Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 131, Issue 5, Pages E813-E821Publisher
WILEY
DOI: 10.1002/ijc.27379
Keywords
chemotherapy-induced alopecia; cyclophosphamide; PTH-CBD agonist; PTH-CBD antagonist; bone mineral density; Parathyroid hormone
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Funding
- Ochsner Clinic Foundation, New Orleans, LA
- AR Biosciences Institute (ABI)
- National Institutes of Health Center for Protein Structure and Function [NCRR COBRE 1 P20RR15569, INBRE P20RR16460]
- Japan Society for the Promotion of Science
- Kagawa University
- Grants-in-Aid for Scientific Research [23590516] Funding Source: KAKEN
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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(733)-CBD and PTH([-1]-33)-CBD, also bound collagen and antagonized PTH(134) effect in SaOS-2 cells; however, PTH(733)-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(733)-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.
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