Cancer gene therapy mediated by CTS1, a p53 derivative: advantage over wild-type p53 in growth inhibition of human tumors overexpressing MDM2.
Recently, a new p53 derivative has been designed, namely chimeric tumor suppressor 1 (CTS1), in which the p53 domains that are known to mediate p53 inactivation have been replaced. In this study, the antitumoral activity of CTS1 mediated by adenovirus vector has been evaluated in comparison with a p53 adenovirus vector in various human tumor cell lines. In vitro, in terms of cell growth inhibition, the CTS1 vector was significantly (P < .01) more efficient (2- to 7-fold) than the p53 vector in tumor models overexpressing an inhibitor of p53, murine double minute-2. This result was confirmed in vivo in a pre-established tumor developed in nude mice. In an osteosarcoma model overexpressing murine double minute-2, we have shown a significantly (P < .05) higher tumor growth delay with the CTS1 vector compared with the p53 vector (25.6 days compared with 12.4 days). Furthermore, both in vitro and in vivo, we have shown that this higher inhibition of tumor growth with the CTS1 vector was correlated with a higher induction of apoptosis. Therefore, CTS1 is a potentially improved tumor suppressor gene for the treatment of human tumors resistant to wild-type p53 gene therapy.
Bougeret
C
C
Aventis, Gencell, Oncology Department, Centre de Recherche de Vitry-Alfortville, Vitry-sur-Seine, France.
Virone-Oddos
A
A
Adeline
E
E
Lacroix
F
F
Lefranc
C
C
Ferrero
L
L
Huet
T
T
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000628:therapy; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D016158:Genes, p53 / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000628:therapy; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000628:therapy*; D009687:Nuclear Proteins; D012516:Osteosarcoma / Q000628:therapy; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D013997:Time Factors; D014407:Tumor Cells, Cultured
D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2