Sorafenib and radiation: a promising combination in colorectal cancer.
OBJECTIVE
To examine the combination of radiation and the multikinase inhibitor sorafenib in human colorectal cancer cell lines and xenografts.


METHODS
HT29 and SW48 colorectal cancer cells were studied in vitro using MTT assays to establish the optimal timing of radiation and sorafenib. This optimal timing was then investigated in clonogenic survival assays. Xenografts were established, and the effect of a 3-week schedule of daily radiation and sorafenib was studied by growth delay.


RESULTS
Sorafenib predominantly had minimal effects on cell growth or radiation response in MTT growth assays, though growth inhibition was significantly enhanced in HT29 cells when sorafenib was administered after radiation. The highest dose of sorafenib altered the alpha component of the cell survival curve in clonogenic assays. The combination of radiation and sorafenib was synergistic in SW48 xenografts, with a mean time to threshold tumor size of 11.4 +/- 1.0 days, 37.0 +/- 9.5 days, 15.5 +/- 3.2 days, and 98.0 +/- 11.7 days in the control, radiation, sorafenib, and combined treatment group, respectively. The effect on HT29 tumors was additive, with mean time to threshold volume of 12.6 +/- 1.1 days, 61.0 +/- 4.3 days, 42.6 +/- 11.7 days, and 100.2 +/- 12.4 days.


CONCLUSIONS
Sorafenib had little effect on radiation response in vitro but was highly effective when combined with radiation in vivo, suggesting that inhibition of proliferation and interference with angiogenesis may be the basis for the interaction.
Suen
Andrew W
AW
Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI, USA.
Galoforo
Sandra
S
Marples
Brian
B
McGonagle
Michele
M
Downing
Laura
L
Martinez
Alvaro A
AA
Robertson
John M
JM
Wilson
George D
GD
D000230:Adenocarcinoma / Q000188:drug therapy / Q000532:radiotherapy; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001557:Benzenesulfonates / Q000008:administration & dosage*; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D003131:Combined Modality Therapy / Q000379:methods; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage*; D011836:Radiation Tolerance / Q000187:drug effects*; D011879:Radiotherapy Dosage; D011897:Random Allocation; D000077157:Sorafenib; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay / Q000379:methods
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib