![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
CELLULAR AND MOLECULAR
Department of Preclinical Research and Exploratory Development, SUGEN, Inc., South San Francisco, California (K.G.M., J.M.C., D.B.M., A.D.L.); and Department of Medical Oncology, Peter MacCallum Cancer Institute, Victoria, Australia (G.C.T.)
Deregulated activation of the KIT receptor tyrosine kinase has been implicated in several human cancers and in inflammation, making it an attractive target for therapeutic intervention. Conversely, deficiencies in KIT signaling have been implicated in human and animal hair pigmentation disorders, reflecting a role for KIT in the development and function of melanocytes. The goal of this study was to explore the potential utility of hair depigmentation as a biological readout for systemic inhibition of KIT by SU11248 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide), an oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity through targeting platelet-derived growth factor receptors, vascular endothelial growth factor receptors, KIT, and FLT3. Oral SU11248 treatment induced dose-dependent depigmentation of newly regrown hair in depilated C57BL/6 mice. Similar effects were seen after administration of a KIT-neutralizing antibody. SU11248-induced hair depigmentation was reversible with cessation of treatment. Histological and immunohistochemical evaluation of mouse skin samples supported these observations and revealed that SU11248 has no effect on levels of KIT-positive melanocytes associated with hair follicles, indicating that the inhibitory effect is at the level of melanocyte function rather than their development/survival. Similar hair depigmentation has been noted in several cancer patients receiving SU11248 in phase I trials. Strikingly, patient scalp hair exhibits bands of depigmentation and pigmentation that correspond, respectively, to periods of treatment and dosing rest periods. These data demonstrate that hair pigmentation can serve as a dose-dependent, dynamic, biological readout for KIT inhibition in mice, and, apparently, in humans.
Address correspondence to: Dr. A. Douglas Laird, 117 16th Avenue, San Mateo, CA 94402. E-mail: douglaslaird2000{at}yahoo.com
This article has been cited by other articles:
|
|
 |
|
  H. M. Prince, D. Honemann, A. Spencer, D. A. Rizzieri, E. A. Stadtmauer, A. W. Roberts, N. Bahlis, G. Tricot, B. Bell, D. J. DeMarini, et al. Vascular endothelial growth factor inhibition is not an effective therapeutic strategy for relapsed or refractory multiple myeloma: a phase 2 study of pazopanib (GW786034) Blood, May 7, 2009; 113(19): 4819 - 4820. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Patyna, C. Arrigoni, A. Terron, T.-W. Kim, J. K. Heward, S. L. Vonderfecht, R. Denlinger, S. E. Turnquist, and W. Evering Nonclinical Safety Evaluation of Sunitinib: A Potent Inhibitor of VEGF, PDGF, KIT, FLT3, and RET Receptors Toxicol Pathol, December 1, 2008; 36(7): 905 - 916. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. T. Hartmann and L. Kanz Sunitinib and Periodic Hair Depigmentation Due to Temporary c-KIT Inhibition Arch Dermatol, November 1, 2008; 144(11): 1525 - 1526. [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Lacouture, S. Wu, C. Robert, M. B. Atkins, H. H. Kong, J. Guitart, C. Garbe, A. Hauschild, I. Puzanov, D. T. Alexandrescu, et al. Evolving Strategies for the Management of Hand-Foot Skin Reaction Associated with the Multitargeted Kinase Inhibitors Sorafenib and Sunitinib Oncologist, September 1, 2008; 13(9): 1001 - 1011. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. A Randall, T. J Jenner, N. A Hibberts, I. O De Oliveira, and T. Vafaee Stem cell factor/c-Kit signalling in normal and androgenetic alopecia hair follicles J. Endocrinol., April 1, 2008; 197(1): 11 - 23. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Mannavola, P. Coco, G. Vannucchi, R. Bertuelli, M. Carletto, P. G. Casali, P. Beck-Peccoz, and L. Fugazzola A Novel Tyrosine-Kinase Selective Inhibitor, Sunitinib, Induces Transient Hypothyroidism by Blocking Iodine Uptake J. Clin. Endocrinol. Metab., September 1, 2007; 92(9): 3531 - 3534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Li, J. Quirt, H. Q. Do, K. Lyte, F. Fellows, C. G. Goodyer, and R. Wang Expression of c-Kit receptor tyrosine kinase and effect on beta-cell development in the human fetal pancreas Am J Physiol Endocrinol Metab, August 1, 2007; 293(2): E475 - E483. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Q.M. Chow and S. G. Eckhardt Sunitinib: From Rational Design to Clinical Efficacy J. Clin. Oncol., March 1, 2007; 25(7): 884 - 896. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Routhouska, A. C. Gilliam, and P. Mirmirani Hair Depigmentation During Chemotherapy With a Class III/V Receptor Tyrosine Kinase Inhibitor. Arch Dermatol, November 1, 2006; 142(11): 1477 - 1479. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Patyna, A. D. Laird, D. B. Mendel, A.-M. O'Farrell, C. Liang, H. Guan, T. Vojkovsky, S. Vasile, X. Wang, J. Chen, et al. SU14813: a novel multiple receptor tyrosine kinase inhibitor with potent antiangiogenic and antitumor activity. Mol. Cancer Ther., July 1, 2006; 5(7): 1774 - 1782. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Faivre, C. Delbaldo, K. Vera, C. Robert, S. Lozahic, N. Lassau, C. Bello, S. Deprimo, N. Brega, G. Massimini, et al. Safety, Pharmacokinetic, and Antitumor Activity of SU11248, a Novel Oral Multitarget Tyrosine Kinase Inhibitor, in Patients With Cancer J. Clin. Oncol., January 1, 2006; 24(1): 25 - 35. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. L. Sawyers Opportunities and challenges in the development of kinase inhibitor therapy for cancer Genes & Dev., December 15, 2003; 17(24): 2998 - 3010. [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
