A new strategy for modulating chemotherapy-induced alopecia, using PTH/PTHrP receptor agonist and antagonist.
Parathyroid hormone (PTH) related peptide (PTHrP) and the PTH/PTHrP receptor (PTH/PTHrP-R) show prominent cutaneous expression, where this signaling system may exert important paracrine and/or autocrine functions, such as in hair growth control. Chemotherapy-induced alopecia - one of the fundamental unsolved problems of clinical oncology - is driven in part by defined abnormalities in hair follicle cycling. We have therefore explored the therapeutic potential of a PTH/PTHrP-R agonist and two PTH/PTHrP-R antagonists in a mouse model of cyclophosphamide-induced alopecia. Intraperitoneal administration of the agonist PTH(1-34) or the antagonists PTH(7-34) and PTHrP(7-34) significantly altered the follicular response to cyclophosphamide in vivo. PTH(7-34) and PTHrP(7-34) shifted it towards a mild form of "dystrophic anagen", associated with a significant reduction in apoptotic (TUNEL+) hair bulb cells, thus mitigating the degree of follicle damage and retarding the onset of cyclophosphamide-induced alopecia. PTH(1-34), in contrast, forced hair follicles into "dystrophic catagen", associated with enhanced intrafollicular apoptosis. We had previously shown that an induced shift in the follicular damage-response towards "dystrophic catagen" mitigates cyclophosphamide-induced alopecia, whereas a shift towards "dystrophic catagen" initially enhanced the hair loss, yet subsequently promoted accelerated hair follicle recovery. Therefore, this study in an established animal model of chemotherapy-induced alopecia, which closely mimics human chemotherapy-induced alopecia, strongly encourages the exploration of PTH/PTHrP-R agonists and antagonists as novel therapeutic agents in chemotherapy-induced alopecia.
Peters
E M
EM
Department of Medicine, Boston University Medical Center, MA 02118, USA.
Foitzik
K
K
Paus
R
R
Ray
S
S
Holick
M F
MF
D000505:Alopecia / Q000139:chemically induced / Q000188:drug therapy*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003520:Cyclophosphamide / Q000494:pharmacology*; D005260:Female; D018859:Hair Follicle / Q000187:drug effects / Q000473:pathology; D006727:Hormone Antagonists / Q000819:agonists / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D015603:Keratinocytes / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy; D010281:Parathyroid Hormone / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010446:Peptide Fragments / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011506:Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019379:Teriparatide / Q000819:agonists / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology
D018906:Antineoplastic Agents, Alkylating; D006727:Hormone Antagonists; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D011506:Proteins; D019379:Teriparatide; C064776:parathyroid hormone-related protein (7-34)amide; D003520:Cyclophosphamide; C035748:parathyroid hormone (1-34)amide