Design considerations for incorporating sodium iodide symporter reporter gene imaging into prostate cancer gene therapy trials.
This study was done to aid in the design of a phase I gene therapy trial in patients with prostate cancer. We determined the dosimetric characteristics of our reporter gene system when coupled with intravenous administration of radioactive sodium pertechnetate (Na(99m) TcO(4)) and determined the feasibility of using human sodium iodide symporter (hNIS) as a reporter gene to study the dynamics of adenoviral transgene expression in a large animal tumor. A replication-competent Ad5-yCD/mutTK(SR39) rep-hNIS adenovirus was injected into the prostate gland of dogs for dosimetry purposes, and into a canine soft tissue sarcoma (STS) for imaging purposes. After resection of the prostate, the amount of (99m)TcO(4)() sequestered in the prostate was determined, the radiation dose absorbed by the prostate and nontarget critical organs was calculated, and hNIS reporter gene expression was imaged in the STS by single-photon emission computed tomography (SPECT). On the basis of the findings from 25 dogs, the amount of (99m)TcO (4)() sequestered in the prostate ranged from 13 to 276 muCi. Using the highest value observed, absorbed radiation dose to critical organs was calculated and found to be below U.S. Food and Drug Administration limits for diagnostic imaging. Also, (99m)TcO (4)() uptake was readily detected by SPECT and found to persist in vivo for at least 4 days. On the basis of our dosimetry calculations, up to five imaging procedures can be safely performed in humans after intraprostatic injection of the Ad5-yCD/mutTK(SR39)rep-hNIS adenovirus and the hNIS reporter gene system can be used to study the dynamics of adenoviral gene therapy vectors in large animal tumors.
Siddiqui
Farzan
F
Department of Radiation Oncology, Henry Ford Health System, Detroit, MI 48202.
Barton
Kenneth N
KN
Stricker
Hans J
HJ
Steyn
Phillip F
PF
Larue
Susan M
SM
Karvelis
Kastytis C
KC
Sparks
Richard B
RB
Kim
Jae Ho
JH
Brown
Stephen L
SL
Freytag
Svend O
SO
D000818:Animals; D017321:Clinical Trials, Phase I as Topic / Q000592:standards*; D004285:Dogs; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000628:therapy*; D011857:Radiographic Image Interpretation, Computer-Assisted; D012107:Research Design; D013670:Sodium Pertechnetate Tc 99m / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D027981:Symporters / Q000235:genetics*; D014018:Tissue Distribution; D000099209:Sodium-Iodide Symporters
D013670:Sodium Pertechnetate Tc 99m; D027981:Symporters; D000099209:Sodium-Iodide Symporters