Increased injection number enhances adenoviral genetic radiotherapy.
Intratumoral injection of an adenoviral vector containing radiation-inducible DNA sequences of the early growth response gene (Egr-1) promoter ligated to a cDNA encoding tumor necrosis factor-alpha (TNF-alpha; Ad.Egr-TNF) increases the radiation killing of a human radioresistant xenograft (SQ-20B). Viral dose-escalation experiments demonstrated that SQ-20B growth inhibition correlated with viral titer. Injection of 5 x 10(8) PFU Ad.Egr-TNF produced regression to a mean volume of 22 +/- 13% of the original tumor volume, 1 x 10(8) PFU to a mean of 62 +/- 24%, and 5 x 10(7) PFU to a mean of 67 +/- 27%. No regression was observed when tumors were injected with 1 x 10(7) PFU Ad.Egr-TNF or with the null viral vector (Ad.null). When two injections of vector (2 x 10(8) PFU Ad.Egr-TNF) were combined with 50 Gy, a significant increase in tumor regression was observed compared with injection of buffer, Ad.Egr-TNF, or 50 Gy. The interactive killing between TNF and radiation was enhanced significantly (P = 0.05) when the number of injections was increased from two to five while maintaining a constant viral titer (2 x 10(8) PFU Ad.Egr-TNF) and a constant radiation dose (50 Gy). Significant TNF-alpha levels were present in irradiated vs. unirradiated tumors following injection with Ad.Egr-TNF. Taken together, these data suggest that the volumetric reduction produced by the combined effects of Ad.Egr-TNF and radiation is enhanced with increasing vector concentration and the number of vector injections.
Mauceri
H J
HJ
Department of Radiation and Cellular Oncology, Pritzker School of Medicine, University of Chicago, USA.
Seung
L P
LP
Grdina
W L
WL
Swedberg
K A
KA
Weichselbaum
R R
RR
D000256:Adenoviridae; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000532:radiotherapy / Q000628:therapy*; D003131:Combined Modality Therapy / Q000379:methods; D004268:DNA-Binding Proteins / Q000494:pharmacology; D051766:Early Growth Response Protein 1; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D017874:Immediate-Early Proteins; D015552:Injections, Intralesional; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014157:Transcription Factors / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha