Prevention of chemotherapy-induced alopecia in rats by CDK inhibitors.
Most traditional cytotoxic anticancer agents ablate the rapidly dividing epithelium of the hair follicle and induce alopecia (hair loss). Inhibition of cyclin-dependent kinase 2 (CDK2), a positive regulator of eukaryotic cell cycle progression, may represent a therapeutic strategy for prevention of chemotherapy-induced alopecia (CIA) by arresting the cell cycle and reducing the sensitivity of the epithelium to many cell cycle-active antitumor agents. Potent small-molecule inhibitors of CDK2 were developed using structure-based methods. Topical application of these compounds in a neonatal rat model of CIA reduced hair loss at the site of application in 33 to 50% of the animals. Thus, inhibition of CDK2 represents a potentially useful approach for the prevention of CIA in cancer patients.
Davis
S T
ST
Department of Cancer Biology, Glaxo Wellcome Research and Development, Research Triangle Park, NC 27709, USA. std41085@glaxowellcome.com
Benson
B G
BG
Bramson
H N
HN
Chapman
D E
DE
Dickerson
S H
SH
Dold
K M
KM
Eberwein
D J
DJ
Edelstein
M
M
Frye
S V
SV
Gampe
R T
RT
Griffin
R J
RJ
Harris
P A
PA
Hassell
A M
AM
Holmes
W D
WD
Hunter
R N
RN
Knick
V B
VB
Lackey
K
K
Lovejoy
B
B
Luzzio
M J
MJ
Murray
D
D
Parker
P
P
Rocque
W J
WJ
Shewchuk
L
L
Veal
J M
JM
Walker
D H
DH
Kuyper
L F
LF
D000505:Alopecia / Q000139:chemically induced* / Q000517:prevention & control*; D000818:Animals; D000831:Animals, Newborn; D000970:Antineoplastic Agents / Q000633:toxicity*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003520:Cyclophosphamide / Q000633:toxicity; D019610:Cytoprotection / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004317:Doxorubicin / Q000633:toxicity; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004848:Epithelium / Q000187:drug effects; D005047:Etoposide / Q000633:toxicity; D018859:Hair Follicle / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D016513:Mice, SCID; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D016160:Retinoblastoma Protein / Q000378:metabolism; D012535:Scalp / Q000637:transplantation; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014183:Transplantation, Heterologous
C418464:2-(4-((6,7-dihydro-7-oxo-5H-thiazolo(5,4-e)indol-8-ylidene)amino)phenylsulfamido)pyridine; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D016160:Retinoblastoma Protein; D013449:Sulfonamides; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases