Haruhiko Kawaguchi

An Anti-GD2 Monoclonal Antibody Enhances Apoptotic Effects of Anti-cancer Drugs against Small Cell Lung Cancer Cells via JNK (c-Jun Terminal Kinase) Activation

Small cell lung cancer (SCLC) cell lines specifically express ganglioside GD2, and anti‐GD2 monoclonal antibodies (mAbs) caused suppression of cell growth and induced apoptosis of SCLC cells with single use. Here, enhancement of the cytotoxic effects of various anti‐cancer drugs with an anti‐GD2 mAb was demonstrated. The cytotoxicity of all six drugs examined was markedly enhanced, i.e. 2.4–7.8–fold increase of cell sensitivity in terms of IC50. In particular, the combination of cisplatin (CDDP) with an anti‐GD2 mAb resulted in prominent enhancement of cytotoxicity even in low‐moderate GD2–expressing lines. The anti‐GD2 mAb induced weak activation of c‐Jun terminal kinase (JNK) in SCLC cells, and all anti‐cancer drugs also induced its activation to various degrees. When CDDP and an anti‐GD2 mAb were used together, significantly stronger JNK activation was observed corresponding to the cytotoxic effects, suggesting that synergistic phosphorylation of JNK with two reagents induced prominent apoptosis. The essential role of JNK in the induction of SCLC apoptosis with CDDP and anti‐GD2 mAb was confirmed by experiments with a JNK inhibitor, curcumin. These results suggest that anti‐GD2 mAbs would be very efficient in combination with anti‐cancer drugs, both to achieve SCLC‐specific cytotoxicity and to enhance its magnitude.

Serum Lysozyme Levels and Clinical Features of Sarcoidosis

Abstract. Serum lysozyme is used as a marker of sarcoidosis disease activity. In this study we examined the association between lysozyme levels and the clinical features of sarcoidosis and thus the clinical usability of this parameter in a large population. One hundred ten sarcoidosis patients from central Japan were examined for clinical features and serum lysozyme level at the first visit to our hospital and on a regular basis thereafter. The sensitivity of lysozyme for predicting sarcoidosis was 79.1%, whereas that of serum angiotensin-converting enzyme (ACE) was 59.0%. Even in the cases without an elevated serum ACE level, a value of 72.1% was obtained. The serum lysozyme level demonstrated a significant tendency to increase with the number of organs involved (p < 0.01). There were significant differences among the four radiographic stages (p < 0.05). The maximum serum lysozyme levels of patients without a disappearance of abnormal shadows on chest radiography within 5 years were significantly greater than those of individuals with a disappearance (p < 0.05). A positive correlation between serum lysozyme and serum ACE levels was observed. Because serum lysozyme is much less specific for sarcoidosis than serum ACE, its diagnostic value may be limited. However, the sensitivity was high even when serum ACE levels were within normal limits and correlated well with clinical features in sarcoidosis. Therefore, this parameter seems suitable for disease monitoring in proven cases.

p185HER-2/neu and p21CIP1/WAF1 Expression in Primary Tumors and Lymph Node Metastases in Non-small Cell Lung Cancer

p185HER‐2/neu, a tyrosine kinase receptor, is one of the target molecules for cancer therapy, and its expression may reduce the sensitivity of tumor cells to anti‐cancer drugs. p21CIP1/WAF1 is a cyclindependent kinase inhibitor, and its expression may also be involved in chemoresistance. Non‐small cell lung cancer (NSCLC) is a potentially systemic disease, and systemic therapies play an important role in its treatment. However, there have been no studies comparing the expression of these molecules between primary and metastatic tumors. We investigated the expression of p185HER‐2/neu and p21CIP1/WAF1 in 57 paired samples of primary NSCLC tumors and corresponding lymph node metastases by immunohistochemistry. Expression of each of p185HER‐2/neu and p21CIP1/WAF1 was highly correlated between primary tumors and lymph node metastases, and similar correlations were also obtained when adenocarcinoma and squamous cell carcinoma cases were analyzed individually. However we failed to detect any correlation between p185HER‐2/neu and p21CIP1/WAF1 expression. Our results suggested that expression of both p185HER‐2/neu and p21CIP1/WAF1 is concordant between primary and metastatic tumors.