title: Treatment for chemotherapy-induced alopecia in mice using parathyroid hormone agonists and antagonists linked to a collagen binding domain.
abstract: Parathyroid hormone (PTH) agonists and antagonists have been shown to improve hair growth after chemotherapy; however, rapid clearance and systemic side-effects complicate their usage. To facilitate delivery and retention to skin, we fused PTH agonists and antagonists to the collagen binding domain (CBD) of Clostridium histolyticum collagenase. in-vitro studies showed that the agonist fusion protein, PTH-CBD, bound collagen and activated the PTH/parathyroid hormone-related peptide receptor in SaOS-2 cells. The antagonist fusion proteins, PTH(7-33)-CBD and PTH([-1]-33)-CBD, also bound collagen and antagonized PTH(1-34) effect in SaOS-2 cells; however, PTH(7-33)-CBD had lower intrinsic activity. Distribution studies confirmed uptake of PTH-CBD to the skin at 1 and 12 hr after subcutaneous injection. We assessed in vivo efficacy of PTH-CBD and PTH(7-33)-CBD in C57BL/6J mice. Animals were depilated to synchronize the hair follicles; treated on Day 7 with agonist, antagonist, or vehicle; treated on Day 9 with cyclophosphamide (150 mg/kg i.p.) or vehicle; and sacrificed on Day 39. Normal mice (no chemo and no treatment) showed rapid regrowth of hair and normal histology. Chemo+Vehicle mice showed reduced hair regrowth and decreased pigmentation; histology revealed reduced number and dystrophic anagen/catagen follicles. Chemo+Antagonist mice were grossly and histologically indistinguishable from Chemo+Vehicle mice. Chemo+Agonist mice showed more rapid regrowth and repigmentation of hair; histologically, there was a normal number of hair follicles, most of which were in the anagen phase. Overall, the agonist PTH-CBD had prominent effects in reducing chemotherapy-induced damage of hair follicles and may show promise as a therapy for chemotherapy-induced alopecia.
authors: Department of Pediatric Endocrinology, Children's Hospital at Montefiore and Albert Einstein College of Medicine, Bronx, NY 10467, USA.
authors: Ranjitha
authors: R
authors: Katikaneni
authors: Tulasi
authors: T
authors: Ponnapakkam
authors: Hirofumi
authors: H
authors: Suda
authors: Shigeru
authors: S
authors: Miyata
authors: Joshua
authors: J
authors: Sakon
authors: Osamu
authors: O
authors: Matsushita
authors: Robert C
authors: RC
authors: Gensure
mesh_terms: D000505:Alopecia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D003094:Collagen / Q000378:metabolism*; D003520:Cyclophosphamide / Q000009:adverse effects*; D005260:Female; D006727:Hormone Antagonists / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010281:Parathyroid Hormone / Q000819:agonists* / Q000037:antagonists & inhibitors*; D010446:Peptide Fragments / Q000494:pharmacology*; D011485:Protein Binding; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism
chemical_list: D006727:Hormone Antagonists; D007166:Immunosuppressive Agents; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D044168:Receptor, Parathyroid Hormone, Type 1; D003520:Cyclophosphamide; D003094:Collagen