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Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug.

Sharpe MA, Livingston AD, Gist TL, Ghosh P, Han J, Baskin DS - EBioMedicine (2015)

Bottom Line: Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Kenneth R. Peak Brain and Pituitary Tumor Center, Houston Methodist Hospital, 6565 Fannin, Suite 944, Houston, TX 77030, United States.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Glioblastoma successfully treated by MP-MUS in an intracranial xenograft model.(A) Kaplan–Meier plot of mice after intracranial injection following 3 × Saline or 3 × MP-MUS (8 mg/kg) tail vein injections, n = 11.(B) Alteration in mouse body mass during course of trial shows that MP-MUS treated gain and hold body weight better than saline treated.(C) Labeling of uninjected hemisphere of saline treated mouse with (I) anti-vimentin (human glioblastoma cells) IgG, (III) CD3-ε (mouse immune cells) and (II) no-primary IgG control (background peroxidase activity).(D) Images of C. (I) taken as increasing magnification demonstrating the pattern of infiltration of the brain by the glioblastoma cells.(E) Unambiguous demonstration that vimentin labeling co-localized with DAPI/nuclear DNA can be seen by attenuation of fluorescent nuclei within glioblastoma DAB staining.(F) Levels of glioma and CD3-ε in MP-MUS treated brain (right hemispheres).MP-MUS #1 displays vimentin in human glioblastoma, found only on a single slide, but CD3-ε labeling is found throughout hemisphere.MP-MUS #8 has the most vimentin signal, hence glioblastoma cells, of any of the MP-MUS treated mice.
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f0035: Glioblastoma successfully treated by MP-MUS in an intracranial xenograft model.(A) Kaplan–Meier plot of mice after intracranial injection following 3 × Saline or 3 × MP-MUS (8 mg/kg) tail vein injections, n = 11.(B) Alteration in mouse body mass during course of trial shows that MP-MUS treated gain and hold body weight better than saline treated.(C) Labeling of uninjected hemisphere of saline treated mouse with (I) anti-vimentin (human glioblastoma cells) IgG, (III) CD3-ε (mouse immune cells) and (II) no-primary IgG control (background peroxidase activity).(D) Images of C. (I) taken as increasing magnification demonstrating the pattern of infiltration of the brain by the glioblastoma cells.(E) Unambiguous demonstration that vimentin labeling co-localized with DAPI/nuclear DNA can be seen by attenuation of fluorescent nuclei within glioblastoma DAB staining.(F) Levels of glioma and CD3-ε in MP-MUS treated brain (right hemispheres).MP-MUS #1 displays vimentin in human glioblastoma, found only on a single slide, but CD3-ε labeling is found throughout hemisphere.MP-MUS #8 has the most vimentin signal, hence glioblastoma cells, of any of the MP-MUS treated mice.

Mentions: To study the effects of MP-MUS on morbidity and body mass, we used an intracranial mouse model of primary human GBM (Fig. 7A and 7B). NOD/SCID mice were randomized into two treatment groups (n = 11 mice per group). Primary human GBM cells encased in a Matrigel matrix were injected into the right hemisphere of the brain of each mouse using the method developed by Iwami and co-workers (Iwami et al., 2012). The first of three tail-vein injections of saline or 0.2 mg MP-MUS, 8 mg/kg, was delivered on day 115. The saline-treated group exhibited morbidity in 50% of animals on day 248, whereas the MP-MUS treatment group had only one symptomatic mouse during the entire experimental period. Shortly after the final injection, animals in the MP-MUS-treated group steadily gained weight. In contrast, control mice showed a delayed weight gain after the final saline injection. Saline controls initially averaged 95% of the weight of MP-MUS-treated animals; however, the body weights of control animals declined consistently after day 250 until weights were about 88% of the final average weight of the MP-MUS-treated mice. In addition to a failure to thrive, most of the control mice lost clumps of body hair throughout the study, typically prior to the onset of neurological deficits or sudden weight loss; in contrast, only 40% of the MP-MUS-treated group exhibited these changes. Fig. S5 shows the surviving control mice on day 307 compared with four representative MP-MUS treated animals.


Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug.

