In vivo expression and antitumor activity of p53 gene transfer with naked plasmid DNA in an ovarian cancer xenograft model in nude mice.
BACKGROUND
Abnormalities in the p53 and p16 tumor suppressor genes are one of the most common occurrences associated with human neoplasia. Consequently, restoration of wild-type p53 or p16 functions is seen as a particularly promising approach for cancer gene therapy. In vitro and in vivo data have demonstrated that virus-mediated p53 gene transfer can induce active cell death and ovarian tumor regression.


OBJECTIVE
To evaluate the efficiency of intratumoral injection of naked DNA in tumor growth inhibition in an ovarian xenograft model. For that purpose, plasmid vectors encoding wild-type p53 (wt-p53) or p16 alone or in combination were used.


METHODS
Nude mice were injected subcutaneously with the human ovarian adenocarcinoma cell line SKOV3. Three weeks after xenograft, tumor-bearing mice were injected twice a week with plasmid vectors carrying WT-p53 and/or WT-p16 cDNA. Empty plasmids and saline buffer were used as control. Tumor growth was monitored to evaluate the inhibition potential with p53 and/or p16 restoration.


RESULTS
When compared to the control, intratumoral repeated injections of naked plasmid DNA encoding wt-p53 were inhibiting tumor growth. This inhibition was not observed with p16 and no synergy could be obtained between p53 and p16. p53 expression was restored in 84% of mice injected with plasmid encoding wt-p53. p16 expression was restored in 63% of mice injected with plasmid encoding p16.


CONCLUSIONS
In this report we demonstrated that: (i) naked DNA represents an efficient gene transfer in the SKOV3 xenograft model; (ii) restoration of wt-p53 gene allows tumor growth inhibition; and (iii) this inhibition could be correlated with p53 expression as seen in 84% of treated mice after repeated naked DNA injections. These results allow us to envisage naked DNA as a therapeutic adjuvant in ovarian cancer treatment, concomitantly with tumor resection and chemotherapy.
Collinet
Pierre
P
Hôpital Jeanne de Flandre, Clinique de Gynécologie-Obstétrique CHRU Lille, Lille Cedex, France. p-collinet@chru-lille.fr
Vereecque
Rodolphe
R
Sabban
Frédéric
F
Vinatier
Denis
D
Leblanc
Eric
E
Narducci
Frabrice
F
Querleu
Denis
D
Quesnel
Bruno
B
D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D002455:Cell Division; D045744:Cell Line, Tumor; D004247:DNA / Q000008:administration & dosage / Q000235:genetics; D005260:Female; D015870:Gene Expression; D019942:Genes, p16 / Q000502:physiology; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D010957:Plasmids / Q000235:genetics; D014162:Transfection; D014183:Transplantation, Heterologous
D004247:DNA