Purine Nucleoside Phosphorylase mediated molecular chemotherapy and conventional chemotherapy: A tangible union against chemoresistant cancer

BMC Cancer

Preetinder P Singh¹  Swapna Joshi⁴  Pamela J Russell⁵  Sham Nair³  Aparajita Khatri² 

[1] Prince Henry's Institute, Block E Level 4, Monash Medical Centre, 246 Clayton Road, Clayton VIC 3168, Australia

[2] Faculty of Medicine, University of New South Wales, Kensington, NSW, 2036, Australia

[3] School of Biological Sciences, Macquarie University, Herring Road, North Ryde, Sydney, Australia

[4] Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales, 2031, Australia

[5] Australian Prostate Cancer Research Centre-Queensland, Princess Alexandra Hospital, Woollangabba, QLD; Cells and Tissue Domain, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue Kelvin Grove QLD 4059 Australia

关键词: Cancer;    Ovarian cancer;    Gene directed enzyme prodrug therapy (GDEPT);    Fludarabine Phosphate (Fludara);    Purine nucleoside phosphorylase (PNP);    Molecular chemotherapy;    Chemotherapy;   

Others  :  1080767
DOI  :  10.1186/1471-2407-11-368

 received in 2011-02-25, accepted in 2011-08-24,  发布年份 2011

【 摘 要 】

Background

Late stage Ovarian Cancer is essentially incurable primarily due to late diagnosis and its inherent heterogeneity. Single agent treatments are inadequate and generally lead to severe side effects at therapeutic doses. It is crucial to develop clinically relevant novel combination regimens involving synergistic modalities that target a wider repertoire of cells and lead to lowered individual doses. Stemming from this premise, this is the first report of two- and three-way synergies between Adenovirus-mediated Purine Nucleoside Phosphorylase based gene directed enzyme prodrug therapy (PNP-GDEPT), docetaxel and/or carboplatin in multidrug-resistant ovarian cancer cells.

Methods

The effects of PNP-GDEPT on different cellular processes were determined using Shotgun Proteomics analyses. The in vitro cell growth inhibition in differentially treated drug resistant human ovarian cancer cell lines was established using a cell-viability assay. The extent of synergy, additivity, or antagonism between treatments was evaluated using CalcuSyn statistical analyses. The involvement of apoptosis and implicated proteins in effects of different treatments was established using flow cytometry based detection of M30 (an early marker of apoptosis), cell cycle analyses and finally western blot based analyses.

Results

Efficacy of the trimodal treatment was significantly greater than that achieved with bimodal- or individual treatments with potential for 10-50 fold dose reduction compared to that required for individual treatments. Of note was the marked enhancement in apoptosis that specifically accompanied the combinations that included PNP-GDEPT and accordingly correlated with a shift in the expression of anti- and pro-apoptotic proteins. PNP-GDEPT mediated enhancement of apoptosis was reinforced by cell cycle analyses. Proteomic analyses of PNP-GDEPT treated cells indicated a dowregulation of proteins involved in oncogenesis or cancer drug resistance in treated cells with accompanying upregulation of apoptotic- and tumour- suppressor proteins.

Conclusion

Inclusion of PNP-GDEPT in regular chemotherapy regimens can lead to significant enhancement of the cancer cell susceptibility to the combined treatment. Overall, these data will underpin the development of regimens that can benefit patients with late stage ovarian cancer leading to significantly improved efficacy and increased quality of life.

【 授权许可】

   
2011 Singh et al; licensee BioMed Central Ltd.

【 图 表 】

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