Cisplatin-induced in vivo differentiation of human embryonal carcinoma.
OBJECTIVE
To investigate the differentiation of embryonal carcinoma (EC) by cisplatin, and the underlying mechanism, as untreated metastases of nonseminomatous germ cell tumours rarely consist of fully differentiated mature somatic tissues, but such mature metastases are more common after various treatments, including chemotherapy.


METHODS
The TTSC-3 human testicular EC line heterotransplanted into nude mice was used as a target. After treating tumour-bearing mice with intraperitoneal injections of varying doses of cisplatin, the histopathology of the tumours was assessed and various gene expressions in the tumours determined by cDNA-array technology.


RESULTS
When cisplatin at 1 mg/kg/week was injected intraperitoneally into TTSC-3-bearing mice, there was no effect on tumour growth. However, injecting cisplatin at 5 mg/kg/week induced a marked regression of the tumour. In contrast, cisplatin at 3 mg/kg/week had a modest inhibitory effect on tumour growth and induced tumour dormancy. Histological examination showed that 5 weeks after injecting cisplatin (3 mg/kg/week), primitive mesenchymal-like cells increased, and 10 weeks afterward cartilage and well-developed glands (teratoma) were apparent; at > 15 weeks afterward there were no EC cells visible. cDNA probes from reverse-transcribed mRNAs of TTSC-3 treated with cisplatin or saline for 10 weeks were compared to identify genes differentially expressed in cisplatin-treated TTSC-3. Of 1176 different human cDNA transcripts in cisplatin-treated TTSC-3, three genes (tumour necrosis factor receptor 1, caspase 8 and Apaf1), which are associated with apoptosis, were expressed markedly more than after saline injection.


CONCLUSIONS
The intermediate dose of cisplatin inhibited tumour growth of EC by inducing differentiation and enhancing apoptosis-related gene expression. These findings suggest that cisplatin may play a significant role in the differentiation of EC in vivo.
Mizutani
Y
Y
Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan. ymizutan@koto.kpu-m.ac.jp
Sato
N
N
Kawauchi
A
A
Nonomura
N
N
Fukushima
M
M
Miki
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis; D018236:Carcinoma, Embryonal / Q000188:drug therapy*; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D002945:Cisplatin / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013736:Testicular Neoplasms / Q000188:drug therapy*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002945:Cisplatin