An adenovirus with enhanced infectivity mediates molecular chemotherapy ofovarian cancer cells and allows imaging of gene expression

The adenovirus (Ad) is a useful vector for cancer gene therapy due to its u nparalleled gene transfer efficiency to dividing and quiescent cells. Prima ry cancer cells, however, often have highly variable or low levels of the r equisite coxsackie-adenovirus receptor (CAR). Also, assessment of gene tran sfer and vector persistence has been logistically difficult in human clinic al trials. We describe here two novel bicistronic adenoviral (Ad) vectors, AdTKSSTR and RGDTKSSTR, which contain the herpes simplex virus thymidine ki nase gene (TK) for molecular chemotherapy and bystander effect. In addition , the viruses contain the human somatostatin receptor subtype-2 gene (SSTR2 ), the expression of which can be noninvasively imaged. We enhanced the inf ectivity of RGDTKSSTR by genetically incorporating the RGD-4C motif into th e HI-loop of the fiber. This allows the virus to circumvent CAR deficiency by binding to alpha (v)beta (3), and alpha (v)beta (5) integrins, which are highly expressed on most ovarian cancers. The expanded tropism of RGDTKSST R results in increased infectivity of purified primary ovarian cancer cells and allows enhanced gene transfer in the presence of malignant ascites con taining anti-Ad antibodies. RGDTKSSTR may be a useful agent for treating ov arian cancer in clinical trials.