Adenovirus serotype 11 causes less long-term intraperitoneal inflammation than serotype 5: Implications for ovarian cancer therapy

TY - JOUR

T1 - Adenovirus serotype 11 causes less long-term intraperitoneal inflammation than serotype 5

T2 - Implications for ovarian cancer therapy

AU - Thoma, Clemens

AU - Bachy, Veronique

AU - Seaton, Patricia

AU - Green, Nicola K.

AU - Greaves, David R.

AU - Klavinskis, Linda

AU - Seymour, Leonard W.

AU - Morrison, Joanne

PY - 2013/12

Y1 - 2013/12

N2 - In a phase II/III clinical trial intraperitoneal (i.p.) administration of a group C adenovirus vector (Ad5) caused bowel adhesion formation, perforation and obstruction. However, we had found that i.p. group B, in contrast to group C adenoviruses, did not cause adhesions in nude BALB/c ovarian cancer models, prompting further investigation. Ex vivo, group B Ad11 caused lower inflammatory responses than Ad5 on BALB/c peritoneal macrophages. In vivo, i.p. Ad11 triggered short-term cytokine and cellular responses equal to Ad5 in both human CD46-positive and -negative mice. In contrast, in a long-term study of repeated i.p. administration, Ad11 caused no/mild, whereas Ad5 induced moderate/severe adhesions and substantial liver toxicity accompanied by elevated levels of IFN gamma and VEGF and loss of i.p. macrophages, regardless of CD46 expression. It appears that, although i.p. Ad11 evokes immediate inflammation similar to Ad5, repeated administration of Ad11 is better tolerated and long-term fibrotic tissue remodelling is reduced. 

AB - In a phase II/III clinical trial intraperitoneal (i.p.) administration of a group C adenovirus vector (Ad5) caused bowel adhesion formation, perforation and obstruction. However, we had found that i.p. group B, in contrast to group C adenoviruses, did not cause adhesions in nude BALB/c ovarian cancer models, prompting further investigation. Ex vivo, group B Ad11 caused lower inflammatory responses than Ad5 on BALB/c peritoneal macrophages. In vivo, i.p. Ad11 triggered short-term cytokine and cellular responses equal to Ad5 in both human CD46-positive and -negative mice. In contrast, in a long-term study of repeated i.p. administration, Ad11 caused no/mild, whereas Ad5 induced moderate/severe adhesions and substantial liver toxicity accompanied by elevated levels of IFN gamma and VEGF and loss of i.p. macrophages, regardless of CD46 expression. It appears that, although i.p. Ad11 evokes immediate inflammation similar to Ad5, repeated administration of Ad11 is better tolerated and long-term fibrotic tissue remodelling is reduced. 

KW - Adenovirus

KW - Ad5

KW - Ad11

KW - Intraperitoneal inflammation

KW - Ovarian cancer

KW - Gene therapy

KW - Virotherapy

KW - CD46-transgenic mice

KW - COMPLEMENT-REGULATORY PROTEINS

KW - PERITONEAL ADHESION FORMATION

KW - GROWTH-FACTOR RECEPTOR

KW - KINASE GENE-THERAPY

KW - CELLULAR RECEPTOR

KW - SPECIES-B

KW - FOLLOW-UP

KW - IN-VIVO

KW - PHASE-I

KW - MACROPHAGE

U2 - 10.1016/j.virol.2013.08.032

DO - 10.1016/j.virol.2013.08.032

M3 - Article

SN - 0042-6822

VL - 447

SP - 74

EP - 83

JO - Virology

JF - Virology

IS - 1-2

M1 - N/A

ER -