Systemic gene therapy with p53 reduces growth and metastases of a malignant human breast cancer in nude mice.
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.
Lesoon-Wood
L A
LA
National Institute of Diabetes, Digestive and Kidney Diseases, Molecular and Cellular Endocrinology Branch, National Institutes of Health, Bethesda, MD 20892, USA.
Kim
W H
WH
Kleinman
H K
HK
Weintraub
B D
BD
Mixson
A J
AJ
D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002277:Carcinoma / Q000517:prevention & control / Q000556:secondary* / Q000628:therapy; D018450:Disease Progression; D017930:Genes, Reporter; D016158:Genes, p53; D015316:Genetic Therapy; D006801:Humans; D007275:Injections, Intravenous; D008081:Liposomes; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000637:transplantation; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000502:physiology; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
D008081:Liposomes; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D001616:beta-Galactosidase