ADENOVIRAL THYMIDINE KINASE PRODRUG GENE-THERAPY INHIBITS SARCOMA GROWTH IN-VIVO

Local recurrence of sarcoma is due to residual tumor cells remaining a fter surgical resection and is associ ated with decreased survival. We implemented adenoviral-mediated transfer of the herpes simplex thymid ine kinase (HSTK) gene with subsequent ganciclovir (GCV) administratio n to treat a model of residual sarcoma. [H-3]Thymidine uptake in MCA s arcoma cells was determined after infection with replication incompete nt adenovirus of the AdMLP.HSTK construct in the presence of GCV. In v ivo efficacy was evaluated in a model of residual sarcoma when 9 mg of MCA tumor was implanted into the latissimus muscle of Fischer 344 rat s. Three days after implantation, animals were randomized to receive A dMLP.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: [H-3]-thymidine incorporation was sign ificantly decreased in MCA sarcoma cells infected with AdMLP.HSTK in t he presence of GCV (P < 0.05). In vivo: Growth of MCA sarcoma treated with AdMLP.HSTK and GCV was significantly inhibited. Final tumor weigh ts 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 administrat ion, both in vitro and in an in vivo model of residual disease. This p rodrug gene therapy strategy warrants investigation as an adjuvant mod ality in the management of sarcoma. (C) 1997 Academic Press.