Identification of postoperative adjuvant chemotherapy responders in non‐small cell lung cancer by novel biomarker

Abstract

Cisplatin-based (CDDP-based) adjuvant chemotherapy of nonsmall cell lung cancer (NSCLC) was reported to yield 5-15% improvement in 5-year survival compared to complete resection alone. The importance of information concerning preselection of good responders has become increasingly evident. The purpose of our study is the establishment of a preselection of good responders for CDDP-based adjuvant chemotherapy. We investigated protein expressions comparing intensity between parent strains (H69 and PC14 lung cancer cultured cells) and resistant strains against CDDP using 2-dimensional polyacrylamide gel electrophoresis (2-DE). Immunohistochemically, we evaluated the relationship between protein expression associated with CDDP-resistance and the clinical effects of platinum-based postoperative adjuvant chemotherapy using 126 surgically-resected NCLC materials. We detected 2 kinds of polypeptides that changed expression levels on 2-DE gels. The analyses of the amino acid sequence showed that these polypeptides were reticulocalbin (RCN) and glutathione-Stransferase-p (GST-p). The 2-DE analysis showed decreased expression in RCN and overexpression in GST-p with the acquisition of CDDP-drug resistance. RCN-transfectant of H69 CDDPresistant strain showed intermediate sensitivity between the parent strain and the CDDP-resistant strain. RCN-positive cases showed a statistically significant better disease-free survival only in the cases receiving postoperative platinum-based adjuvant chemotherapy after curative resection (p 5 0.007). In addition, cases that were both RCN-positive and GST-p-negative showed a statistically significantly better outcome (p 5 0.0150). In the cases without postoperative adjuvant chemotherapy no relationship between the outcome and these expressions was seen. The evaluation of RCN and GST-p might provide valuable information concerning postoperatively therapeutic strategy from the standpoint of individualized postoperative therapy. ' 2005 Wiley-Liss, Inc.Key words: reticulocalbin; glutathione-S-transferase-p; cisplatin; individual therapy; non-small cell lung cancer Death due to lung cancer is still increasing in Japan and most Western countries, despite intensive application of various therapeutic strategies, and it is still the leading cause of cancer death in Japan. Though the opportunities of relatively early detection and treatment increase, still more than half of cases of primary lung cancer show advanced stage at the initial definitive diagnoses. Several years ago, we routinely carried out postoperative adjuvant chemotherapy using platinum (cisplatin [CDDP] or carboplatin) for patients with advanced stage non-small cell lung carcinoma (NSCLC) because distant metastasis occurred frequently after surgical treatment only. Clinically favorable outcome was not obtained, however, and the 5-year survival of Stage IIIA was approximately 25%, despite postoperative adjuvant chemotherapy. It had been believed that the efficacy of adjuvant chemotherapy in surgically resected lung cancer was controvers...

Differential Liver Protein Expression during Schistosomiasis

“…While the exact function of reticulcalbin is unknown, it is believed to be essential for protein processing (35), and the Small eye Harwell mutation, believed to be a deletion of the reticulocalbin gene, leads to early lethality (37). Moreover, overexpression of reticulocalbin has been linked to the invasiveness of breast cancer cell lines, yet downregulation of reticulocalbin appears to correlate with the acquisition of drug resistance in non-small-cell lung cancer (32). Together, these findings show that reticulocalbin is centrally involved in normal cellular function and that its expression is significantly and distinctly altered in various pathogenic states, including schistosomiasis.…”

Shotgun Glycopeptide Capture Approach Coupled with Mass Spectrometry for Comprehensive Glycoproteomics

“…For instance, the folate receptor (42,43), the insulin-like growth factor receptor (44), and the epidermal growth factor receptor (45) are overexpressed in cancer cells and are used as drug delivery targets. The tumor-associated calcium signal transducer 1 (46), tumor necrosis factor receptor (46 -48), metastasis suppressor protein 1 (46), heat shock protein HSP 90 (49), laminin (46,50,51), and reticulocalbin-1 (52) have been reported to be associated with ovarian carcinogenesis. Increased expression of disulfide isomerase (46,53) and ADAM 10 (54) is strongly correlated with cisplatin resistance.…”

Distribution and Variable Expression of Secretory Pathway Protein Reticulocalbin in Normal Human Organs and Non-neoplastic Pathological Conditions

“…Furthermore, Liu et al (1997) reported that the mammary cancer cell line with an aggressive nature expressed RCN, but noninvasive lines did not. Hirano et al (2005) reported decreased RCN expression in cisplatin-resistant human lung cancer. In this context, the study of RCN expression in each cell in normal organs is important to understand pathophysiological roles under various pathological conditions and its implications in oncogenesis of RCN.…”

“…The monoclonal antibody to RCN (clone 6A1; IBL, Takasaki, Japan) was used as described elsewhere (Hirano et al 2005). The monoclonal antibody to Ki-67 was purchased from Immunotec (Marseille, France).…”

“…In addition, because full-length RCN DNA has been cloned (Hirano et al 2005), recombinant RCN was purified and used for absorption of the primary antibody. Sections of lung cancer and breast cancer were used as positive controls (Liu et al 1997;Hirano et al 2005). In addition, because the FOC3 ovarian cancer cell line showed expression of RCN mRNA, a section obtained from serous papillary ovarian carcinoma was also used as a control.…”