a cells to grow in an anchorage-independent manner. We used an inducible c-Jun system under the regulation of doxycycline in Rat1a cells to identify potential c-Jun target genes necessary for c-Jun-induced anchorage-independent growth. Induction of c-Jun results in sustained expression of cyclin A in the nonadherent state with only minimal expression in the absence of c-Jun. The promoter activity of cyclin A2 was 4-fold higher in Rat1a cells in which c-Jun expression was induced compared with the control cells. Chromatin immunoprecipitation demonstrated that c-Jun bound directly to the cyclin A2 promoter. Mutation analysis of the cyclin A2 promoter mapped the c-Jun regulatory site to an ATF site at position -80. c-Jun was able to bind to this site both in vitro and in vivo, and mutation of this site completely abolished promoter activity. Cyclin A1 was also elevated in c-Jun-overexpressing Rat1a cells; however, c-Jun did not regulate this gene directly, since it did not bind directly to the cyclin A1 promoter. Suppression of cyclin A expression via the introduction of a cyclin A antisense sequences significantly reduced the ability of c-Jun-overexpressing Rat1a cells to grow in an anchorage-independent fashion. Taken together, these results suggest that cyclin A is a target of c-Jun and is necessary but not sufficient for c-Jun-induced anchorage-independent growth. In addition, we demonstrated that the cytoplasmic oncogenes Ras and Src transcriptionally activated the cyclin A2 promoter via the ATF site at position -80. Using a dominant negative c-Jun mutant, TAM67, we showed that this transcriptional activation of cyclin A2 requires c-Jun. Thus, our results suggest that c-Jun is a mediator of the aberrant cyclin A2 expression associated with Ras/Src-induced transformation.

Animals↗

PubMed2004

B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression.

PURPOSE: B7-H1/PD-L1 (B7-H1) and B7-DC/PD-L2 (B7-DC) are ligands for the receptor PD-1, which is known to negatively regulate T-cell activation. In the present study, we investigated the expression of B7-H1 and B7-DC in tumor specimens of non-small cell lung cancer and their relationships with clinicopathological variables and postoperative survival. Furthermore, we examined the correlation between B7-H1 expression on tumor cells and the number of tumor-infiltrating lymphocytes (TILs) or PD-1 expression on TILs. EXPERIMENTAL DESIGN: The expression of B7-H1 and B7-DC in 52 surgically resected specimens of non-small cell lung cancer was evaluated immunohistochemically. RESULTS: Expression of B7-H1 and B7-DC was focally observed in all non-small cell lung cancer tumor specimens. No relationship was found between the expression of B7-H1 or B7-DC and clinicopathological variables or postoperative survival. However, in the same sections evaluated, significantly fewer TILs were identified in B7-H1-positive tumor regions than in B7-H1-negative tumor regions in a subset of five patients (P = 0.01). Moreover, the percentage of TILs expressing PD-1 was significantly lower in B7-H1-positive tumor regions than in B7-H1-negative tumor regions (P = 0.02). CONCLUSIONS: The expression of B7-H1 on tumor cells in local areas reciprocally correlated with the number of TILs, and this may contribute to negative regulation in antitumor immune responses in non-small cell lung cancer.

Adult↗

PubMed2004

Phase I trial of carboplatin and weekly paclitaxel in patients with advanced non-small-cell lung cancer.

OBJECTIVE: This study was designed to determine the maximum tolerated dose of paclitaxel administered weekly in combination with carboplatin and to assess its dose limiting toxicity and preliminary activity in patients with previously untreated, advanced non-small-cell lung cancer. METHODS: Carboplatin was administered at a fixed dose that maintained an area under the curve of 6. Paclitaxel was given over 1 h once a week for 3 weeks starting at 60 mg/m(2) and escalated in 10 mg/m(2) increments. RESULTS: Twenty-one patients were treated with six dose levels (60, 70, 80, 90, 100, 110 mg/m(2)) of paclitaxel. The dose limiting toxicity was infection and the maximum tolerated dose was 110 mg/m(2). Nine of 21 (42.9%) patients demonstrated a therapeutic response. CONCLUSION: Weekly paclitaxel and carboplatin were well tolerated. Based on our results, 100 mg/m(2) of paclitaxel for 3 weeks of a 4-week cycle, in combination with carboplatin, was recommended for a phase II study.

Adenocarcinoma↗

PubMed2004

Paraneoplastic cerebellar degeneration (PCD) associated with squamous cell carcinoma of the lung.

We report a case of a 71-year-old man who presented with cerebellar dysfunction. He was diagnosed as having squamous cell carcinoma of the lung (T2N3M0, Stage IIIB). No anti-onconeural antibodies were found in his serum. Cerebral spinal fluid (CSF) examination showed mild mononuclear pleocytosis alone. Magnetic resonance imaging (MRI) of the brain and spinal cord revealed no abnormalities. At autopsy, there was complete disappearance of Purkinje cells with reactive astrocytosis. These findings are compatible with paraneoplastic cerebellar degeneration (PCD). To our knowledge, no case of PCD has been reported previously in patients with squamous cell carcinoma of the lung.

Aged↗

PubMed2004

[A case of paclitaxel-induced pneumonitis].

A 79-year-old woman with small-cell lung cancer was treated weekly with paclitaxel after previous treatment with carboplatin and etoposide. Within the first course of paclitaxel, chest radiography and CT revealed thickening of the bronchovascular bundle and interlobular septa, and infiltrates in both lung fields. A marked increase in the number of lymphocytes was found on bronchoalveolar lavage (BAL). Microorganisms such as Cytomegalovirus, Mycobacteria, and Pneumocystis carinii were absent from the BAL fluid. Interstitial infiltration was partially improved simply by stopping paclitaxel administration, without the need for any additional therapy. Drug-induced pneumonitis caused by paclitaxel was diagnosed on the basis of the clinical course and findings, although a drug lymphocyte stimulation test yielded negative results for paclitaxel. Interstitial infiltrates on imaging, symptoms and arterial blood gas results improved with administration of oral prednisolone. The possibility of pneumonitis induced by paclitaxel should be considered even in cases without interstitial lung disease.

Aged↗

PubMed2003

Retinoic acid inhibits interleukin-4-induced eotaxin production in a human bronchial epithelial cell line.

Retinoic acid (RA) is known to accelerate wound healing and induce cell differentiation. All-trans RA (ATRA) exerts its effect by binding retinoic acid receptors, which are members of the nuclear receptor family. We investigated whether RA can alter expression of eotaxin, a potent eosinophil chemoattractant that is regulated by the transcription factors signal transducer and activator of transcription 6 (STAT6) and NF-kappaB. We examined the effects of RA on eotaxin expression in a human bronchial epithelial cell line BEAS-2B. ATRA and its stereodimer 9-cis retinoic acid (9-cis RA) inhibited IL-4-induced release of eotaxin at 10(-6) M by 78.0 and 52.0%, respectively (P < 0.05). ATRA and 9-cis RA also significantly inhibited IL-4-induced eotaxin mRNA expression at 10(-6) M by 52.3 and 53.5%, respectively (P < 0.05). In contrast, neither ATRA nor 9-cis RA had any effects on TNF-alpha-induced eotaxin production. In transfection studies using eotaxin promoter luciferase plasmids, the inhibitory effect of ATRA on IL-4-induced eotaxin production was confirmed at the transcriptional level. Interestingly, ATRA had no effects on IL-4-induced tyrosine phosphorylation, nuclear translocation, or DNA binding activity of STAT6. Activating protein-1 was not involved in ATRA-mediated transrepression of eotaxin with IL-4 stimulation. The mechanism of the inhibitory effect of ATRA on IL-4-induced eotaxin production in human bronchial epithelial cells has not been elucidated but does not appear to be due to an effect on STAT6 activation. These findings raise the possibility that RA may reduce eosinophilic airway inflammation, one of the prominent pathological features of allergic diseases such as bronchial asthma.

Active Transport, Cell Nucleus↗

PubMed2003

AP-1 complexes containing cJun and JunB cause cellular transformation of Rat1a fibroblasts and share transcriptional targets.

To investigate the role of individual Jun proteins in cell growth and transformation, we have used a doxycycline-inducible retroviral vector to regulate their expression in rat fibroblasts. AP-1 complexes enriched with cJun and JunB result in morphological alterations and anchorage-independent cell growth consistent with a transformation-like phenotype, whereas complexes enriched with JunD had an antiproliferative effect. These results suggest that genes regulated by both cJun and JunB are potentially involved in transformation and that they can be distinguished from those regulated by AP-1 complexes containing JunD. To identify genes regulated by cJun and JunB that may have a role in anchorage-independent growth, we investigated differential gene expression by each of the Jun family members using the Affymetrix Rat oligonucleotide microarray, RG_U34A containing approximately 8000 genes. Differentially regulated genes were identified and grouped for correlation with regulation by the different Jun proteins. A total of 33 candidate genes were found to be differentially regulated by both cJun and JunB and not by JunD. These genes have roles in cell metabolism, growth, signal transduction, migration and adhesion. We validated the differential regulation by cJun and JunB of 10 candidate genes by Northern blot analysis. Of these, eight were further characterized as potential direct targets of AP-1 regulation based on Northern blot results showing differential regulation that correlate with cJun expression. Our results show that inducible cJun and JunB expression result in anchorage-independent growth of Rat1a cells, distinct from JunD-expressing cells. This model system and a functional genomic approach enabled us to differentiate AP-1-regulated genes involved in transformation from AP-1-regulated genes known as bystander genes. This approach significantly reduces the number of bystanders and allows for the targeting of genes specifically involved in transformation.

Animals↗

PubMed2003

Granulocyte-macrophage colony-stimulating factor gene-transduced tumor cells combined with tumor-derived gp96 inhibit tumor growth in mice.

Granulocyte-macrophage colony-stimulating factor (GM-CSF)-based cancer cell vaccines have been shown to be potent inducers of antitumor immunity in several murine models, but the antitumor effects on established tumors have been minimal. Conversely, the major role of the heat shock protein gp96, localized in the endoplasmic reticulum (ER), is to act as a molecular chaperone to assist the folding of nascent polypeptide chains in the ER. gp96 derived from tumor cells elicits specific protective immunity against parental tumors, presumably through the transport of tumor-specific peptides to antigen-presenting cells and the maturation of dendritic cells (DCs). However, the therapeutic effects of tumor-derived gp96 on established tumors have not been promising. The present study analyzes the therapeutic effects of GM-CSF gene-transduced Lewis lung cancer (LLC/GM) cells combined with LLC-derived gp96 on established wild-type LLC tumors in immunocompetent C57BL/6 mice. Therapy with either irradiated LLC/GM cells or LLC-derived gp96 barely affected established LLC tumor growth. The antitumor effect was significantly enhanced when 1 microg of LLC-derived gp96 was administered together with 1 x 10(6) irradiated LLC/GM cells (p < 0.05). The antitumor effects of irradiated LLC/GM cells and LLC-derived gp96 required mainly CD8(+) T cells. Spleen cells obtained from mice vaccinated with irradiated LLC/GM cells and LLC-derived gp96 showed specific CD8 cytotoxic activities against LLC cells (specific lysis rate of approximately 28%). This antibody response was not associated with a synergic effect of the combination therapy. Moreover, draining lymph nodes from mice immunized with irradiated LLC/GM cells and LLC-derived gp96 contained more migrating mature CD11c(+) cells (higher levels of CD86 and major histocompatibility complex [MHC] class II molecules) compared with those from any other immunization protocols. These results suggest that the combination of irradiated LLC/GM cells and tumor-derived gp96 has potential as a new immunogene therapeutic strategy against lung cancer.

Animals↗

PubMed2003

Identification of cJun-responsive genes in Rat-1a cells using multiple techniques: increased expression of stathmin is necessary for cJun-mediated anchorage-independent growth.

cJun is a major component of the transcription factor AP-1 and mediates a diverse set of biologic properties including proliferation, differentiation, and apoptosis. To identify cJun-responsive genes, we inducibly expressed cJun in Rat-1a cells and observed two distinct phenotypes: changes in cellular morphology with adherent growth and anchorage-independent growth. The biologic effects of cJun were entirely reversible demonstrating that they require the continued presence of cJun. To determine the genes, which mediate the biologic effects of cJun, we employed multiple methods including differential gene analysis, suppression subtractive hybridization, and cDNA microarrays. We identified 38 cJun-responsive genes including three uncharacterized genes under adherent and/or nonadherent conditions. Half of the known 36 genes were cytoskeleton- and adhesion-related genes, suggesting a major role of cJun in the regulation of the genes related to cell morphology. As proof of the principle that this approach could identify genes whose upregulation was necessary for nonadherent growth, we investigated one gene, stathmin whose upregulation by cJun was observed only under these conditions. Although overexpression of stathmin did not result in nonadherent growth, inhibition of stathmin protein expression by antisense oligonucleotides in cJun-induced Rat-1a cells prevented nonadherent growth. These results suggest that stathmin plays an essential role in anchorage-independent growth by cJun and may be a potential target for specific inhibitors for AP-1-dependent processes involved in carcinogenesis.

