Intraneoplastic polymer-based delivery of cyclophosphamide for intratumoral bioconversion by a replicating oncolytic viral vector.
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.
Ichikawa
T
T
Molecular Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
Petros
W P
WP
Ludeman
S M
SM
Fangmeier
J
J
Hochberg
F H
FH
Colvin
O M
OM
Chiocca
E A
EA
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001672:Biocompatible Materials / Q000008:administration & dosage; D001711:Biotransformation; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D019362:Cytochrome P-450 CYP2B1 / Q000235:genetics* / Q000378:metabolism; D003652:Decanoic Acids / Q000008:administration & dosage*; D004337:Drug Carriers; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D006561:Herpes Simplex / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D015552:Injections, Intralesional; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D010752:Phosphoramide Mustards / Q000493:pharmacokinetics; D011091:Polyesters / Q000008:administration & dosage*; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics; D051381:Rats; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D001672:Biocompatible Materials; D003652:Decanoic Acids; D004337:Drug Carriers; D010752:Phosphoramide Mustards; D011091:Polyesters; D011355:Prodrugs; C012358:4-hydroxycyclophosphamide; C006446:aldophosphamide; D003520:Cyclophosphamide; C055401:decanedioic acid-4,4'-(1,3-propanediylbis(oxy))bis(benzoic acid) copolymer; D019362:Cytochrome P-450 CYP2B1