Conditionally replicating adenoviruses (CRAds) selectively replicate in and thereby kill
cancer cells. The CRAd AdDelta24 with pRb-binding-deficient E1A kills
cancer cells efficiently. Arming CRAds with genes encoding
prodrug-converting
enzymes could allow for enhanced anticancer efficacy by the combined effects of oncolytic replication and local
prodrug activation. Here, we investigated combination treatment of human
colon cancer cell lines with AdDelta24-type CRAds and gene-directed
enzyme prodrug therapy (GDEPT) using two different
enzyme/
prodrug systems, that is,
thymidine kinase/
ganciclovir (TK/GCV) and
carboxylesterase (CE)/
CPT-11. On all three cell lines tested, GDEPT with TK/GCV made CRAd treatment less efficacious. In contrast, expression of a secreted form of CE (sCE2) combined with
CPT-11 treatment markedly enhanced the efficacy of AdDelta24 virotherapy. Based on this observation, we constructed an AdDelta24 variant expressing sCE2. In the absence of
CPT-11, this new CRAd Ad5-Delta24.E3-sCE2 was similarly effective as its parent in killing human
colon cancer cells. Low concentrations of
CPT-11 inhibited Ad5-Delta24.E3-sCE2 propagation. Nevertheless,
CPT-11 specifically augmented the cytotoxicity of Ad5-Delta24.E3-sCE2 against all three-
colon cancer cell lines. Hence, the positive contribution of sCE2/
CPT-11 GDEPT to
colon cancer cytotoxicity outweighed its negative influence on CRAd propagation. Therefore, CRAd-sCE2/
CPT-11 combination
therapy appears useful for more effective treatment of
colon cancer.