Adenovirus-mediated p53 gene therapy in osteosarcoma cell lines: sensitization to cisplatin and doxorubicin.
The poor prognosis for patients with metastatic osteosarcoma (OS) indicates that new therapeutic options should be explored. Studies with adenoviral-mediated p53 gene transfer have been conducted in many cancer types including cervical, ovarian, prostatic and head and neck tumors. However, limited work has been carried out with pediatric cancers, including OS. Using three viral constructs containing cDNA for wild-type p53, mutant p53 (Cys135Ser) and lacZ, we studied the effect of adenoviral-mediated gene therapy in four OS cell lines: Saos-2 (p53-/-), HOS (R156P), KHOS/NP (R156P) and MNNG (R156P, F270L). We demonstrated that the virus efficiently enters the cells using the beta-galactosidase assay. Using the MTT assay, we have shown a dose-dependent decrease in cell viability 72 h post-treatment that occurs with Ad-wtp53 but not with Ad-mutp53. We have also shown that treatment with Ad-wtp53 significantly increases sensitivity of the cell lines to cisplatin and doxorubicin, chemotherapeutic agents commonly used in the treatment of OS. Our results indicate that restoration of wt p53 function in OS cells provides a basis for novel approaches to treatment of this disease.
Ganjavi
H
H
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Gee
M
M
Narendran
A
A
Parkinson
N
N
Krishnamoorthy
M
M
Freedman
M H
MH
Malkin
D
D
D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D002945:Cisplatin / Q000494:pharmacology*; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D009154:Mutation; D012516:Osteosarcoma; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics*
D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D002945:Cisplatin