title: Recombinant adenovirus-p21 attenuates proliferative responses associated with excessive scarring.
abstract: Excessive cutaneous scarring is an important clinical disorder resulting in adverse tissue growth and function as well as undesirable cosmetic appearance. p21WAF-1/Cip-1 is a cyclin-dependent kinase inhibitor that blocks cell cycle progression and inhibits cell proliferation. We used a recombinant adenovirus containing the human p21WAF-1/Cip-1 cDNA (rAd-p21) to evaluate proliferative responses in skin models. In vitro dose-response studies using primary human dermal fibroblasts resulted in a dose-dependent expression of p21WAF-1/Cip-1 protein and a 3- to 80-fold reduction in cell proliferation as measured by 5-bromodeoxyuridine incorporation. Further, rAd-p21 reduced type I procollagen production when compared to control virus. A rat polyvinyl alcohol sponge model was used to determine rAd-p21 effects on granulation tissue formation in vivo. Sponges pretreated with a granulation tissue stimulator, rAd-PDGF-B and subsequently rAd-p21 on a second injection, showed a p21WAF-1/Cip-1 specific dose-dependent decrease in percent granulation fill as the rAd-p21 dose increased (p < 0.001). Immunohistochemistry identified human p21WAF-1/Cip-1 expression in sponges treated with rAd-p21 5 days postinjection. Additionally, 5-bromodeoxyuridine and Ki67 staining in sponges treated with rAd-p21 showed a significant decrease in proliferation when compared to rAd-platelet-derived growth factor-B alone or vehicle control groups (p < 0.01). These data support the utility of p21WAF-1/Cip-1 in targeting hyperproliferative disorders of the skin.
authors.affiliation: Department of Pharmacology, Canji Inc., San Diego, California 92121, USA.
authors.forename: Danling
authors.initials: D
authors.lastname: Gu
authors.forename: Isabella
authors.initials: I
authors.lastname: Atencio
authors.forename: David W
authors.initials: DW
authors.lastname: Kang
authors.forename: L David
authors.initials: LD
authors.lastname: Looper
authors.forename: C M I
authors.initials: CM
authors.lastname: Ahmed
authors.forename: Alina
authors.initials: A
authors.lastname: Levy
authors.forename: Dan
authors.initials: D
authors.lastname: Maneval
authors.forename: Monica L
authors.initials: ML
authors.lastname: Zepeda
mesh_terms: D000256:Adenoviridae; D000328:Adult; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D002921:Cicatrix / Q000235:genetics / Q000628:therapy*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D005347:Fibroblasts; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D023421:Models, Animal; D011347:Procollagen / Q000235:genetics; D051381:Rats; D012867:Skin / Q000503:physiopathology; D014945:Wound Healing / Q000235:genetics*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D011347:Procollagen