This study determined the effect of Ad-E1A gene therapy in vivo. TC71 cells (2 x 10(6)) injected subcutaneously into nude mice resulted in
tumor development (1-3 mm) 6 days later. Animals were then treated with Ad-E1A or Ad-beta-gal (5 x 10(9) plaque-forming units) by intratumoral injection twice weekly for 2 weeks. Animals received 8 mg/kg
VP-16 given by
intraperitoneal injection daily for 5 days following the first week of treatment with Ad-E1A or Ad-beta-gal. Control animals received no
therapy or
VP-16 only after
tumor cells were injected. When
tumors exceeded 2 x 2 cm, the mice were sacrificed and the
tumors underwent histologic and immunohistochemical analysis.
Tumors from mice treated with Ad-E1A plus
VP-16 were 9.6-fold smaller than those treated with
VP-16 alone and 6.3-fold smaller than those treated with Ad-E1A alone. HER2/neu p185
protein expression decreased in all
tumors that received Ad-E1A
therapy. TUNEL fluorescence staining revealed more apoptosis in the
tumors from animals treated with Ad-E1A plus
VP-16 than in those from animals treated with Ad-E1A alone, Ad-beta-gal plus
VP-16, or
VP-16 alone. These data demonstrated that Ad-E1A gene therapy down-regulated HER2/neu expression, increased
tumor cell apoptosis induced by
VP-16, and enhanced
tumor cell sensitivity to
VP-16. Ad-E1A may have potential in the treatment of relapsed
drug-resistant
Ewing's sarcoma.