In vivo molecular chemotherapy and noninvasive imaging with an infectivity-enhanced adenovirus.
BACKGROUND
Adenovirus-based gene therapy is a promising approach to treat advanced cancers that are resistant to other treatments. However, many primary cells lack the requisite coxsackie-adenovirus receptor (CAR), limiting the in vivo efficacy of gene therapy. Recently, a modified adenovirus that is not dependent on CAR expression for infectivity was developed. We used noninvasive imaging to investigate the in vivo antitumor efficacy of gene therapy using this adenovirus in an animal model of ovarian cancer.


METHODS
The adenoviral vectors RGDTKSSTR (CAR-independent) and AdTKSSTR (CAR-dependent) express herpes simplex virus thymidine kinase (TK) for molecular chemotherapy and the human somatostatin receptor subtype 2 (SSTR) for noninvasive nuclear imaging. Subcutaneous or peritoneal human xenograft ovarian cancers were established from highly aggressive SKOV3.ip1 cells in immune-deficient mice. Adenoviral constructs were infected intratumorally or intraperitoneally once a day for 3 days. Control mice received three injections, one per day, of Ad5Luc1, a CAR-dependent adenoviral vector that includes a luciferase marker gene. The somatostatin analogue (99m)Tc-P2045 was used for noninvasive in vivo imaging of RGDTKSSTR that was injected into subcutaneous tumors. For mice with peritoneal tumors, survival was compared among the different treatment groups using Kaplan-Meier analysis with the log-rank statistic. All statistical tests were two-sided.


RESULTS
Tumor-associated RGDTKSSTR could be detected 15 days after introduction of the vector. In the subcutaneous model, tumors injected with RGDTKSSTR were statistically significantly smaller than those injected with AdTKSSTR (P<.001). In the intraperitoneal model, mice treated with RGDTKSSTR lived longer (survival at day 45 = 63.6%; 95% confidence interval [CI] = 35.2% to 92.0%) than those treated with AdTKSSTR (survival at day 45 = 0%) or Ad5Luc1 (survival at day 45 = 18.1%; 95% CI = 0.0% to 41.0%).


CONCLUSIONS
RGDTKSSTR shows antitumor efficacy against ovarian cancer in vivo in animal models. The virus can be imaged noninvasively and may have the potential to be a useful agent for treating ovarian cancer.
Hemminki
Akseli
A
Division of Human Gene Therapy and Gene Therapy Center, Department of Medicine, University of Alabama at Birmingham, 35294-3300, USA. akseli@uab.edu
Zinn
Kurt R
KR
Liu
Bin
B
Chaudhuri
Tandra R
TR
Desmond
Renee A
RA
Rogers
Buck E
BE
Barnes
Mack N
MN
Alvarez
Ronald D
RD
Curiel
David T
DT
D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D003952:Diagnostic Imaging / Q000379:methods*; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000502:physiology; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009928:Organ Specificity; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy* / Q000821:virology; D011868:Radioisotopes; D017481:Receptors, Somatostatin / Q000235:genetics / Q000378:metabolism; D011991:Receptors, Virus / Q000378:metabolism; D013937:Thymidine Kinase / Q000235:genetics / Q000627:therapeutic use; D013997:Time Factors; D014407:Tumor Cells, Cultured
C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D011868:Radioisotopes; D017481:Receptors, Somatostatin; D011991:Receptors, Virus; D013937:Thymidine Kinase