Back to Search
Start Over
Concurrent versus sequential sorafenib therapy in combination with radiation for hepatocellular carcinoma.
- Source :
-
PloS one [PLoS One] 2013 Jun 06; Vol. 8 (6), pp. e65726. Date of Electronic Publication: 2013 Jun 06 (Print Publication: 2013). - Publication Year :
- 2013
-
Abstract
- Sorafenib (SOR) is the only systemic agent known to improve survival for hepatocellular carcinoma (HCC). However, SOR prolongs survival by less than 3 months and does not alter symptomatic progression. To improve outcomes, several phase I-II trials are currently examining SOR with radiation (RT) for HCC utilizing heterogeneous concurrent and sequential treatment regimens. Our study provides preclinical data characterizing the effects of concurrent versus sequential RT-SOR on HCC cells both in vitro and in vivo. Concurrent and sequential RT-SOR regimens were tested for efficacy among 4 HCC cell lines in vitro by assessment of clonogenic survival, apoptosis, cell cycle distribution, and γ-H2AX foci formation. Results were confirmed in vivo by evaluating tumor growth delay and performing immunofluorescence staining in a hind-flank xenograft model. In vitro, concurrent RT-SOR produced radioprotection in 3 of 4 cell lines, whereas sequential RT-SOR produced decreased colony formation among all 4. Sequential RT-SOR increased apoptosis compared to RT alone, while concurrent RT-SOR did not. Sorafenib induced reassortment into less radiosensitive phases of the cell cycle through G1-S delay and cell cycle slowing. More double-strand breaks (DSBs) persisted 24 h post-irradiation for RT alone versus concurrent RT-SOR. In vivo, sequential RT-SOR produced the greatest tumor growth delay, while concurrent RT-SOR was similar to RT alone. More persistent DSBs were observed in xenografts treated with sequential RT-SOR or RT alone versus concurrent RT-SOR. Sequential RT-SOR additionally produced a greater reduction in xenograft tumor vascularity and mitotic index than either concurrent RT-SOR or RT alone. In conclusion, sequential RT-SOR demonstrates greater efficacy against HCC than concurrent RT-SOR both in vitro and in vivo. These results may have implications for clinical decision-making and prospective trial design.
- Subjects :
- Animals
Apoptosis drug effects
Apoptosis radiation effects
Carcinoma, Hepatocellular blood supply
Carcinoma, Hepatocellular genetics
Carcinoma, Hepatocellular pathology
Cell Cycle drug effects
Cell Cycle radiation effects
Cell Line, Tumor
Clinical Trials as Topic
DNA Breaks, Double-Stranded drug effects
DNA Breaks, Double-Stranded radiation effects
Gene Expression drug effects
Gene Expression radiation effects
Hindlimb blood supply
Hindlimb metabolism
Hindlimb pathology
Histones metabolism
Humans
Liver Neoplasms blood supply
Liver Neoplasms genetics
Liver Neoplasms pathology
Mice
Mice, Nude
Neovascularization, Pathologic prevention & control
Niacinamide therapeutic use
Radiation Tolerance
Sorafenib
Tumor Burden drug effects
Xenograft Model Antitumor Assays
Antineoplastic Agents therapeutic use
Carcinoma, Hepatocellular therapy
Combined Modality Therapy methods
Gamma Rays therapeutic use
Histones genetics
Liver Neoplasms therapy
Niacinamide analogs & derivatives
Phenylurea Compounds therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 8
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 23762417
- Full Text :
- https://doi.org/10.1371/journal.pone.0065726