Systemic Gene Therapy with p53 Reduces Growth and Metastases of a Malignant Human Breast Cancer in Nude Mice

Abstract

We report on an in vivo delivery system that attenuates the growth, in nude mice, of a malignant human breast cancer cell line containing a p53 mutation. Nude mice, inoculated with breast carcinoma cells, were injected every 10-12 days with a liposome-p53 complex via the tail vein. A significant reduction of greater than 60% in primary tumor volume was observed as compared to the control groups. Furthermore, when individual growth patterns of the tumors were assessed, we found that primary tumor size regressed in the majority of p53-treated animals (8/15), whereas only one tumor in the control groups (1/22) regressed. The eight tumors that regressed with the liposome-p53 complex showed no evidence of relapse for 1 month after the cessation of treatment. We also determined that the administration of the liposome-p53 complex reduced the incidence of metastases. The MDA-MB-435 tumor cells, transduced with the lacZ gene, facilitated quantitation of beta-galactosidase activity and tumor burden in the lungs. The number of metastatic cells in the lung was significantly lower in the p53-treated group (0.53 +/- 0.43 x 10(6), p < 0.01) than in either the vector-treated (8.1 +/- 3.7 x 10(6)) or untreated control groups (15.8 +/- 5.9 x 10(6)). Thus, systemic administration of the liposome-p53 complex reduced not only the size of the primary tumors but, more importantly, prevented the relapse and metastases of these tumors.

Biological activity and safety of adenoviral vector-expressed wild-type p53 after intratumoral injection in melanoma and breast cancer patients with p53-overexpressing tumors

“…26,27 After the delivery of normal p53 via liposomes, tumor regressions and decreased metastatic spread occurred in xenografts of a p53 mutant human breast cancer in athymic mice. 28 Regression of xenografts derived from three breast carcinoma lines has also been reported in severe combined immunodeficient and athymic mice after the injection of the wt p53 adenoviral construct (SCH 58500) used in the present study. 29 A phase I study was performed to examine the ability to alter the p53 phenotype in cutaneous tumors from patients with melanoma or breast cancer after the injection of a wt p53 contained in a replication-defective adenovirus vector.…”

Inhibition effect of pcDNA-tum-5 on the growth of S180 tumor

“…Although viral vectors are commonly used for gene transfer due to their high transfection efficiency, safety issues and the toxicity of viral vectors may preclude their use in humans in the near future (Chen et al 1999). Nonviral vectors have been shown to be effective in gene transfer (Lesson-Wood et al 1995;Nabel et al 1992;Stewart et al 1992;Xu et al 1997).…”

Small interfering RNA targeting Raf-1 inhibits tumor growth in vitro and in vivo

“…21,22 DOTAP liposomes were prepared as previously described. 23 siRNA The Raf-1 siRNA duplex, directed against the sequence 5 0 -AAU GUC CAC AUG GUC AGC ACC-3 0 , was designed to target both human (913-933) and mouse Raf-1 (1089-1109). b-Galactosidase siRNA duplex (234-254) was prepared as a control and directed against the following sequence: 5 0 -AAC UUA AUC GCC UUG CAG CAC-3 0 .…”