Nonclinical safety evaluation of sunitinib: A potent inhibitor of VEGF, PDGF, KIT, FLT3, and RET receptors

Toxicologic Pathology

Volumn 36, Issue 7, 2008, Pages 905-916

  Patyna, Shem ^a   Arrigoni, Claudio ^b   Terron, Andrea ^c   Kim, Tae Won ^d   Heward, Joyce K ^e   Vonderfecht, Steven L ^f   Denlinger, Robert ^a   Turnquist, Susan E ^a   Evering, Winston ^a  

^a PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United States)

^b NERVIANO MEDICAL SCIENCES   (Italy)

^c GSK   (Italy)

^d ISIS PHARMACEUTICALS   (United States)

^e PFIZER INC   (United States)

^f AMGEN INC   (United States)

Author keywords

Anti angiogenesis; Nonclinical toxicity; Receptor tyrosine kinase inhibitor; Sunitinib malate

Indexed keywords

EOSIN; FLT3 LIGAND; HEMATOXYLIN; PLATELET DERIVED GROWTH FACTOR; PROTEIN RET; STEM CELL FACTOR; SUNITINIB; VASCULOTROPIN; ANTINEOPLASTIC AGENT; INDOLE DERIVATIVE; PROTEIN TYROSINE KINASE; PYRROLE DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; AUTOPSY; CONVALESCENCE; DRUG TOLERABILITY; ELECTRON MICROSCOPY; EPIPHYSIS; EXPERIMENTAL MONKEY; HISTOPATHOLOGY; HUMAN; LABORATORY TEST; MEDICAL RECORD; NEOVASCULARIZATION (PATHOLOGY); NONHUMAN; PALLOR; PRIORITY JOURNAL; RAT; UTERUS WEIGHT; ADRENAL GLAND; ANIMAL; BONE MARROW; CHEMICALLY INDUCED DISORDER; DRUG ANTAGONISM; DRUG EFFECT; EVALUATION; FEMALE; GASTROINTESTINAL TRACT; GROWTH PLATE; INCISOR; LYMPHOID TISSUE; MACACA; MALE; METHODOLOGY; OVARY; PANCREAS; PATHOLOGY; SIGNAL TRANSDUCTION; SPRAGUE DAWLEY RAT; TOXICITY TESTING;

MACACA FASCICULARIS; RATTUS;

ADRENAL GLANDS; ANIMALS; ANTINEOPLASTIC AGENTS; BONE MARROW; FEMALE; GASTROINTESTINAL TRACT; GROWTH PLATE; INCISOR; INDOLES; LYMPHOID TISSUE; MACACA FASCICULARIS; MALE; MICROSCOPY, ELECTRON; NEOVASCULARIZATION, PATHOLOGIC; OVARY; PANCREAS; PYRROLES; RATS; RATS, SPRAGUE-DAWLEY; RECEPTOR PROTEIN-TYROSINE KINASES; RECOVERY OF FUNCTION; SIGNAL TRANSDUCTION; TOXICITY TESTS, CHRONIC;

EID: 67649246190     PISSN: 01926233     EISSN: 15331601     Source Type: Journal    
DOI: 10.1177/0192623308326151     Document Type: Article

References (43)

1. Abrams, T.J., Lee, L.B., Murray, L.J., Pryer, N.K., and Cherrington, J.M. (2003). SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther 2, 471-478.
2. Baffert, F., Le, T., Sennino, B., Thurston, G., Kuo, C.J., Hu-Lowe, D., and McDonald, D.M. (2006). Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signaling. Am J Physiol Heart Circ Physiol 290, H547-59.
3. Bergers, G., Song, S., Meyer-Morse, N., Bergsland, E., and Hanahan, D. (2003). Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 111, 1287-1295.
4. Bi, Y. and Williams, J.A. (2004). Receptor biology and signal transduction in pancreatic acinar cells. Curr Opin Gastroenterol 20, 427-434.
5. Carlevaro, M.F., Cermelli, S., Cancedda, R., and Descalzi Cancedda, F. (2000). Vascular endothelial growth factor (VEGF) in cartilage neovascularization and chondrocyte differentiation: auto-paracrine role during endochondral bone formation. J Cell Sci 113, 59-69.
6. Carmeliet, P., Ferreria, V., Breier, G., Pollefeyt, S., Kieckens, L., Gertstein, M., Fahrig, M., Vandenhoeck, A., Harpal, K., Eberhardt, C., Declecq, C., Pawling, J., Moons, L., Collen, D., Risau, W., and Nagy, A. (1996). Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380, 435-439.
7. Cohen, M. H., Williams, G., Johnson, J. R., Duan, J., Gobburu, J., Rahman, A., Bensen, K., Leighton J., Kim, S. K., Wood, R., Rothmann, M., Chen, G. U. K. M., Staten, A. M., and Pazdur, R. (2002). Approval summary of imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res 8, 935-942.
8. Correll, P.H., Paulson, R.F., and Wei, X. (2006). Molecular regulation of receptor tyrosine kinases in hematopoietic malignancies. Gene 374, 26-38.
9. Erber, R., Thurnher, A., Katsen, A.D., Groth, G., Kerger, H., Hammes, H-P., Menger, M.D., Ullrich, A., and Vajkoczy, P. (2004). Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J 18, 338-340.
10. Ferrara, N. (2001). Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am J Physiol Cell Physiol 280, C1358-66.
11. Ferrara, N. (2004). Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25, 581-611. (Pubitemid 39099316)
12. Ferrara, N., Carver-Moore, K., Chen, H., Dowd, M., Lu, L., OgShea, K.S., Powell-Braxton, L., Hillan, K.J., and Moore, M.W. (1996). Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380, 439-442.
13. Ferrara, N., Gerber, H.P., and LeCouter, J. (2003). The biology of VEGF and its receptors. Nat Med 9, 669-676.
14. Folkman, J. (1974). Tumor angiogenesis. Adv Cancer Res 19, 331-358.
15. Franklin, W.A., Veve, R., Hirsch, F.R., Helfrich, B.A., and Bunn, P.A. Jr. (2002). Epidermal growth factor receptor family in lung cancer and pre-malignancy. Semin Oncol 29 (1 Suppl 4). 3-14.
16. Hard, G.C., and Khan, K.N. (2004). A contemporary overview of chronic progressive nephropathy in the laboratory rat, and its significance for human risk assessment. Toxicol Pathol 32, 171-180.
17. Igarashi, H., Esumi, M., Ishida, H., and Okada, K. (2002). Vascular endothelial growth factor overexpression is correlated with von Hippel-Lindau tumor suppressor gene inactivation in patients with sporadic renal cell carcinoma. Cancer 95, 47-53.
18. Jones, A.V., and Cross, N.C. (2004). Oncogenic derivatives of platelet-derived growth factor receptors. Cell Mol Life Sci 61, 2912-2923.
19. Kamba, T., Tam, B.Y.Y., Hashizume, H., Haskell, A., Sennino, B., Mancuso, M.R., Norberg, S.N., OgBrien, S.N., Davis, R.B., Gowen, L.C., Anderson, K.D., Thurston, G., Joho, S., Springer, M.L., Kuo, C.J., and McDonald, D.M. (2006). VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature. Am J Physiol Heart Circ Physiol 290, H560-76.
20. Law, K.T., Lee, C.K., King, N.M., and Rabie, A.B. (2003). The relationship between eruption and length of mandibular incisors in young rats. Med Sci Monit 9, BR47-53.
21. Mancuso, M.R., Davis, R., Norberg, S.M., OgBrien, S., Sennino, B., Nakahara, T., Yao, V.J., Inai, T., Brooks, P., Freimark, B., Shalinsky, D.R., Hu-Lowe, D.D., and McDonald, D.M. (2006). Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest 116, 2610-2621.
22. Manzke, E., Katchburian, E., Faria, F.P., and Freymuller, E. (2005). Structural features of forming and developing blood capillaries of the enamel organ of rat molar tooth germs observed by light and electron microscopy. J Morphol 265, 335-342.
