Complete prevention of radiation-induced dermatitis using topical adrenergic vasoconstrictors
Tóm tắt
Radiation dermatitis is a commonly occurring, painful, side effect of cancer radiotherapy that causes some patients to withdraw from the radiotherapy course. Our goal was to test and optimize topical application of an adrenergic vasoconstrictor to rat skin in a preclinical test to prevent radiation-induced dermatitis. A radiation dermatitis assay was developed in which 17.2 Gy to a 1.5 × 3.0 cm rectangle on the clipped dorsal back of rats yielded Grade 3 radiation dermatitis over the irradiated area 13 days later. Single, topical applications of each of three adrenergic vasoconstrictors, epinephrine, norepinephrine, or phenylephrine, in various vehicle formulations, doses, and application schedules, were tested to determine their efficacy in preventing radiation dermatitis. Each of the three adrenergic agonists conferred 100 % prevention of radiation dermatitis in linear, dose-dependent manners and their EC50 potencies in preventing radiation dermatitis correlated well with their individual K d association constants for binding to mammalian α-adrenergic receptors. Topical vasoconstrictor application as little as 3–12 min before irradiation gave 80–100 % prevention, respectively, of radiation dermatitis. There was a strong correlation between the extent (0–100 %) of skin blanch present in skin immediately before irradiation and prevention of radiation dermatitis scored 13 days after irradiation. The data presented here demonstrate that topical application of adrenergic vasoconstrictors to rat skin before a large, 17.2 Gy, radiation insult confers 100 % protection against radiation dermatitis and support ongoing clinical trials and commercial development of a vasoconstrictor-based product to prevent radiotherapy-induced dermatitis.
Tài liệu tham khảo
citation_journal_title=Oncology; citation_title=The effect of treatment interruptions in the postoperative irradiation of breast cancer; citation_author=NS Bese, PA Sut, A Ober; citation_volume=69; citation_publication_date=2005; citation_pages=214-223; citation_doi=10.1159/000087909; citation_id=CR1
citation_journal_title=Dermatology; citation_title=Safety of tumescent liposuction under local anesthesia in a series of 4380 patients; citation_author=R Boeni; citation_volume=222; citation_publication_date=2011; citation_pages=278-281; citation_doi=10.1159/000327375; citation_id=CR2
citation_journal_title=Lancet; citation_title=Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomized trials; citation_author=M Clarke, R Collins, S Darby, C Davies, P Elphinstone, E Evans, J Godwin, R Gray, C Hicks, S James, E MacKinnon, P McGale, T McHugh, R Peto, C Taylor, Y Wang; citation_volume=366; citation_publication_date=2005; citation_pages=2087-2106; citation_doi=10.1016/S0140-6736(05)67887-7; citation_id=CR3
citation_journal_title=J Clin Oncol; citation_title=Radioprotection study of topical norepinephrine in postsurgical breast cancer patients; citation_author=JF Cleary, GM Cannon, JC Eickhoff, WE Fahl; citation_volume=30; citation_issue=15 suppl; citation_publication_date=2012; citation_pages=TPS9152; citation_id=CR4
citation_journal_title=J Natl Cancer Inst Monogr; citation_title=Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast; citation_author=C Correa, P McGale, C Taylor, Y Wang, M Clarke, C Davies, R Peto, N Bijker, L Solin, S Darby; citation_volume=2010; citation_issue=41; citation_publication_date=2010; citation_pages=162-177; citation_doi=10.1093/jncimonographs/lgq039; citation_id=CR5
Fahl WE (2012) Formulation of small adrenergic agonist salt forms in organic solvents. U.S. Patent application #14/122,442.
http://portal.uspto.gov/pair/PublicPair
. Accessed 30 Sept 2016
Fahl WE, Peebles DD, Copp RC (2004) Amino thiol compounds and compositions for use in conjunction with cancer therapy. U.S. Patent 7,314,959.
http://patft.uspto.gov/netahtml/PTO/srchnum.html
. Accessed 30 Sept 2016
citation_journal_title=Ann Surg; citation_title=Institutional variation in the surgical treatment of breast cancer: a study of the NCCN; citation_author=CC Greenberg, SR Lipsitz, ME Hughes, SB Edge, R Theriault, JL Wilson, WB Carter, DW Blayney, J Niland, JC Weeks; citation_volume=254; citation_publication_date=2011; citation_pages=339-345; citation_doi=10.1097/SLA.0b013e3182263bb0; citation_id=CR8
citation_title=Radiobiology for the radiobiologist; citation_publication_date=2012; citation_id=CR9; citation_author=EJ Hall; citation_author=AJ Giaccia; citation_publisher=Lippincott
citation_journal_title=Clin Oncol; citation_title=A modeled comparison of the effects of using different ways to compensate for missed treatment days in radiotherapy; citation_author=JH Hendry, SM Bentzen, RG Dale, JF Fowler, TE Wheldon, B Jones, AJ Munro, NJ Slevin, AG Robertson; citation_volume=8; citation_publication_date=1996; citation_pages=297-307; citation_doi=10.1016/S0936-6555(05)80715-0; citation_id=CR10
citation_journal_title=Am J Physiol; citation_title=Characterization of stimulation of phosphoinositide hydrolysis by ∝
1-adrenergic agonists in adult rat hearts; citation_author=A Lazou, SJ Fuller, MA Bogoyevitch, KA Orfali, PH Sugden; citation_volume=267; citation_publication_date=1994; citation_pages=H970-H978; citation_id=CR11
citation_journal_title=Eur J Dermatol; citation_title=A double-blind, randomised, vehicle-controlled clinical study to evaluate the efficacy of MAS065D in limiting the effects of radiation on the skin: interim analysis; citation_author=MC Leonardi, S Gariboldi, GB Ivaldi, A Ferrari, F Serafini, F Didier, L Mariani, S Castiglioni, R Orecchia; citation_volume=18; citation_publication_date=2008; citation_pages=317-322; citation_id=CR12
citation_journal_title=Int J Radiat Oncol Biol Phys; citation_title=Mometasone furoate effect on acute skin toxicity in breast cancer patients receiving radiotherapy: a phase 3 double-blind, randomized trial from the North Central Cancer Treatment Group N06C4; citation_author=RC Miller, DJ Schwartz, JA Sloan, PC Griffin, RL Deming, JC Anders, TJ Stoffel, RE Haselow, PL Schaefer, JD Bearden, PJ Atherton, CL Loprinzi, JA Martenson; citation_volume=79; citation_publication_date=2011; citation_pages=1460-1466; citation_doi=10.1016/j.ijrobp.2010.01.031; citation_id=CR13
citation_journal_title=Radiat Res; citation_title=ROS-scavenger and radioprotective efficacy of the new PrC-210 aminothiol; citation_author=DD Peebles, CM Soref, RR Copp, WE Fahl; citation_volume=178; citation_publication_date=2012; citation_pages=57-68; citation_doi=10.1667/RR2806.1; citation_id=CR14
citation_journal_title=Eur J Cancer Care; citation_title=Skin reactions during radiotherapy for breast cancer: the use and impact of topical agents and dressings; citation_author=D Porock, L Kristjanson; citation_volume=8; citation_publication_date=1999; citation_pages=143-153; citation_doi=10.1046/j.1365-2354.1999.00153.x; citation_id=CR15
citation_journal_title=Curr Oncol; citation_title=Prophylaxis and management of acute radiation-induced skin reactions: a systematic review of the literature; citation_author=N Salvo, E Barnes, J Draanan, E Stacey, G Mitera, D Breen, A Giotis, G Czarnota, J Pang, C Angelis; citation_volume=17; citation_publication_date=2010; citation_pages=94-112; citation_id=CR16
citation_journal_title=Br J Dermatol; citation_title=Topical corticosteroid therapy for acute radiation dermatitis: a prospective, randomized, double blind study; citation_author=M Schmuth, MA Wimmer, S Hofer, A Sztankay, G Weinlich, DM Linder, PM Elias, PO Fritsch, E Fritsch; citation_volume=146; citation_publication_date=2002; citation_pages=983-991; citation_doi=10.1046/j.1365-2133.2002.04751.x; citation_id=CR17
citation_journal_title=Psychooncology; citation_title=A qualitative analysis of acute skin toxicity among breast cancer radiotherapy patients; citation_author=JB Schnur, SC Ouellette, TA Dilorenzo, S Green, GH Montgomery; citation_volume=20; citation_publication_date=2011; citation_pages=260-268; citation_doi=10.1002/pon.1734; citation_id=CR18
citation_journal_title=Strahlentherapie; citation_title=Beta-adrenergic mechanism of mammalian cells radioprotection by isoproterenol; citation_author=AS Sobolev, YY Chirkov; citation_volume=158; citation_publication_date=1982; citation_pages=747-751; citation_id=CR19
citation_journal_title=Radiat Res; citation_title=Radioprotection of the rat parotid gland by WR-2721 and isoproterenol and its modification by propranolol; citation_author=M Sodicoff, AD Conger; citation_volume=94; citation_publication_date=1983; citation_pages=97-104; citation_doi=10.2307/3575867; citation_id=CR20
citation_journal_title=Oral Surg Oral Med Oral Pathol Oral Radiol; citation_title=A new topical vasoconstrictor-based strategy for prevention of oral mucositis; citation_author=CM Soref, WE Fahl; citation_volume=117; citation_publication_date=2014; citation_pages=454-461; citation_doi=10.1016/j.oooo.2013.12.005; citation_id=CR21
citation_journal_title=Int J Cancer; citation_title=A new strategy to prevent chemotherapy and radiotherapy-induced alopecia using topically applied vasoconstrictor; citation_author=CM Soref, WE Fahl; citation_volume=136; citation_publication_date=2015; citation_pages=195-203; citation_doi=10.1002/ijc.28961; citation_id=CR22