Animals↗

PubMed2003

CD4+ T cells in cancer stroma, not CD8+ T cells in cancer cell nests, are associated with favorable prognosis in human non-small cell lung cancers.

We investigated intratumoral tumor-infiltrating lymphocytes (TILs), including CD4(+) and CD8(+) T cells, in non-small cell lung cancers (NSCLCs) and their relationships with clinicopathological variables and post-operative survival. Tumor specimens from 178 NSCLCs were consecutively obtained by surgery at the Hokkaido University Medical Hospital between 1976 and 1994. CD8(+) T cells, CD4(+) T cells and Ki-67/CD8(+) T cells were visualized immunohistochemically, and counted within cancer cell nests and in cancer stroma. CD8(+) T cells and CD4(+) T cells were observed at higher frequencies within cancer cell nests in moderately and poorly differentiated tumors compared with well differentiated tumors (P < 0.01), and in tumors with high Ki-67 expression compared with low Ki-67 expression (P < 0.01), that showed severe cellular atypia and a higher growth rate. Patients with higher numbers of CD8(+) T cells within cancer cell nests showed significantly shorter survival times compared to those with lower numbers of CD8(+) T cells within cancer cell nests (5-year survival rates, 47% and 60%, respectively; P = 0.03). Moreover, patients with higher labeling index of Ki-67/CD8(+) T cells showed significantly shorter survival than those with lower labeling index of Ki-67/CD8(+) T cells within cancer cell nests (5-year survival rates, 41% and 69%, respectively; P = 0.02), and the labeling index of Ki-67/CD8(+) T cells within cancer cell nests was found to be a significant and independent unfavorable prognostic factor by multivariate analysis (P = 0.01). On the other hand, higher numbers of CD4(+) T cells in cancer stroma, but not within cancer cell nests, were correlated with longer survival times in patients with NSCLC (5-year survival rates, 64% and 43%, respectively; P = 0.04). CD4(+) T cells in cancer stroma might reflect immune responses against cancer cells, while CD8(+) T cells do not appear to work as effectors in tumor tissues of NSCLC. Moreover, the higher labeling index of Ki-67/CD8(+) T cells within cancer cell nests is a strong indicator of unfavorable clinical outcome.

Adenocarcinoma↗

PubMed2003

Predictive value of expression of P53, Bcl-2 and lung resistance-related protein for response to chemotherapy in non-small cell lung cancers.

Chemoresistance is a major problem in the chemotherapy of non-small cell lung cancers (NSCLCs). Several mechanisms are thought to be involved in drug resistance, including those associated with apoptosis, drug transport and detoxification. Here, we investigated the predictive value of P53, Bcl-2 and lung resistance-related protein (LRP) expression for response to platinum-based chemotherapy, using transbronchial biopsy (TBB) specimens from patients with NSCLC. We evaluated TBB specimens from 57 patients with NSCLC who had not previously been treated with either chemotherapy or radiotherapy before TBB, and who were treated with systemic platinum-based chemotherapy. The specimens included 33 adenocarcinomas, 22 squamous cell carcinomas and two large cell carcinomas. One to 6 courses of chemotherapy were administered. Expression of P53, Bcl-2 and LRP was analyzed by immunohistochemistry using TBB specimens. Positive expression of P53, Bcl-2 and LRP was observed in 28 (49%), 41 (71%) and 42 (73%) of the 57 NSCLCs, respectively. P53 expression correlated significantly with response to chemotherapy in nonsquamous cell carcinomas, including adenocarcinomas and large cell carcinomas (response rates, 38% and 6% for patients with P53-positive and P53-negative tumors, respectively, P = 0.03). LRP expression significantly correlated inversely with response to chemotherapy in squamous cell carcinomas (response rates, 33% and 100% for patients with LRP-positive and LRP-negative tumors, respectively, P = 0.02). Bcl-2 expression did not correlate with response to chemotherapy. These findings indicate that immunostaining for P53 and LRP using TBB specimens may be useful for dividing patients with NSCLC into chemoresponsive and chemoresistant groups.

Adenocarcinoma↗