Adenovirus mediated p53 gene therapy has greater efficacy when combined with chemotherapy against human head and neck, ovarian, prostate, and breast cancer

Purpose: Adenovirus-mediated p53 gene therapy for cancer is currently under going phase I/II clinical trials. The drug used in our clinical trials (p53 Ad; ACN53; SCH58500) consists of a replication-deficient, type 5 adenoviru s vector expressing human wildtype p53 tumor suppressor under the control o f the cytomegalovirus promoter. In preclinical models, p53 Ad has therapeut ic efficacy against a wide range of human tumor types containing nonfunctio nal p53, both in vitro and in vivo. Results from early clinical trials usin g p53 gene therapy by itself support optimism for the future of this therap eutic approach. However, it is likely that many phase II/III trials will in corporate an arm comparing traditional chemotherapy against chemotherapy co mbined with p53 gene therapy. Therefore, it is important to study possible interactions between p53 Ad and chemotherapeutic drugs in preclinical model s before starting the clinical trials. Methods: Proliferation of tumor cell s was quantitated after incubation with various combinations of p53 Ad and chemotherapeutic drugs. Human tumor xenografts in scid mice were dosed with intraperitoneal or intratumoral p53 Ad with or without chemotherapeutic dr ugs and the tumor burden after therapy monitored. Results: p53 Ad combined with cisplatin, doxorubicin, 5-fluorouracil, methotrexate, or etoposide inh ibited cell proliferation more effectively than chemotherapy alone in SCC-9 head and neck: SCC-15 head and neck, SCC-25 head and neck, SK-OV-3 ovarian , DU-145 prostate, MDA-MB-468 breast, and MDA-MB-231 breast tumor cells. No obvious dependence on dosing schedule was observed. Greater anticancer eff icacy was also demonstrated in four human tumor xenograft models in vivo. O f particular significance, there was enhanced efficacy using the three drug combination of p53 Ad, cisplatin, and paclitaxel in an ovarian cancer mode l. Conclusion: These results support the combination of p53 gene therapy wi th chemotherapy in clinical trials.