SYSTEMIC DELIVERY OF P53 INHIBITS BREAST CANCER

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DESCRIPTION: (Applicant's Abstract) The applicant has reported that a tumor suppressor gene (p53) complexed to liposomes attenuates the growth of a malignant human breast tumor. In these studies, nude mice, inoculated with breast carcinoma cells, were injected every 10-12 days with a liposome:p53 complex via the tail vein. A marked reduction of greater than 60% in primary tumor volume was observed. Furthermore, it was found that primary tumor size was not only inhibited but regressed in the majority of p53-treated animals. It was also determined that the administration of the liposome:p53 complex reduced the incidence of metastases in these animals. This is the first report for any cancer that demonstrates the effectiveness of gene therapy systemically delivered that has inhibited the primary tumor and its metastases. In this application one of the goals is to determine the mechanism of action of this therapy. Several hypotheses for the reduction of tumor growth by wild-type p53 will be investigated: 1) activation of the apoptotic pathway, 2) inhibition of the cell cycle, and 3) inhibition of angiogenesis. Whether transfected p53 leads to apoptosis or G1 arrest in tissue culture experiments with endothelial and MDA-MB-435 cells will be examined. Investigation of the number of cells in G1 arrest after harvesting the cells from the primary tumor will also be made. Since increased apoptosis in the p53-treated animals were noted in the first study, examination of tumors for the presence and extent of apoptosis will be undertaken. However, instead of using a liposome:p53 complex which is difficult to detect, either a liposome:CAT or liposome:beta-galactosidase gene will be used to determine the distribution. If the liposome:CAT/beta-galactosidase marker does not transfect the tumor cells efficiently, then this suggests that the liposome:p53 complex is acting through a bystander effect. This bystander effect may be due to inhibition of angiogenesis or the induction of IGF-BP3 by p53. In addition, whether p53 and other genes are more effective than p53 alone will be determined.