This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Ichikawa, T. Articles by Chiocca, E. A. Search for Related Content PubMed PubMed Citation Articles by Ichikawa, T. Articles by Chiocca, E. A.

Intraneoplastic Polymer-based Delivery of Cyclophosphamide for Intratumoral Bioconversion by a Replicating Oncolytic Viral Vector¹

Molecular Neuro-Oncology Laboratory, Neurosurgery Service [T. I., E. A. C.], and Neurology Service [F. H. H.], Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; and Duke Comprehensive Cancer Center, Durham, North Carolina 27710 [W. P. P., S. M. L., J. F., O. M. C.]

rRp450 is an oncolytic herpesvirus that expresses the CYP2B1 cDNA, responsible for bioconverting cyclophosphamide (CPA) into the active metabolites 4-hydroxyCPA/aldophosphamide (AP). However, formal proof of prodrug activation is lacking. We report that activation of CPA in cells infected with rRp450 generates a time-dependent increase of diffusible 4-hydroxyCPA/AP. For in vivo applications, a CPA-impregnated polymer was implanted into human tumor xenografts inoculated with rRp450. The area under the curve for 4-hydroxyCPA/AP was 806 µg/g of tumor tissue/h when CPA was administered via intraneoplastic polymer and 3 µg/g of tumor tissue/h when CPA was administered i.p. Therefore, (a) a lytic virus expressing a "suicide" gene can activate a prodrug; and (b) within rRp450-infected tumor, more prolonged and higher concentrations of activated metabolites are generated by intraneoplastic compared with systemic administration of prodrug.

This article has been cited by other articles:

				Y. Jounaidi, C.-S. Chen, G. J. Veal, and D. J. Waxman Enhanced antitumor activity of P450 prodrug-based gene therapy using the low Km cyclophosphamide 4-hydroxylase P450 2B11. Mol. Cancer Ther., March 1, 2006; 5(3): 541 - 555. [Abstract] [Full Text] [PDF]

				D. S. Riddick, C. Lee, S. Ramji, E. C. Chinje, R. L. Cowen, K. J. Williams, A. V. Patterson, I. J. Stratford, C. S. Morrow, A. J. Townsend, et al. CANCER CHEMOTHERAPY AND DRUG METABOLISM Drug Metab. Dispos., August 1, 2005; 33(8): 1083 - 1096. [Abstract] [Full Text] [PDF]

				E. Tyminski, S. LeRoy, K. Terada, D. M. Finkelstein, J. L. Hyatt, M. K. Danks, P. M. Potter, Y. Saeki, and E. A. Chiocca Brain Tumor Oncolysis with Replication-Conditional Herpes Simplex Virus Type 1 Expressing the Prodrug-Activating Genes, CYP2B1 and Secreted Human Intestinal Carboxylesterase, in Combination with Cyclophosphamide and Irinotecan Cancer Res., August 1, 2005; 65(15): 6850 - 6857. [Abstract] [Full Text] [PDF]

				E. A. Chiocca Oncolytic Viral Therapeutics Based on Herpes Simplex Virus Type I Am. Assoc. Cancer Res. Educ. Book, April 1, 2005; 2005(1): 139 - 140. [Full Text] [PDF]

				C.-S. Chen, J. T. Lin, K. A. Goss, Y.-a. He, J. R. Halpert, and D. J. Waxman Activation of the Anticancer Prodrugs Cyclophosphamide and Ifosfamide: Identification of Cytochrome P450 2B Enzymes and Site-Specific Mutants with Improved Enzyme Kinetics Mol. Pharmacol., May 1, 2004; 65(5): 1278 - 1285. [Abstract] [Full Text]

				D. J. Waxman and P. S. Schwartz Harnessing Apoptosis for Improved Anticancer Gene Therapy Cancer Res., December 15, 2003; 63(24): 8563 - 8572. [Abstract] [Full Text] [PDF]