title: Adenoviral thymidine kinase prodrug gene therapy inhibits sarcoma growth in vivo.
abstract: Local recurrence of sarcoma is due to residual tumor cells remaining after surgical resection and is associated with decreased survival. We implemented adenoviral-mediated transfer of the herpes simplex thymidine kinase (HSTK) gene with subsequent ganciclovir (GCV) administration to treat a model of residual sarcoma, [3H]Thymidine uptake in MCA sarcoma cells was determined after infection with replication incompetent adenovirus of the AdMLP.HSTK construct in the presence of GCV. In vivo efficacy was evaluated in a model of residual sarcoma when 9 mg of MCA tumor was implanted into the latissimus muscle of Fischer 344 rats. Three days after implantation, animals were randomized to receive AdMLP.HSTK, AdCMV. Null, or viral suspension buffer intratumorally. From Day 4, animals were administered b.i.d. GCV (50 mg/kg) or saline ip. Tumors were excised on Day 14 and weighed. Statistical analysis was by Mann-Whitney U test. In vitro: [3H]thymidine incorporation was significantly decreased in MCA sarcoma cells infected with AdMLP.HSTK in the presence of GCV (P < 0.05). In vivo: Growth of MCA sarcoma treated with AdMLP.HSTK and GCV was significantly inhibited. Final tumor weights in the AdMLP.HSTK/GCV group were lower than all control groups (P < 0.05). A significant antitumor growth effect on MCA sarcoma was seen with adenoviral-mediated transfer of the HSTK gene and GCV administration, both in vitro and in an in vivo model of residual disease. This prodrug gene therapy strategy warrants investigation as an adjuvant modality in the management of sarcoma.
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: H M
authors.initials: HM
authors.lastname: Ross
authors.forename: E A
authors.initials: EA
authors.lastname: Hirschowitz
authors.forename: T J
authors.initials: TJ
authors.lastname: Russi
authors.forename: R G
authors.initials: RG
authors.lastname: Crystal
authors.forename: S
authors.initials: S
authors.lastname: Nawata
authors.forename: M E
authors.initials: ME
authors.lastname: Burt
authors.forename: M F
authors.initials: MF
authors.lastname: Brennan
authors.forename: J J
authors.initials: JJ
authors.lastname: Lewis
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002455:Cell Division; D015774:Ganciclovir / Q000627:therapeutic use*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D009364:Neoplasm Recurrence, Local; D009368:Neoplasm Transplantation; D051381:Rats; D011916:Rats, Inbred F344; D012513:Sarcoma, Experimental / Q000473:pathology / Q000628:therapy*; D013937:Thymidine Kinase / Q000235:genetics*; D014407:Tumor Cells, Cultured; D001616:beta-Galactosidase / Q000235:genetics
chemical_list: D013937:Thymidine Kinase; D001616:beta-Galactosidase; D015774:Ganciclovir