Trojan p16 peptide suppresses pancreatic cancer growth and prolongs survival in mice.
OBJECTIVE
The tumor suppressor gene p16INK4A is inactivated frequently in a large number of human cancers, and many investigators have attempted to restore the function of p16 using the p16 wild-type gene and viral vectors. In this study, we treated the tumor-bearing animals with the p16-derived synthetic peptide coupled with the Antennapedia carrier sequence, which we designated as Trojan p16 peptide.


METHODS
Injections (i.p.) of the Trojan p16 peptide (100 microg/mouse/day) were given for 3 weeks in the AsPC-1 and BxPC-3 s.c. tumor models. Tumor growth, histopathology, and TUNEL staining of the tumor and toxicity of the animals were evaluated. To examine its influence on the survival of tumor-bearing mice, Trojan p16 was administered in the AsPC-1 peritoneal dissemination model.


RESULTS
In the AsPC-1 s.c. tumor model, a significant growth inhibition was obtained by the Trojan p16 treatment when compared with the three control treatments, i.e., vehicle, unconjugated form of p16, or Trojan peptide alone. Tumor growth inhibition was almost complete in the BxPC-3 tumor, a relatively slow growing tumor. Neither hematological cytotoxicity or body weight loss were observed. Histopathology of the BxPC-3 s.c. tumor in the Trojan p16 treatment group revealed marked vacuole formation and apoptotic death of cancer cells. In the AsPC-1 peritoneal dissemination model, the survival curve of mice treated with Trojan p16 was significantly longer than that of control.


CONCLUSIONS
These results provide evidence that the Trojan p16 peptide system, a gene-oriented peptide coupled with a peptide vector, functions for experimental pancreatic cancer therapy.
Hosotani
Ryo
R
Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan. hoso@h8.dion.ne.jp
Miyamoto
Yoshiharu
Y
Fujimoto
Koji
K
Doi
Ryuichiro
R
Otaka
Akira
A
Fujii
Nobutaka
N
Imamura
Masayuki
M
D000595:Amino Acid Sequence; D000818:Animals; D001772:Blood Cell Count; D001835:Body Weight / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology*; D016019:Survival Analysis; D015996:Survival Rate; D014407:Tumor Cells, Cultured / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D019941:Cyclin-Dependent Kinase Inhibitor p16; D010446:Peptide Fragments