23. Mendel, D.B., Laird, A.D., Xin, X., Louie, S.G., Christensen, J.G., Li, G., Schreck, R.E., Abrams, T.J., Ngai, T.J., Lee, L.B., Murray, L.J., Carver, J., Chan, E., Moss, K.G., Haznedar, J.O., Sukbuntherng, J., Blake, R.A., Sun, L., Tang, C., Miller, T., Shirazian, S., McMahon, G., and Cherrington, J.M. (2003). In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9, 327-337. (Pubitemid 36109749)
24. Moss, K.G., Toner, G.C., Cherrington, J.M., Mendel, D.B., and Laird, A.D. (2003). Hair depigmentation is a biological readout for pharmacological inhibition of KIT in mice and humans. J Pharmacol Exp Ther 307, 476-480.
25. Motzer, R.J., Hoosen, S., Bello, C.L., and Christensen, J.G. (2006). Sunitinib malate for the treatment of solid tumours: a review of current clinical data. Expert Opin Investig Drugs 15, 553-561.
26. Murray, L.J., Abrams, T.J., Long, K.R., Ngai, T.J., Olson, L.M., Hong, W., Keast, P.K., Brassard, J.A., OgFarrell, A.M., Cherrington, J.M., and Pryer, N.K. (2003). SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model. Clin Exp Metastasis 20, 757-766.
27. Nexavar Summary of Product Characteristics. Bayer, plc. 2007.
28. OgFarrell, A.M., Abrams, T.J., Yuan, H.A., Ngai, T.J., Louie, S.G., Yee, K.W., Wong, L.M., Hong, W., Lee, L.B., Town, A., Smolich, B.D., Manning, W.C., Murray, L.J., Heinrich, M.C., and Cherrington, J.M. (2003). SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 101, 3597-3605.
29. Ono, M., and Kuwano, M. (2006). Molecular mechanisms of epidermal growth factor receptor (EGFR) activation and response to gefitinib and other EGFR-targeting drugs. Clin Cancer Res 12, 7242-7251.
30. Pfizer Inc., data on file (including Pharmacia and Upjohn toxicology studies 2001-0010, 2003-0390, 2000-0532, and 2003-0386).
31. Punyadeera, C., Thijssen, V.L., Tchaikovski, S., Kamps, R., Delvoux, B., Dunselman, G.A., de Goeij, A.F., Griffioen, A.W., and Groothuis, P.G. (2006). Expression and regulation of vascular endothelial growth factor ligands and receptors during menstruation and post-menstrual repair of human endometrium. Mol Hum Reprod 12, 367-375.
32. Reilly, J.T. (2003). Receptor tyrosine kinases in normal and malignant haematopoiesis. Blood Rev 17, 241-248.
33. Ribelin, W.E. (1984). The effects of drugs and chemicals upon the structure of the adrenal gland. Fundam Appl Toxicol 4, 105-119.
34. Rock, E.P., Goodman, V., Jiang, J.X., Mahjoob, K., Verbois, S.L., Morse, D., Dagher, R., Justice, R., and Pazdur, R. (2007). Food and Drug Administration drug approval summary: sunitinib malate for the treatment of gastrointestinal stromal tumor and advanced renal cell carcinoma. Oncologist 12, 107-113. (Pubitemid 46143508)
35. Ryan, A.M., Eppler, D.B., Hagler, K.E., Bruner, R.H., Thomford, P.J., Hall, R.L., Shopp, G.M., and OgNeill, C.A. (1999). Preclinical safety evaluation of rhuMabVEGF, an antiangiogenic humanized monoclonal antibody. Toxicol Pathol 27, 78-86.
36. Satoh, A., Gukovskaya, A.S., Edderkaoui, M., Daghighian, M.S., Reeve, J.R. Jr, Shimosegawa, T., and Pandol, S.J. (2005). Tumor necrosis factor-alpha mediates pancreatitis responses in acinar cells via protein kinase C and proline-rich tyrosine kinase 2. Gastroenterology 129, 639-651.
37. SUTENT (sunitinib malate) prescribing information. Available at: www.sutent.com (accessed June 2008)
38. Taylor, R.N., Lebovic, D.I., Hornung, D., and Mueller, M.D. (2001). Endocrine and paracrine regulation of endometrial angiogenesis. Ann NY Acad Sci 943, 109-121.
39. Thompson, K. (2007). Bones and joints. In Pathology of Domestic Animals (M. G. Maxie, ed.). Vol. 1, pp. 1-184.
40. Trueta, J., and Amato, V.P. (1960). The vascular contribution to osteogenesis. III. Changes in the growth cartilage caused by experimentally induced ischaemia. J Bone Joint Surg Br 42-B, 571-587.
41. Williams, J.A. (2002). Receptor biology and intracellular regulatory mechanisms in pancreatic acinar cells. Curr Opin Gastroenterol 18, 529-535.
42. Woodard, J.C., and Jee, W.S.S. (1991). Skeletal system. In Handbook of Toxicologic Pathology (W. Haschek and C. Rousseaux, eds.). pp. 489-537.
43. Ziegler, B.L., Valteri, M., Porada, G.A., DeMaria, R., Muller, R., Masella, B., Gabbianelli, M., Casella, I., Pelosi, E., Bock, T., Zanjani, E.D., and Peschle, C. (1999). KDR receptor: A key marker defining hematopoietic stem cells. Science 285, 1553-1558.