Tumor suppression and therapy sensitization of localized and metastatic breast cancer by adenovirus p53

We have examined the effects of a replication-defective adenovirus encoding p53 (RPR/INGN 201 [Ad5CMV-p53]; Adp53), alone or in combination with the b reast cancer therapeutic doxorubicin (Adriamycin), to suppress growth and i nduce apoptosis in breast cancer cells in vitro. We have also examined the in vivo effect of intratumoral administration of Adp53, alone or in combina tion with doxorubicin, to suppress the growth of established subcutaneous M DA-MB-435 breast cancer tumors. Finally, using the MDA-MB-435 orthotopic mo del of metastatic breast cancer, we have examined the effect of systemic ad ministration of Adp53, alone or in combination with doxorubicin, to reduce the incidence of metastases. We find that whereas in vitro treatment of cel ls with Adp53 reduces [H-3]thymidine incorporation by about 90% at 48 hr, c ell viability at 6 days is reduced by only some 50% relative to controls. A lthough apoptosis is detectable in Adp53-treated cultures, these results su ggest that a large fraction of Adp53-treated cells merely undergo reversibl e cell cycle arrest. Combined treatment with Adp53 and doxorubicin results in a greater than additive loss of viability in vitro and increased apoptos is. In vivo, locally administered Adp53 suppresses growth of established su bcutaneous tumors in nude mice and suppression is enhanced by doxorubicin. In the metastatic breast cancer model, systemic administration of Adp53 plu s doxorubicin leads to a significant reduction in the incidence of metastas es relative to Adp53 or doxorubicin alone. Taken together, these data indic ate an additive to synergistic effect of Adp53 and doxorubicin for the trea tment of primary and metastatic breast cancer.