Naslov
Mn porphyrin-based cellular redox modulators are prospective drugs for treating brain tumors

Autori
Dewhirst, Mark W. ; Rajić, Zrinka ; Keir, Stephen T. ; Tovmasyan, Artak ; Spasojevic, Ivan ; Weitner, Tin ; Park, Won ; Bigner, Darell D. ; Batinic-Haberle, Ines

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
From molecular information to cancer medicine / - , 2011

Skup
From molecular information to cancer medicine, NCI Translational Science Meeting 2011

Mjesto i datum
Washington D.C., Sjedinjene Američke Države, 28.07.2011. - 29.07.2011

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Nije recenziran

Ključne riječi
Mn porphyrin; brain tumor; oxidative stress; MnTnHex-2-PyP5+

Sažetak
During the last two decades it became obvious that oxidative stress, the redox imbalance between cellular reactive species and endogenous antioxidant defenses, is common to numerous diseases, cancer included. For two decades we have successfully developed Mn porphyrin-based therapeutics, originally designed as SOD mimics. The ability to dismute O2.- parallels their ability to remove other major oxidizing species, peroxynitrite, ONOO-, and to modulate redox-sensitive transcriptional activity, such asHIF-1, NF-B, AP-1, and SP-1. These effects suppress excessive inflammatory and immune responses. The Mn porphyrins offer remarkable protection in many models of oxidative stress injury, such as cancer, diabetes, stroke, pain and radiation injury. Despite intensive efforts to improve multimodal treatment of brain tumors, survival remains limited. Identifying novel targeted therapies is therefore at the forefront of brain tumor research. We have recently found that a lipophilic manganese(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP5+ , is active as a single agent in adult and pediatric glioblastoma multiforme (D-54 MG, D-245 MG, D-256 MG, D-456 MG) and pediatric medulloblastoma (D-341 MED). The effect is presumably due to the prevention of the activation of HIF-1, AP-1 and NF-B ; removal of signaling reactive species and/or oxidation of transcription factors has been suggested mechanism/s of action. Growth delays for mice bearing subcutaneous xenografts ranged from 3 (D-54 MG) to 34 days (D-341 MED). With mice bearing intracranial xenografts, MnTnHex-2-PyP5+ increased median survival by 33% (D-256 MG) and 173% (D-341 MED). We also showed that MnTnHex-2-PyP5+ significantly enhanced the radiation effects (increasing tumor growth delay for ~10 days) when given sc at 1.6 mg/kg bid over 58 days to nude mice bearing D-245 xenografts. We have recently succeeded in optimizing Mn porphyrin structure. A new drug, MnTnBuOE-2-PyP5+ has high antioxidant potency, high lipophilicity and diminished toxicity. We have found that MnTnBuOE-2-PyP5+ enhanced growth delay by 10 days when combined with radiation and temozolomide in a D-245 MG xenograft tumor line. Importantly, the compound is ~5 –fold less toxic than MnTnHex-2-PyP5+.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti, Farmacija

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