Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug.
The last major advance in the treatment of glioblastoma multiforme (GBM) was the introduction of temozolomide in 1999. Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone. However, virtually all glioblastoma patients experience disease progression within 7 to 10 months. Although many salvage treatments, including bevacizumab, rechallenge with temozolomide, and other alkylating agents, have been evaluated, none of these clearly improves survival. Monoamine oxidase B (MAOB) is highly expressed in glioblastoma cell mitochondria, and mitochondrial function is intimately tied to treatment-resistant glioblastoma progression. These glioblastoma properties provide a strong rationale for pursuing a MAOB-selective pro-drug treatment approach that, upon drug activation, targets glioblastoma mitochondria, especially mitochondrial DNA. MP-MUS is the lead compound in a family of pro-drugs designed to treat GBM that is converted into the mature, mitochondria-targeting drug, P(+)-MUS, by MAOB. We show that MP-MUS can successfully kill primary gliomas in vitro and in vivo mouse xenograft models.
Department of Neurosurgery, Kenneth R. Peak Brain and Pituitary Tumor Center, Houston Methodist Hospital, 6565 Fannin, Suite 944, Houston, TX 77030, United States.
Martyn A
MA
Sharpe
Department of Neurosurgery, Kenneth R. Peak Brain and Pituitary Tumor Center, Houston Methodist Hospital, 6565 Fannin, Suite 944, Houston, TX 77030, United States.
Andrew D
AD
Livingston
Department of Neurosurgery, Kenneth R. Peak Brain and Pituitary Tumor Center, Houston Methodist Hospital, 6565 Fannin, Suite 944, Houston, TX 77030, United States.
Taylor L
TL
Gist
Center for Molecular Imaging, Institute of Molecular Medicine, UT Health Science Center-Houston, Houston, TX 77030, United States.
Pardip
P
Ghosh
Department of Neurosurgery, Kenneth R. Peak Brain and Pituitary Tumor Center, Houston Methodist Hospital, 6565 Fannin, Suite 944, Houston, TX 77030, United States.
Junyan
J
Han
Department of Neurosurgery, Kenneth R. Peak Brain and Pituitary Tumor Center, Houston Methodist Hospital, 6565 Fannin, Suite 944, Houston, TX 77030, United States.
David S
DS
Baskin
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008819:Mice, Nude; D008995:Monoamine Oxidase / Q000378:metabolism*; D010300:Parkinson Disease / Q000150:complications; D010641:Phenotype; D011355:Prodrugs / Q000494:pharmacology / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D004272:DNA, Mitochondrial; D011355:Prodrugs; D017382:Reactive Oxygen Species; D007770:L-Lactate Dehydrogenase; D008995:Monoamine Oxidase
Chemotherapy; Glioblastoma multiforme; MP-MUS; Monoamine oxidase B; Pro-drug; Xenograft