An oncolytic herpes simplex virus type 1 selectively destroys diffuse liver metastases from colon carcinoma

Abstract

Viruses used for gene therapy are usually genetically modified to deliver therapeutic transgenes and prevent viral replication. In contrast, replication-competent viruses may be used for cancer therapy because replication of some viruses within cancer cells can result in their destruction (oncolysis). Viral ribonucleotide reductase expression is defective in the HSV1 mutant hrR3. Cellular ribonucleotide reductase, which is scarce in normal liver and abundant in liver metastases, can substitute for its viral counterpart to allow hrR3 replication in infected cells. Two or three log orders more of hrR3 virions are produced from infection of colon carcinoma cells than from infection of normal hepatocytes in viral replication assays. This viral replication is oncolytic. A single intravascular administration of hrR3 into immune-competent mice bearing diffuse liver metastases dramatically reduces tumor burden. hrR3-mediated tumor inhibition is equivalent in immune-competent and immune-incompetent mice, suggesting that viral oncolysis and not the host immune response is the primary mechanism of tumor destruction. HSV1-mediated oncolysis of diffuse liver metastases is effective in mice preimmunized against HSV1. These results indicate that replication-competent HSV1 mutants hold significant promise as cancer therapeutic agents. Yoon, S. S., Nakamura, H., Carroll, N. M., Bode, B. P., Chiocca, E. A., Tanabe, K. K. An oncolytic herpes simplex virus type 1 selectively destroys diffuse liver metastases from colon carcinoma.

Prodrug bioactivation and oncolysis of diffuse liver metastases by a herpes simplex virus 1 mutant that expresses the CYP2B1 transgene

“…BALB/c mice weighing [15][16][17][18][19][20] into the spleens of BALB/c mice. Animals were treated three days later with a single intrasplenic administration of either 5 ϫ 10 7 pfu rRp450 or mock-infected control media.…”

“…16,21 To examine the therapeutic potential of rRp450 against diffuse colon carcinoma liver metastases, MC26 liver metastases were established in BALB/c mice, and the mice were subsequently treated with a single intraportal inoculation of mock-infected media or 5 ϫ 10 6 pfu rRp450 three days later. Mice were randomized to receive a single intraperitoneal injection of either PBS or cyclophosphamide (30 mg/kg) two days following virus administration.…”

“…15 We have previously reported that intravascular administration of an HSV-1 mutant that is defective in ribonucleotide reductase to mice with diffuse colon carcinoma liver metastases significantly reduces liver tumor. 16 With the goal of enhancing the therapeutic efficacy of this approach, we engineered a replicationconditional HSV-1 mutant such that it is defective in expression of the large subunit of viral ribonucleotide reductase and expresses the rat cytochrome P450 2B1 (CYP2B1) transgene; 17 CYP2B1 initiates bioactivation of the prodrug cyclophosphamide into its active cytotoxic metabolites. rRp450-mediated delivery of this type of suicide gene provides a means for intratumoral generation of alkylating metabolites.…”

Oncolytic recombinant herpes simplex virus for treatment of orthotopic liver tumors in nude mice

“…The antitumor effect of rHSV is reported to be much greater than its evident distribution throughout tumors (20)(21)(22)(23)(24)(25). HSV infection induces apoptosis in adjacent, uninfected cells in vitro and in vivo (26).…”

Effective Intravenous Therapy of Murine Pulmonary Metastases with an Oncolytic Herpes Virus Expressing Interleukin 12

“…Similarly, viral delivery to tumor confined within an anatomical compartment, such as the peritoneal cavity, pleural cavity, or the bladder, also exhibits significant antitumoral effects (19 -21). Studies have also shown that selective intra- portal or intrasplenic delivery of an oncolytic virus may effectively treat animal models of liver tumors (22,23). The potential of these agents to treat regionally metastatic nodal disease has also been demonstrated previously (24).…”