Oncolysis of diffuse hepatocellular carcinoma by intravascular administration of a replication-competent, genetically engineered herpesvirus.
Herpes simplex virus type 1 (HSV-1) replication within tumors can mediate tumor regression (oncolysis). The genetically engineered, HSV-1 mutant rRp450 does not express viral ribonucleotide reductase and is therefore replication conditional. During the course of infection, rRp450 expresses the cytochrome P450 transgene and HSV-1 thymidine kinase gene, thereby enabling it to bioactivate the prodrugs cyclophosphamide and ganciclovir, respectively. rRp450 replication in hepatocellular carcinoma (HCC) cells is cytotoxic and liberates progeny virion that infect adjacent tumor cells. rRp450-mediated oncolysis is enhanced in the presence of cyclophosphamide, whereas it is inhibited in the presence of ganciclovir. As a consequence of defective viral ribonucleotide reductase expression, the yield of rRp450 progeny virions from infection of HCC cells is 3 to 4 log orders greater than that from infection of normal hepatocytes. This is associated with dramatic tumor reduction of diffuse HCC after a single intravascular administration of rRp450. rRp450 holds the promise of the dual therapeutic benefit of selective oncolysis and P450 transgene delivery.
Pawlik
T M
TM
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
Nakamura
H
H
Yoon
S S
SS
Mullen
J T
JT
Chandrasekhar
S
S
Chiocca
E A
EA
Tanabe
K K
KK
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000628:therapy*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003520:Cyclophosphamide / Q000494:pharmacology; D019362:Cytochrome P-450 CYP2B1 / Q000235:genetics; D015774:Ganciclovir / Q000494:pharmacology; D005786:Gene Expression Regulation; D005818:Genetic Engineering; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000628:therapy*; D008114:Liver Neoplasms, Experimental / Q000628:therapy*; D051379:Mice; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000378:metabolism; D051381:Rats; D019076:Transgenes; D014407:Tumor Cells, Cultured; D014709:Vero Cells
D018906:Antineoplastic Agents, Alkylating; D000998:Antiviral Agents; D011355:Prodrugs; D003520:Cyclophosphamide; D019362:Cytochrome P-450 CYP2B1; D015774:Ganciclovir