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 microg/g of tumor tissue/h when CPA was administered via intraneoplastic polymer and 3 microg/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.
Publication types
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Antineoplastic Agents, Alkylating / administration & dosage*
-
Antineoplastic Agents, Alkylating / pharmacokinetics*
-
Biocompatible Materials / administration & dosage
-
Biotransformation
-
Cyclophosphamide / administration & dosage*
-
Cyclophosphamide / analogs & derivatives
-
Cyclophosphamide / pharmacokinetics*
-
Cytochrome P-450 CYP2B1 / genetics*
-
Cytochrome P-450 CYP2B1 / metabolism
-
Decanoic Acids / administration & dosage*
-
Drug Carriers
-
Genetic Therapy / methods
-
Genetic Vectors / genetics
-
Glioblastoma / drug therapy
-
Glioblastoma / metabolism
-
Glioblastoma / virology
-
Herpes Simplex / metabolism
-
Herpesvirus 1, Human / enzymology
-
Herpesvirus 1, Human / genetics*
-
Humans
-
Injections, Intralesional
-
Kinetics
-
Mice
-
Mice, Nude
-
Phosphoramide Mustards / pharmacokinetics
-
Polyesters / administration & dosage*
-
Prodrugs / administration & dosage
-
Prodrugs / pharmacokinetics
-
Rats
-
Tumor Cells, Cultured
-
Xenograft Model Antitumor Assays
Substances
-
Antineoplastic Agents, Alkylating
-
Biocompatible Materials
-
Decanoic Acids
-
Drug Carriers
-
Phosphoramide Mustards
-
Polyesters
-
Prodrugs
-
4-hydroxycyclophosphamide
-
aldophosphamide
-
Cyclophosphamide
-
decanedioic acid-4,4'-(1,3-propanediylbis(oxy))bis(benzoic acid) copolymer
-
Cytochrome P-450 CYP2B1