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

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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 β-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 × 106, p < 0.01) than in either the vector-treated (8.1 ± 3.7 × 106) or untreated control groups (15.8 ± 5.9 × 106). 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. Systemic gene therapy with liposome–p53 complexes caused a significant reduction of greater than 60% in primary tumor volume as compared to the control groups. Analyses of the growth patterns revealed that the majority of the p53-treated animals had tumors that regressed. Induction of p21, marked histological changes, and increased apoptosis were present in the tumors of the p53-treated group. In addition, the p53-treated group had significantly fewer lung metastases.