Conditionally replicative adenoviruses (CRAds) represent novel therapeutic agents which have been recently applied in the context of cancer therapy. Indeed, recent reports investigating CRAds in the context of squamous cell carcinomas of the head and neck represent the first true clinical efficacy results achieved in human clinical cancer gene therapy to date. Clearly, the application of CRAds to cancer of the ovary thus represents a highly desirable endeavor whereby these promising agents may be evaluated in this desperate disease context. Of note, an initial clinical trial has demonstrated the feasibility of utilizing CRAds in an ovarian cancer clinical context. We postulate that the limited clinical effect noted in this initial trial may be related to deficiencies in two key biologic principles that mitigate CRAd efficacy. These important characteristics include (1) the ability of the virus to infect target tumor cells and to infect laterally post-replication and (2) the ability of the virus to replicate specifically within the tumor target. Addressing deficiencies in these areas will likely enhance the therapeutic index of CRAds in the context of ovarian cancer and is the basis of this proposal. The foregoing considerations have established several key principles with respect to our overall strategy to develop the optimal CRAd agent for carcinoma of the ovary. To reiterate, CRAd efficacy is clearly predicated upon the achievement of effective primary and lateral tumor cell infection and upon the achievement of tumor-specific replication. We hypothesize that the incorporation of infectivity enhancement and replication specific properties that address deficiencies in these key areas in current CRAd systems will facilitate the development of a CRAd agent with an enhanced therapeutic index for treatment of patients with ovarian carcinoma. Support via this competitive renewal will allow construction and validation of advanced generation CRAds that will combine new approaches to achieve enhanced infectivity and tissue specific replication. As well, proof-of principle studies in model systems will establish the rationale for an advanced human clinical trial for cancer of the ovary with derived advanced generation CRAd agents.