Combination of vandetanib, radiotherapy, and irinotecan in the LoVo human colorectal cancer xenograft model.
OBJECTIVE
The tumor growth kinetics of the human LoVo colorectal xenograft model was assessed in response to vandetanib, an orally available receptor tyrosine kinase inhibitor, radiotherapy (RT), or irinotecan (CPT-11), as single therapies and in combination.


METHODS
LoVo cells were injected subcutaneously into the right hind limb (5 x 10(6) cells in 100 microL phosphate-buffered saline) of athymic NCR NUM mice and tumors were grown to a volume of 200-300 mm(3) before treatment. Vandetanib was administered at 50 mg/kg daily orally for 14 days starting on Day 1. RT was given as three fractions (3 x 3 Gy) on Days 1, 2, and 3. CPT-11 was given at 15 mg/kg intraperitoneally on Days 1 and 3. Tumor volumes were measured on a daily basis and calculated by measuring tumor diameters with digital calipers in two orthogonal dimensions.


RESULTS
All three single treatments (vandetanib, CPT-11, and radiation) significantly slowed LoVo colorectal tumor growth. Vandetanib significantly increased the antitumor effects of CPT-11 and radiation when given in combination with either of these treatments. These treatment combinations resulted in a slow tumor growth rate during the 2 weeks of vandetanib administration. The triple combination of vandetanib, CPT-11, and radiation produced the most marked improvement in response as observed by measurable shrinkage of tumors during the first week of treatment.


CONCLUSIONS
The tumor growth delay kinetics observed in this study of the LoVo colorectal model suggest concurrent and sustained post-sequencing of vandetanib with cytotoxic therapy may be beneficial in tumors of this type.
Department of Radiation Oncology, Thomas Jefferson University, 111 South 11th Street, Philadelphia, PA 19107, USA. Phyllis.wachsberger@jeffersonhospital.org
Phyllis
P
Wachsberger
Randy
R
Burd
Anderson
A
Ryan
Constantine
C
Daskalakis
Adam P
AP
Dicker
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D003131:Combined Modality Therapy / Q000379:methods; D019583:Dose Fractionation, Radiation; D066246:ErbB Receptors; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D010880:Piperidines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077146:Irinotecan; D066246:ErbB Receptors; D002166:Camptothecin; C452423:vandetanib