Adenovirus-E1A gene therapy enhances the in vivo sensitivity of Ewing's sarcoma to VP-16.
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.
Zhou
Rong-Rong
RR
Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Jia
Shu-Fang
SF
Zhou
Zhichao
Z
Wang
Yunfang
Y
Bucana
Corazon D
CD
Kleinerman
Eugenie S
ES
D000256:Adenoviridae / Q000235:genetics; D017500:Adenovirus E1A Proteins / Q000235:genetics*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis; D015536:Down-Regulation; D005047:Etoposide / Q000378:metabolism / Q000627:therapeutic use*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012512:Sarcoma, Ewing / Q000628:therapy*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D017500:Adenovirus E1A Proteins; D000972:Antineoplastic Agents, Phytogenic; D005047:Etoposide; D018719:Erb-b2 Receptor Tyrosine Kinases