Combination of cabazitaxel and p53 gene therapy abolishes prostate carcinoma tumor growth
| Autor: | Rodrigo Esaki Tamura, Bryan E. Strauss, Marlous G Lana, Eugenia Costanzi-Strauss |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male medicine.medical_treatment Genetic enhancement Mice Nude Antineoplastic Agents Apoptosis Biology Disease-Free Survival 03 medical and health sciences Prostate cancer Mice 0302 clinical medicine Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols Genetics medicine Animals Humans Molecular Biology Survival rate Mitoxantrone Chemotherapy Mice Inbred BALB C Prostate Prostatic Neoplasms Genetic Therapy medicine.disease Genes p53 Xenograft Model Antitumor Assays Gene Expression Regulation Neoplastic 030104 developmental biology Docetaxel Cabazitaxel Tumor progression MODELOS ANIMAIS 030220 oncology & carcinogenesis Cancer research Molecular Medicine Drug Therapy Combination Taxoids Tumor Suppressor Protein p53 medicine.drug |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| ISSN: | 1476-5462 |
| Popis: | For patients with metastatic prostate cancer, the 5-year survival rate of 31% points to a need for novel therapies and improvement of existing modalities. We propose that p53 gene therapy and chemotherapy, when combined, will provide superior tumor cell killing for the treatment of prostate carcinoma. To this end, we have developed the AdRGD-PGp53 vector which offers autoregulated expression of p53, resulting in enhanced tumor cell killing in vitro and in vivo. Here, we combined AdRGD-PGp53 along with the chemotherapy drugs used in the clinical treatment of prostate carcinoma, mitoxantrone, docetaxel, or cabazitaxel. Our results indicate that all drugs increase phosphorylation of p53, leading to improved induction of p53 targets. In vitro experiments reveal that AdRGD-PGp53 sensitizes prostate cancer cells to each of the drugs tested, conferring increased levels of cell death. In a xenograft mouse model of in situ gene therapy, AdRGD-PGp53 treatment, when combined with cabazitaxel, drastically reduced tumor progression and increased survival rates to 100%. Strikingly, we used a sub-therapeutic dose of cabazitaxel thus avoiding leukopenia, yet still showed potent anti-tumor effects when combined with AdRGD-PGp53 in this mouse model. The AdRGD-PGp53 approach warrants further development for its application in gene therapy of prostate carcinoma. |
| Databáze: | OpenAIRE |
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