Viruses that replicate selectively in
cancer cells constitute an exciting new class of
anticancer agent. The conditionally replicating adenovirus (CRAd)
dl1520, which lacks the E1B-55K gene, has elicited significant clinical responses in humans when used in combination with
chemotherapy. A convergent development has been to use replication-defective viruses to express
prodrug-activating
enzymes in
cancer cells. This can sensitize the
cancer to
prodrug, but depends upon achieving sufficient level, distribution and specificity of
enzyme expression within the tumour. In this study, we have expressed the
prodrug-activating
enzyme nitroreductase (NTR) in the context of an E1B-55K-deleted adenovirus, CRAd-NTR(PS1217H6). We show that CRAd-NTR(PS1217H6) retains oncolytic growth properties, and expresses substantially more NTR than a comparable, replication-defective adenovirus. The combination of viral oncolysis and NTR expression results in significantly greater sensitization of SW480 and WiDr
colorectal cancer cells to the
prodrug CB1954 in vitro. In vivo, CRAd-NTR(PS1217H6) was shown to replicate in subcutaneous SW480 tumour xenografts in immunodeficient mice, resulting in more NTR expression and greater sensitization to
CB1954 than with replication-defective virus. Combination
therapy of CRAd-NTR(PS1217H6) with
CB1954 reduced tumour growth from 13.5- to 2.8-fold over 5 weeks, and extended median survival from 42 to 81 days, compared with no treatment.