Development of a murine orthotopic model of leukemia: evaluation of TP53 gene therapy efficacy.
The onco-suppressor gene TP53 has potential use in the gene therapy of many human cancers including leukemias. The latter indication derived from numerous experimental reports of p53-mediated suppressing effects on human and murine leukemia cells in vitro. However, few in vivo experiments have been performed, and those that have used a subcutaneous injection of p53-transduced leukemia cells. Thus, we developed an orthotopic leukemia model in adult, syngenic mice to evaluate the feasibility of TP53-mediated therapeutic approaches. We found that among other cells, v-src-transformed 32D myeloid progenitors induce leukemia when injected intravenously in syngenic mice. The resulting malignancy resembles the clinical manifestations of human acute myeloid leukemia because it is characterized by a massive invasion of bone marrow compartments, splenomegaly, generalized lymphadenopathy, and a macroscopic or microscopic infiltration of the kidneys, liver, and lungs. When these 32Dv-src cells were infected with a TP53-recombinant retrovirus before intravenous injection, we found a decreased mortality and, in those animals that develop leukemia, a drastic reduction of the generalized organ infiltration, suggesting that exogenous TP53 expression might be used for ex vivo bone marrow purging from leukemia cells.
Bossi
G
G
Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute--Centro Richerche Sperimentali, Rome, Italy.
Scardigli
R
R
Musiani
P
P
Martinelli
R
R
Gentileschi
M P
MP
Soddu
S
S
Sacchi
A
A
D000818:Animals; D004195:Disease Models, Animal; D005240:Feasibility Studies; D015316:Genetic Therapy; D005822:Genetic Vectors; D007938:Leukemia / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D012190:Retroviridae / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use
D016159:Tumor Suppressor Protein p53