Oncolysis of diffuse hepatocellular carcinoma by intravascular administration of a replication-competent, genetically engineered herpesvirus

Timothy M. Pawlik, Hideo Nakamura, Sam S. Yoon, John T. Mullen, Soundararajalu Chandrasekhar, E. Antonio Chiocca, Kenneth K. Tanabe

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2790-2795
Number of pages6
JournalCancer Research
Volume60
Issue number11
StatePublished - Jun 1 2000
Externally publishedYes

Fingerprint

Herpesviridae
Hepatocellular Carcinoma
Human Herpesvirus 1
Ribonucleotide Reductases
Ganciclovir
Transgenes
Virion
Cyclophosphamide
Neoplasms
Infection
Thymidine Kinase
Prodrugs
Virus Replication
Cytochrome P-450 Enzyme System
Hepatocytes
Genes
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Pawlik, T. M., Nakamura, H., Yoon, S. S., Mullen, J. T., Chandrasekhar, S., Chiocca, E. A., & Tanabe, K. K. (2000). Oncolysis of diffuse hepatocellular carcinoma by intravascular administration of a replication-competent, genetically engineered herpesvirus. Cancer Research, 60(11), 2790-2795.

Oncolysis of diffuse hepatocellular carcinoma by intravascular administration of a replication-competent, genetically engineered herpesvirus. / Pawlik, Timothy M.; Nakamura, Hideo; Yoon, Sam S.; Mullen, John T.; Chandrasekhar, Soundararajalu; Chiocca, E. Antonio; Tanabe, Kenneth K.

In: Cancer Research, Vol. 60, No. 11, 01.06.2000, p. 2790-2795.

Research output: Contribution to journalArticle

Pawlik, TM, Nakamura, H, Yoon, SS, Mullen, JT, Chandrasekhar, S, Chiocca, EA & Tanabe, KK 2000, 'Oncolysis of diffuse hepatocellular carcinoma by intravascular administration of a replication-competent, genetically engineered herpesvirus', Cancer Research, vol. 60, no. 11, pp. 2790-2795.
Pawlik TM, Nakamura H, Yoon SS, Mullen JT, Chandrasekhar S, Chiocca EA et al. Oncolysis of diffuse hepatocellular carcinoma by intravascular administration of a replication-competent, genetically engineered herpesvirus. Cancer Research. 2000 Jun 1;60(11):2790-2795.
Pawlik, Timothy M. ; Nakamura, Hideo ; Yoon, Sam S. ; Mullen, John T. ; Chandrasekhar, Soundararajalu ; Chiocca, E. Antonio ; Tanabe, Kenneth K. / Oncolysis of diffuse hepatocellular carcinoma by intravascular administration of a replication-competent, genetically engineered herpesvirus. In: Cancer Research. 2000 ; Vol. 60, No. 11. pp. 2790-2795.
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