The role of a HSV thymidine kinase stimulating substance, scopadulciol, in improving the efficacy of cancer gene therapy.
BACKGROUND
The most extensively investigated strategy of suicide gene therapy for treatment of cancer is the transfer of the herpes simplex virus thymidine kinase (HSV-TK) gene followed by administration of antiviral prodrugs such as acyclovir (ACV) and ganciclovir (GCV). The choice of the agent that can stimulate HSV-TK enzymatic activity is one of the determinants of the usefulness of this strategy. Previously, we found that a diterpenoid, scopadulciol (SDC), produced a significant increase in the active metabolite of ACV. This suggests that SDC may play a role in the HSV-TK/prodrug administration system.


METHODS
The anticancer effect of SDC was evaluated in HSV-TK-expressing (TK+) cancer cells and nude mice bearing TK+ tumors. In vitro and in vivo enzyme assays were performed using TK+ cells and tumors. The phosphorylation of ACV monophosphate (ACV-MP) was measured in TK- cell lysates. The pharmacokinetics of prodrugs was evaluated by calculating area-under-the-concentration-time-curve values.


RESULTS
SDC stimulated HSV-TK activity in TK+ cells and tumors, and increased GCV-TP levels, while no effect of SDC was observed on the phosphorylation of ACV-MP to ACV-TP by cellular kinases. The SDC/prodrug combination altered the pharmacokinetics of the prodrugs. In accord with these findings, SDC enhanced significantly the cell-killing activity of prodrugs. The bystander effect was also significantly augmented by the combined treatment of ACV/GCV and SDC.


CONCLUSIONS
SDC was shown to be effective in the HSV-TK/prodrug administration system and improved the efficiency of the bystander effect of ACV and GCV. The findings will be considerably valuable with respect to the use of GCV in lower doses and less toxic ACV. This novel strategy of drug combination could provide benefit to HSV-TK/prodrug gene therapy.
Hayashi
Kyoko
K
Department of Virology, University of Toyama, Toyama 930-0194, Japan. khayashi@med.u-toyama.ac.jp
Lee
Jung-Bum
JB
Maitani
Yoshie
Y
Toyooka
Naoki
N
Nemoto
Hideo
H
Hayashi
Toshimitsu
T
D045784:Abietanes / Q000737:chemistry / Q000235:genetics* / Q000627:therapeutic use; D000212:Acyclovir / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D001682:Biological Availability; D002277:Carcinoma / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015774:Ganciclovir / Q000493:pharmacokinetics / Q000627:therapeutic use; D052138:Genes, Neoplasm; D015316:Genetic Therapy; D005909:Glioblastoma / Q000473:pathology; D006367:HeLa Cells; D006561:Herpes Simplex / Q000201:enzymology*; D018259:Herpesvirus 1, Human / Q000235:genetics; D006801:Humans; D007822:Laryngeal Neoplasms / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D010957:Plasmids; D011355:Prodrugs / Q000627:therapeutic use; D013937:Thymidine Kinase / Q000235:genetics* / Q000627:therapeutic use; D014162:Transfection; D001749:Urinary Bladder Neoplasms / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D045784:Abietanes; D000998:Antiviral Agents; D011355:Prodrugs; C071755:scopadulciol; D013937:Thymidine Kinase; D015774:Ganciclovir; D000212:Acyclovir