Sharpe MA, Livingston AD, Gist TL, Ghosh P, Han J, Baskin DS - EBioMedicine (2015)

Glioblastoma successfully treated by MP-MUS in an intracranial xenograft model.(A) Kaplan–Meier plot of mice after intracranial injection following 3 × Saline or 3 × MP-MUS (8 mg/kg) tail vein injections, n = 11.(B) Alteration in mouse body mass during course of trial shows that MP-MUS treated gain and hold body weight better than saline treated.(C) Labeling of uninjected hemisphere of saline treated mouse with (I) anti-vimentin (human glioblastoma cells) IgG, (III) CD3-ε (mouse immune cells) and (II) no-primary IgG control (background peroxidase activity).(D) Images of C. (I) taken as increasing magnification demonstrating the pattern of infiltration of the brain by the glioblastoma cells.(E) Unambiguous demonstration that vimentin labeling co-localized with DAPI/nuclear DNA can be seen by attenuation of fluorescent nuclei within glioblastoma DAB staining.(F) Levels of glioma and CD3-ε in MP-MUS treated brain (right hemispheres).MP-MUS #1 displays vimentin in human glioblastoma, found only on a single slide, but CD3-ε labeling is found throughout hemisphere.MP-MUS #8 has the most vimentin signal, hence glioblastoma cells, of any of the MP-MUS treated mice.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4588367&req=5

f0035: Glioblastoma successfully treated by MP-MUS in an intracranial xenograft model.(A) Kaplan–Meier plot of mice after intracranial injection following 3 × Saline or 3 × MP-MUS (8 mg/kg) tail vein injections, n = 11.(B) Alteration in mouse body mass during course of trial shows that MP-MUS treated gain and hold body weight better than saline treated.(C) Labeling of uninjected hemisphere of saline treated mouse with (I) anti-vimentin (human glioblastoma cells) IgG, (III) CD3-ε (mouse immune cells) and (II) no-primary IgG control (background peroxidase activity).(D) Images of C. (I) taken as increasing magnification demonstrating the pattern of infiltration of the brain by the glioblastoma cells.(E) Unambiguous demonstration that vimentin labeling co-localized with DAPI/nuclear DNA can be seen by attenuation of fluorescent nuclei within glioblastoma DAB staining.(F) Levels of glioma and CD3-ε in MP-MUS treated brain (right hemispheres).MP-MUS #1 displays vimentin in human glioblastoma, found only on a single slide, but CD3-ε labeling is found throughout hemisphere.MP-MUS #8 has the most vimentin signal, hence glioblastoma cells, of any of the MP-MUS treated mice.
Mentions: To study the effects of MP-MUS on morbidity and body mass, we used an intracranial mouse model of primary human GBM (Fig. 7A and 7B). NOD/SCID mice were randomized into two treatment groups (n = 11 mice per group). Primary human GBM cells encased in a Matrigel matrix were injected into the right hemisphere of the brain of each mouse using the method developed by Iwami and co-workers (Iwami et al., 2012). The first of three tail-vein injections of saline or 0.2 mg MP-MUS, 8 mg/kg, was delivered on day 115. The saline-treated group exhibited morbidity in 50% of animals on day 248, whereas the MP-MUS treatment group had only one symptomatic mouse during the entire experimental period. Shortly after the final injection, animals in the MP-MUS-treated group steadily gained weight. In contrast, control mice showed a delayed weight gain after the final saline injection. Saline controls initially averaged 95% of the weight of MP-MUS-treated animals; however, the body weights of control animals declined consistently after day 250 until weights were about 88% of the final average weight of the MP-MUS-treated mice. In addition to a failure to thrive, most of the control mice lost clumps of body hair throughout the study, typically prior to the onset of neurological deficits or sudden weight loss; in contrast, only 40% of the MP-MUS-treated group exhibited these changes. Fig. S5 shows the surviving control mice on day 307 compared with four representative MP-MUS treated animals.

Bottom Line: Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Kenneth R. Peak Brain and Pituitary Tumor Center, Houston Methodist Hospital, 6565 Fannin, Suite 944, Houston, TX 77030, United States.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus