TY - JOUR
T1 - Treatment for chemotherapy-induced alopecia in mice using parathyroid hormone agonists and antagonists linked to a collagen binding domain
AU - Katikaneni, Ranjitha
AU - Ponnapakkam, Tulasi
AU - Suda, Hirofumi
AU - Miyata, Shigeru
AU - Sakon, Joshua
AU - Matsushita, Osamu
AU - Gensure, Robert C.
PY - 2012/9/1
Y1 - 2012/9/1
N2 - 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.
AB - 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.
KW - Bone mineral density
KW - Chemotherapy-induced alopecia
KW - Cyclophosphamide
KW - PTH-CBD agonist
KW - PTH-CBD antagonist
KW - Parathyroid hormone
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U2 - 10.1002/ijc.27379
DO - 10.1002/ijc.27379
M3 - Article
C2 - 22130912
AN - SCOPUS:84863201729
SN - 0020-7136
VL - 131
SP - E813-E821
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 5
ER -