PMID- 12839943
OWN - NLM
STAT- MEDLINE
DCOM- 20030825
LR  - 20181130
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 63
IP  - 13
DP  - 2003 Jul 1
TI  - In vivo antitumor activity of pegylated zinc protoporphyrin: targeted inhibition 
      of heme oxygenase in solid tumor.
PG  - 3567-74
AB  - High expression of the inducible isoform of heme oxygenase (HO-1) is now well 
      known in solid tumors in humans and experimental animal models. We reported 
      previously that HO-1 may be involved in tumor growth (Tanaka et al., Br. J. 
      Cancer, 88: 902-909, 2003), in that inhibition of HO activity in tumors by using 
      zinc protoporphyrin (ZnPP) significantly reduced tumor growth in a rat model. We 
      demonstrate here that poly(ethylene glycol)-conjugated ZnPP (PEG-ZnPP), a 
      water-soluble derivative of ZnPP, exhibited potent HO inhibitory activity and had 
      an antitumor effect in vivo. In vitro studies with cultured SW480 cells, which 
      express HO-1, showed that PEG-ZnPP induced oxidative stress, and consequently 
      apoptotic death, of these cells. Pharmacokinetic analysis revealed that 
      PEG-ZnPP-administered i.v. had a circulation time in blood that was 40 times 
      longer than that for nonpegylated ZnPP. More important, PEG-ZnPP preferentially 
      accumulated in solid tumor tissue in a murine model. In vivo treatment with 
      PEG-ZnPP (equivalent to 1.5 or 5 mg of ZnPP/kg, i.v., injected daily for 6 days) 
      remarkably suppressed the growth of Sarcoma 180 tumors implanted in the dorsal 
      skin of ddY mice without any apparent side effects. In addition, this PEG-ZnPP 
      treatment produced tumor-selective suppression of HO activity as well as 
      induction of apoptosis. The major reason for tumor-selective targeting of 
      PEG-ZnPP is attributed to the enhanced permeability and retention effect that is 
      observed commonly in solid tumors for biocompatible macromolecular drugs. These 
      findings suggest that tumor-targeted inhibition of HO activity could be achieved 
      by using PEG-ZnPP, which induces apoptosis in solid tumors, probably through 
      increased oxidative stress.
FAU - Fang, Jun
AU  - Fang J
AD  - Department of Microbiology, Kumamoto University School of Medicine, Kumamoto 
      860-0811, Japan.
FAU - Sawa, Tomohiro
AU  - Sawa T
FAU - Akaike, Takaaki
AU  - Akaike T
FAU - Akuta, Teruo
AU  - Akuta T
FAU - Sahoo, Sanjeeb K
AU  - Sahoo SK
FAU - Khaled, Greish
AU  - Khaled G
FAU - Hamada, Akinobu
AU  - Hamada A
FAU - Maeda, Hiroshi
AU  - Maeda H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Membrane Proteins)
RN  - 0 (Metalloporphyrins)
RN  - 0 (pegylated zinc protoporphyrin)
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - EC 1.14.14.18 (HMOX1 protein, human)
RN  - EC 1.14.14.18 (Heme Oxygenase (Decyclizing))
RN  - EC 1.14.14.18 (Heme Oxygenase-1)
RN  - EC 1.14.14.18 (Hmox1 protein, mouse)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/pharmacokinetics/*therapeutic use
MH  - Apoptosis/drug effects
MH  - Colonic Neoplasms/*drug therapy
MH  - Enzyme Inhibitors/*therapeutic use
MH  - Heme Oxygenase (Decyclizing)/*antagonists & inhibitors
MH  - Heme Oxygenase-1
MH  - Humans
MH  - In Situ Nick-End Labeling
MH  - Male
MH  - Membrane Proteins
MH  - Metalloporphyrins/pharmacokinetics/*therapeutic use
MH  - Mice
MH  - Mice, Inbred Strains
MH  - Polyethylene Glycols/pharmacokinetics/*therapeutic use
MH  - Sarcoma, Experimental/drug therapy/pathology
MH  - Transplantation, Heterologous
MH  - Tumor Cells, Cultured
EDAT- 2003/07/04 05:00
MHDA- 2003/08/26 05:00
CRDT- 2003/07/04 05:00
PHST- 2003/07/04 05:00 [pubmed]
PHST- 2003/08/26 05:00 [medline]
PHST- 2003/07/04 05:00 [entrez]
PST - ppublish
SO  - Cancer Res. 2003 Jul 1;63(13):3567-74.