In vivo antitumor activity of pegylated zinc protoporphyrin: targeted inhibition of heme oxygenase in solid tumor.
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.
Fang
Jun
J
Department of Microbiology, Kumamoto University School of Medicine, Kumamoto 860-0811, Japan.
Sawa
Tomohiro
T
Akaike
Takaaki
T
Akuta
Teruo
T
Sahoo
Sanjeeb K
SK
Khaled
Greish
G
Hamada
Akinobu
A
Maeda
Hiroshi
H
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors*; D051547:Heme Oxygenase-1; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D008565:Membrane Proteins; D008665:Metalloporphyrins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008815:Mice, Inbred Strains; D011092:Polyethylene Glycols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000473:pathology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D008665:Metalloporphyrins; C476103:pegylated zinc protoporphyrin; D011092:Polyethylene Glycols; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse