Prospective antitumor effects of the combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and cisplatin against esophageal squamous cell carcinoma.
OBJECTIVE
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family, which binds to death receptor (DR) 4 and DR5 to mediate apoptosis. Previously, we showed that the combination of TRAIL and cisplatin was effective against esophageal squamous cell carcinoma (ESCC) cell lines in vitro and in vivo, using one of the ESCC cell lines (KYSE 170). KYSE 110 is another ESCC cell line, but it lacks expression of decoy receptors. Thus, by using KYSE 110, we can eliminate any effects from two decoy receptors.


METHODS
We used reverse transcription-polymerase chain reaction (RT-PCR) to reveal the expression of TRAIL receptors. Crystal violet staining and flow cytometry were done to confirm cytotoxicity and induction of apoptosis. KYSE 110 xenografted in nude mice was treated with TRAIL and cisplatin. The tumors were subsequently removed for microscopic studies.


RESULTS
ESCC sensitive to the combination treatment in vitro was also sensitive to the treatment in vivo. Furthermore, induction of apoptosis resulted via the caspase cascade and the mitochondrial pathway. Low doses of both cisplatin and TRAIL sufficed to obtain these effects.


CONCLUSIONS
These findings imply that in clinical application, low doses of both agents could be administered to minimize side effects, while augmenting tumoricidal activities.
Kondo
Kan
K
Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.
Yamasaki
Seiji
S
Inoue
Naoya
N
Sugie
Tomoharu
T
Teratani
Naoki
N
Kan
Takatsugu
T
Shimada
Yutaka
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011446:Prospective Studies; D012334:RNA, Neoplasm / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D012334:RNA, Neoplasm; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D002945:Cisplatin