title: Targeting therapy of hepatocellular carcinoma with doxorubicin prodrug PDOX increases anti-metastatic effect and reduces toxicity: a preclinical study.
abstract: BACKGROUND
  This study was to investigate the effects and safety of cathepsin B-cleavable doxorubicin (DOX)-prodrug (PDOX) for targeting therapy of metastatic human hepatocellular carcinoma (HCC) using DOX as a positive control drug.
  
  
  METHODS
  The orthotopic nude mice model of highly metastatic HCC was established and the animals were randomized and treated with PDOX, DOX and saline, respectively. Hematology, biochemistry and tumor markers were studied. At autopsy, liver tumor weight and size, ascites, abdominal lymph nodes metastases, experimental peritoneal carcinomatosis index (ePCI), and tumor-host body weight ratio were investigated. Immunohistochemical studies and western blotting were done to investigate key molecules involved in the mechanism of action.
  
  
  RESULTS
  Compared with Control, both PDOX and DOX could similarly and significantly reduce liver tumor weight and tumor volume by over 40%, ePCI values, retroperitoneal lymph node metastases and lung metastases and serum AFP levels (P < 0.05). The PDOX group had significantly higher WBC than the DOX group (P < 0.05), and higher PLT than Control (P < 0.05). Serum BUN and Cr levels were lower in the PDOX group than DOX and Control groups (P < 0.05). Compared with Control, DOX increased CK and CK-MB; while PDOX decreased CK compared with DOX (P < 0.05). Multiple spotty degenerative changes of the myocardium were observed in DOX-treated mice, but not in the Control and PDOX groups. PDOX could significantly reduce the Ki-67 positive rate of tumor cells, compared with DOX and Control groups. PDOX produced the effects at least via the ERK pathway.
  
  
  CONCLUSIONS
  Compared with DOX, PDOX may have better anti-metastatic efficacy and reduced side effects especially cardio-toxicities in this HCC model.
authors: Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, No 169 Donghu Road, Wuchang District, 430071 Wuhan, P,R, China. liyansd2@163.com.
authors: Qun
authors: Q
authors: Wang
authors: Yan-Jun
authors: YJ
authors: Zhong
authors: Jing-Ping
authors: JP
authors: Yuan
authors: Li-Hua
authors: LH
authors: Shao
authors: Jue
authors: J
authors: Zhang
authors: Li
authors: L
authors: Tang
authors: Shao-Ping
authors: SP
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; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006403:Hematologic Tests; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000556:secondary*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D011355:Prodrugs / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D009842:Oligopeptides; D011355:Prodrugs; C573848:acetyl-phenylalanyl-lysyl-para-aminobenzyloxycarbonyl-adriamycin; D004317:Doxorubicin; D048049:Extracellular Signal-Regulated MAP Kinases
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