title: Superoxide dismutase mimic, MnTE-2-PyP(5+) ameliorates acute and chronic proctitis following focal proton irradiation of the rat rectum.
abstract: Radiation proctitis, an inflammation and damage to the lower part of colon, is a common adverse event of the radiotherapy of tumors in the abdominal and pelvic region (colon, prostate, cervical). Several Mn(III) porphyrin-based superoxide dismutase mimics have been synthesized and successfully evaluated in preclinical models as radioprotectants. Here we report for the first time the remarkable rectal radioprotection of frequently explored Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP(5+). A batch prepared in compliance with good manufacturing practice (GMP), which has good safety/toxicity profile, was used for this study. MnTE-2-PyP(5+) was given subcutaneously at 5 mg/kg, either 1 h before or 1 h after irradiation, with additional drug administered at weekly intervals thereafter. MnTE-2-PyP(5+) ameliorated both acute and chronic radiation proctitis in male Sprague-Dawley rats irradiated with 20-30 Gy protons delivered to 2.5 cm span of rectum using spread-out Bragg peak of a proton treatment beam. Focal irradiation of the rectum produced acute proctitis, which healed, followed by chronic rectal dilation and symptomatic proctitis. MnTE-2-PyP(5+) protected rectal mucosa from radiation-induced crypt loss measured 10 days post-irradiation. Significant effects were observed with both pre- and post-treatment regimens. However, only MnTE-2-PyP(5+) pre-treatment, but not post-treatment, prevented the development of rectal dilation, indicating that proper dosing regimen is critical for radioprotection. The pre-treatment also prevented or delayed the development of chronic proctitis depending on the radiation dose. Further work aimed at developing MnTE-2-PyP(5+) and similar drugs as adjunctive agents for radiotherapy of pelvic tumors is warranted. The present study substantiates the prospects of employing this and similar analogs in preserving normal tissue during cancer radiation as well as any other radiation exposure.
authors.affiliation: Department of Radiation Medicine, Loma Linda University, Loma Linda, CA, USA.
authors.forename: John O
authors.initials: JO
authors.lastname: Archambeau
authors.affiliation: Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Artak
authors.initials: A
authors.lastname: Tovmasyan
authors.affiliation: Department of Surgery (Neurosurgery), Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Pearlstein
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Denver, CO 80206, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.affiliation: Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Ines
authors.initials: I
authors.lastname: Batinic-Haberle
mesh_terms: D000818:Animals; D040761:Biomimetic Materials; D004305:Dose-Response Relationship, Drug; D007279:Injections, Subcutaneous; D008297:Male; D008665:Metalloporphyrins / Q000008:administration & dosage* / Q000627:therapeutic use; D011349:Proctitis / Q000188:drug therapy* / Q000473:pathology; D011837:Radiation-Protective Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012007:Rectum / Q000473:pathology / Q000528:radiation effects*
chemical_list: D008665:Metalloporphyrins; D011837:Radiation-Protective Agents; C520506:manganese tetrakis-(N-ethyl-2 pyridyl) porphyrin
keywords: AP-1, activator protein-1; CGE, cobalt gray equivalent; GSH, glutathione; HIF-1α, hypoxia inducible factor-1; Mn porphyrin; MnP, Mn(III) porphyrins; MnTDE-2-ImP5+, Mn(III) meso-tetrakis(N,N’-diethylimidazolium-2-yl)porphyrin (AEOL10150); MnTE-2-PyP5+; MnTE-2-PyP5+, Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (AEOL10113, BMX-010); MnTM-2-PyP5+, Mn(III) meso-tetrakis(N-methylpyridinium-2-yl)porphyrin (AEOL10112); MnTnBuOE-2-PyP5+, Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin; MnTnHex-2-PyP5+, Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin (BMX-001); NF-κB, nuclear factor κB; PT, proton therapy; Proton beam therapy; Radiation proctitis; Radioprotector; SOD mimic; SOD, superoxide dismutase; SP-1, specificity protein-1; TF, transcription factor; kcat(O2−), the rate constant for the catalysis of O2− dismutation by Mn porphyrin or SOD enzyme