Expression of inducible nitric oxide synthase during cisplatin-based chemotherapy for gastric cancer.
BACKGROUND
Nitric oxide (NO) has been reported to protect cells from apoptosis during chemotherapy. In this study, the protective role of inducible nitric oxide synthase (iNOS) against cisplatin (CDDP)-induced apoptosis was evaluated in a cell line and in patients with gastric cancer.


METHODS
MKN-45 cells were incubated with CDDP and the correlation between the occurrence of apoptotic cells (evaluated by flow cytometry) and the expression of iNOS messenger RNA (mRNA) in cells was analyzed. In 15 patients with advanced gastric cancer, CDDP-based preoperative chemotherapy was introduced. The expression levels of iNOS mRNA were compared between tumor samples before and after treatment with CDDP. Moreover, the iNOS protein expression and the percentage of apoptotic cancer cells (apoptotic index: AI) were analyzed immunohistochemically in 15 CDDP-treated tumors and in 50 untreated advanced gastric cancers.


RESULTS
High AI was detected after 24 hours of treatment with high-dose CDDP in MKN-45, while the iNOS mRNA expression levels did not change before and after treatment. In 15 patients treated with CDDP, the percentage of iNOS mRNA-positive cases increased from 20% (pretreatment tumors) to 40% (resected tumors). However, the mean AI of iNOS-positive tumors was not different from that of iNOS-negative tumors. Also, in 50 untreated patients, iNOS protein expression did not correlate with the AIs of the tumors.


CONCLUSIONS
Our results demonstrate that iNOS expression may not correlate with the occurrence of apoptosis during CDDP treatment in gastric cancer.
First Department of Surgery, Faculty of Medicine, Tottori University, 36-1 Nishicho, Yonago 683-8504, Japan. masaike@grape.med.tottori-u.ac.jp
Masahide
M
Ikeguchi
Tsuyoshi
T
Ueta
Nobuaki
N
Kaibara
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D012333:RNA, Messenger; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D002945:Cisplatin