Intraneoplastic polymer-based delivery of cyclophosphamide for intratumoral bioconconversion by a replicating oncolytic viral vector

Tomotsugu Ichikawa, William P. Petros, Susan M. Ludeman, Jim Fangmeier, Fred H. Hochberg, O. Michael Colvin, E. Antonio Chiocca

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Abstract

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 lyric 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.

Original languageEnglish
Pages (from-to)864-868
Number of pages5
JournalCancer Research
Volume61
Issue number3
Publication statusPublished - Feb 1 2001

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Ichikawa, T., Petros, W. P., Ludeman, S. M., Fangmeier, J., Hochberg, F. H., Colvin, O. M., & Chiocca, E. A. (2001). Intraneoplastic polymer-based delivery of cyclophosphamide for intratumoral bioconconversion by a replicating oncolytic viral vector. Cancer Research, 61(3), 864-868.