Opportunities for p53 Tumor Suppressor Gene Therapy in Ovarian and
Loretta L. Nielsen, Mark Pegram, Beth Karlan, John Elkas, and Jo Ann Horowitz
Schering-Plough Research Institute is currently sponsoring phase I/II clinical trials of adenovirus-mediated p53 gene therapy for cancer in several countries. The drug used in these clinical trials (Ad p53; ACN53; SCH58500) consists of a replication-deficient, type 5 adenovirus vector expressing human p53 tumor suppressor gene under the control of the cytomegalovirus promoter. Clinical targets for initial trials with p53 gene therapy were chosen on the basis of frequency of p53 mutation and pattern of spread for specific tumors which would make them amenable to local or regional therapy and subsequent biopsy. The incidence of p53 mutations for most tumors is dependent on stage of the disease. In general, early stage disease has a much lower incidence of p53 mutation, with more advanced and invasive cancer having a higher incidence of mutation. The natural history of ovarian cancer results in 75% of patients having cancer spread beyond the ovary and 60% beyond the pelvis at diagnosis. Neoplastic cell dissemination within the peritoneal cavity is the most common pathway for progression in patients with advanced disease. Five year survival for patients with regional disease at diagnosis is 55%. Preexisting anti-adenoviral antibodies and the need to achieve an effective concentration of Ad p53 suggest this drug will be most effective when administered regionally. Ovarian cancer limited to the abdominal cavity, with small volume disease either naturally or optimally ebulked, seems ideal for regional p53 gene therapy.