Tissue inhibitor of metalloproteinases-2 improves antitumor efficacy of a replicating adenovirus in vivo.
Clinical studies of replicating adenoviruses for the treatment of cancer have demonstrated their safety but have yielded disappointing results, indicating the need for new strategies to improve their efficacy. We hypothesized that the efficacy of a replicating adenovirus could be improved by expression of tissue inhibitor of metalloproteinases-2 (TIMP-2), a 21-kDa unglycosylated secretory protein. TIMP-2 specifically inhibits the active forms of a number of matrix metalloproteinases (MMPs) that play a role in the degradation of basement membranes and the extracellular matrix and are therefore involved in the control of the growth, invasion and metastasis of tumor cells, as well as angiogenesis. In addition, TIMP-2 can abrogate tumor growth and angiogenesis by a variety of mechanisms independent of MMP inhibition. In this study, we demonstrate that expression of TIMP-2 enhanced the antitumor efficacy of a replicating adenovirus in vivo, by reducing both tumor growth and angiogenesis.
Kim
Myung-hee
MH
Division of Human Gene Therapy, Department of Medicine, and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Bodenstine
Thomas M
TM
Sumerel
Lucretia A
LA
Rivera
Angel A
AA
Baker
Andrew H
AH
Douglas
Joanne T
JT
D000260:Adenoviruses, Human / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000473:pathology / Q000821:virology*; D045744:Cell Line, Tumor; D003587:Cytomegalovirus / Q000235:genetics; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D011401:Promoter Regions, Genetic; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics*; D014183:Transplantation, Heterologous; D014779:Virus Replication / Q000502:physiology*
D019716:Tissue Inhibitor of Metalloproteinase-2