title: Cathepsin B cleavable novel prodrug Ac-Phe-Lys-PABC-ADM enhances efficacy at reduced toxicity in treating gastric cancer peritoneal carcinomatosis: an experimental study.
abstract: BACKGROUND
  Doxorubicin (Adriamycin) is effective in gastric cancer treatment, but with severe dose-dependent toxicities. A novel prodrug of doxorubicin (Ac-Phe-Lys-PABC-ADM) is designed to deliver free doxorubicin relying on cathepsin B and reduce side effects. The authors examined the antitumor effect and toxicities of Ac-Phe-Lys-PABC-ADM against gastric cancer peritoneal carcinomatosis.
  
  
  METHODS
  SGC-7901 gastric cancer cell line was used for the study. The in vitro study investigated the effects of doxorubicin and Ac-Phe-Lys-PABC-ADM on cell growth dynamics and cell cycle. The in vivo study investigated the efficacy and toxicity of Ac-Phe-Lys-PABC-ADM on a nude mice model of peritoneal carcinomatosis, with doxorubicin as positive control.
  
  
  RESULTS
  In the in vitro study, Ac-Phe-Lys-PABC-ADM had a lower dose-dependent inhibitory effect on SGC-7901 cells. In the in vivo study of control, doxorubicin, and Ac-Phe-Lys-PABC-ADM groups, the median experimental peritoneal carcinomatosis indexes were 6, 1.5, and 1, respectively (P = .004); the body weights were 24.32 ± 1.40 g, 18.40 ± 2.97 g, and 23.61 ± 0.80 g, respectively (P = .000). Biochemical studies showed that Ac-Phe-Lys-PABC-ADM had significantly lower toxicities on the bone marrow, liver, kidney, and particularly heart. Histopathological studies of the control, doxorubicin, and Ac-Phe-Lys-PABC-ADM groups found significant myocardium toxicities in 3, 7, and 4 animals, respectively.
  
  
  CONCLUSIONS
  Ac-Phe-Lys-PABC-ADM could be an effective molecular targeting drug to treat gastric cancer peritoneal carcinomatosis with enhanced efficacy and reduced toxicity.
authors: Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuhan, China.
authors: Li-Hua
authors: LH
authors: Shao
authors: Shao-Ping
authors: SP
authors: Liu
authors: Jin-Xuan
authors: JX
authors: Hou
authors: Yan-Hua
authors: YH
authors: Zhang
authors: Chun-Wei
authors: CW
authors: Peng
authors: Yan-Jun
authors: YJ
authors: Zhong
authors: Xiong
authors: X
authors: Liu
authors: Xiu-Li
authors: XL
authors: Liu
authors: Ya-Ping
authors: YP
authors: Hong
authors: Raymond A
authors: RA
authors: Firestone
authors: Yan
authors: Y
authors: Li
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000188:drug therapy* / Q000556:secondary*; D002401:Cathepsin B / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D006321:Heart / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009842:Oligopeptides / Q000627:therapeutic use*; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D011355:Prodrugs / Q000009:adverse effects / Q000627:therapeutic use*; D013274:Stomach Neoplasms / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D009842:Oligopeptides; D011355:Prodrugs; C573848:acetyl-phenylalanyl-lysyl-para-aminobenzyloxycarbonyl-adriamycin; D004317:Doxorubicin; D002401:Cathepsin B