Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells.
OBJECTIVE
We aimed to find key molecules associated with chemoresistance in ovarian cancer using gene expression profiling as a screening tool.


METHODS
Using two newly established paclitaxel-resistant ovarian cancer cell lines from an original paclitaxel-sensitive cell line and four supersensitive and four refractory surgical ovarian cancer specimens from paclitaxel-based chemotherapy, molecules associated with chemoresistance were screened with gene expression profiling arrays containing 39,000 genes. We further analyzed 44 genes that showed significantly different expressions between paclitaxel-sensitive samples and paclitaxel-resistant samples with permutation tests, which were common in cell lines and patients' tumors.


RESULTS
Eight of these genes showed reproducible results with real-time reverse transcription-PCR, of which indoleamine 2,3-dioxygenase gene expression was the most prominent and consistent. Moreover, by immunohistochemical analysis using a total of 24 serous-type ovarian cancer surgical specimens (stage III, n = 21; stage IV, n = 7), excluding samples used for GeneChip analysis, the Kaplan-Meier survival curve showed a clear relationship between indoleamine 2,3-dioxygenase staining patterns and overall survival (log-rank test, P = 0.0001). All patients classified as negative survived without relapse. The 50% survival of patients classified as sporadic, focal, and diffuse was 41, 17, and 11 months, respectively.


CONCLUSIONS
The indoleamine 2,3-dioxygenase screened with the GeneChip was positively associated with paclitaxel resistance and with impaired survival in patients with serous-type ovarian cancer.
Okamoto
Aikou
A
Department of Obstetrics and Gynecology, Jikei University School of Medicine, Tokyo, Japan.
Nikaido
Takashi
T
Ochiai
Kazunori
K
Takakura
Satoshi
S
Saito
Misato
M
Aoki
Yuko
Y
Ishii
Nobuya
N
Yanaihara
Nozomu
N
Yamada
Kyosuke
K
Takikawa
Osamu
O
Kawaguchi
Rie
R
Isonishi
Seiji
S
Tanaka
Tadao
T
Urashima
Mitsuyoshi
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D016000:Cluster Analysis; D018284:Cystadenocarcinoma, Serous / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics* / Q000378:metabolism; D020128:Inhibitory Concentration 50; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology; D011379:Prognosis; D016019:Survival Analysis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D017239:Paclitaxel; D002945:Cisplatin