This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fang, J. Articles by Maeda, H. Search for Related Content PubMed PubMed Citation Articles by Fang, J. Articles by Maeda, H.

In Vivo Antitumor Activity of Pegylated Zinc Protoporphyrin

Targeted Inhibition of Heme Oxygenase in Solid Tumor¹

Department of Microbiology, Kumamoto University School of Medicine [J. F., T. S., Ta. A., Te. A., S. K. S., G. K., H. M.], and Faculty of Pharmacy, Kumamoto University [A. H.], Kumamoto 860-0811, Japan

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.

This article has been cited by other articles:

				S. A. Rushworth and D. J. MacEwan HO-1 underlies resistance of AML cells to TNF-induced apoptosis Blood, April 1, 2008; 111(7): 3793 - 3801. [Abstract] [Full Text] [PDF]

				N. G. Abraham and A. Kappas Pharmacological and Clinical Aspects of Heme Oxygenase Pharmacol. Rev., March 1, 2008; 60(1): 79 - 127. [Abstract] [Full Text] [PDF]

				M. Mayerhofer, K. V. Gleixner, J. Mayerhofer, G. Hoermann, E. Jaeger, K. J. Aichberger, R. G. Ott, K. Greish, H. Nakamura, S. Derdak, et al. Targeting of heat shock protein 32 (Hsp32)/heme oxygenase-1 (HO-1) in leukemic cells in chronic myeloid leukemia: a novel approach to overcome resistance against imatinib Blood, February 15, 2008; 111(4): 2200 - 2210. [Abstract] [Full Text] [PDF]

				J. Dulak, J. Deshane, A. Jozkowicz, and A. Agarwal Heme Oxygenase-1 and Carbon Monoxide in Vascular Pathobiology: Focus on Angiogenesis Circulation, January 15, 2008; 117(2): 231 - 241. [Abstract] [Full Text] [PDF]

				S.-S. Lo, S.-C. Lin, C.-W. Wu, J.-H. Chen, W.-I Yeh, M.-Y. Chung, and W.-Y. Lui Heme Oxygenase-1 Gene Promoter Polymorphism is Associated with Risk of Gastric Adenocarcinoma and Lymphovascular Tumor Invasion Ann. Surg. Oncol., August 1, 2007; 14(8): 2250 - 2256. [Abstract] [Full Text] [PDF]

				R. Kondo, K. V. Gleixner, M. Mayerhofer, A. Vales, A. Gruze, P. Samorapoompichit, K. Greish, M.-T. Krauth, K. J. Aichberger, W. F. Pickl, et al. Identification of heat shock protein 32 (Hsp32) as a novel survival factor and therapeutic target in neoplastic mast cells Blood, July 15, 2007; 110(2): 661 - 669. [Abstract] [Full Text] [PDF]

				J. Deshane, S. Chen, S. Caballero, A. Grochot-Przeczek, H. Was, S. Li Calzi, R. Lach, T. D. Hock, B. Chen, N. Hill-Kapturczak, et al. Stromal cell-derived factor 1 promotes angiogenesis via a heme oxygenase 1-dependent mechanism J. Exp. Med., March 19, 2007; 204(3): 605 - 618. [Abstract] [Full Text] [PDF]

				I. V. Lebedeva, I. Washington, D. Sarkar, J. A. Clark, R. L. Fine, P. Dent, D. T. Curiel, N. J. Turro, and P. B. Fisher Strategy for reversing resistance to a single anticancer agent in human prostate and pancreatic carcinomas PNAS, February 27, 2007; 104(9): 3484 - 3489. [Abstract] [Full Text] [PDF]

				H. Was, T. Cichon, R. Smolarczyk, D. Rudnicka, M. Stopa, C. Chevalier, J. J. Leger, B. Lackowska, A. Grochot, K. Bojkowska, et al. Overexpression of Heme Oxygenase-1 in Murine Melanoma: Increased Proliferation and Viability of Tumor Cells, Decreased Survival of Mice Am. J. Pathol., December 1, 2006; 169(6): 2181 - 2198. [Abstract] [Full Text] [PDF]

				M.-H. Kweon, V. M. Adhami, J.-S. Lee, and H. Mukhtar Constitutive Overexpression of Nrf2-dependent Heme Oxygenase-1 in A549 Cells Contributes to Resistance to Apoptosis Induced by Epigallocatechin 3-Gallate J. Biol. Chem., November 3, 2006; 281(44): 33761 - 33772. [Abstract] [Full Text] [PDF]

				M. J. Marinissen, T. Tanos, M. Bolos, M. R. de Sagarra, O. A. Coso, and A. Cuadrado Inhibition of Heme Oxygenase-1 Interferes with the Transforming Activity of the Kaposi Sarcoma Herpesvirusencoded G Protein-coupled Receptor J. Biol. Chem., April 21, 2006; 281(16): 11332 - 11346. [Abstract] [Full Text] [PDF]

				S. W. Chung, Y.-H. Chen, S.-F. Yet, M. D. Layne, and M. A. Perrella Endotoxin-Induced Down-Regulation of Elk-3 Facilitates Heme Oxygenase-1 Induction in Macrophages J. Immunol., February 15, 2006; 176(4): 2414 - 2420. [Abstract] [Full Text] [PDF]

				M. Hill, V. Pereira, C. Chauveau, R. Zagani, S. Remy, L. Tesson, D. Mazal, L. Ubillos, R. Brion, K. Ashgar, et al. Heme oxygenase-1 inhibits rat and human breast cancer cell proliferation: mutual cross inhibition with indoleamine 2,3-dioxygenase FASEB J, December 1, 2005; 19(14): 1957 - 1968. [Abstract] [Full Text] [PDF]

				L. Wu and R. Wang Carbon Monoxide: Endogenous Production, Physiological Functions, and Pharmacological Applications Pharmacol. Rev., December 1, 2005; 57(4): 585 - 630. [Abstract] [Full Text] [PDF]

				P. O. Berberat, Z. Dambrauskas, A. Gulbinas, T. Giese, N. Giese, B. Kunzli, F. Autschbach, S. Meuer, M. W. Buchler, and H. Friess Inhibition of Heme Oxygenase-1 Increases Responsiveness of Pancreatic Cancer Cells to Anticancer Treatment Clin. Cancer Res., May 15, 2005; 11(10): 3790 - 3798. [Abstract] [Full Text] [PDF]

				M. Mayerhofer, S. Florian, M.-T. Krauth, K. J. Aichberger, M. Bilban, R. Marculescu, D. Printz, G. Fritsch, O. Wagner, E. Selzer, et al. Identification of Heme Oxygenase-1 As a Novel BCR/ABL-Dependent Survival Factor in Chronic Myeloid Leukemia Cancer Res., May 1, 2004; 64(9): 3148 - 3154. [Abstract] [Full Text] [PDF]