News: Dianhydrogalactitol überwindet TMZ-Resistenzmechanismen

Dianhydrogalactitol überwindet mehrere Temozolomid-Resistenzmechanismen im Glioblastom

Die Resistenz gegen Chemotherapie ist nach wie vor eines der größten Hindernisse in der Glioblastombehandlung. Wissenschaftler des spanischen Nationalen Krebsforschungszentrums haben gezeigt, dass die Kombination von Temozolomid mit Dianhydrogalactitol Glioblastomzellen abtötet, die gegen die herkömmliche Therapie mit alleinigem Temozolomid resistent sind.

Dianhydrogalactitol (Val-083) ist ein Chemotherapeutikum, das in der Lage ist, die Blut-Hirn-Schranke zu überwinden und das zentrale Nervensystem zu erreichen, wo es DNA-Schäden in Tumorzellen induziert. Die Kombination von Temozolomid und Val-083 zeigt einen synergistischen zytotoxischen Effekt bei Tumorzellen in vitro, ex vivo und in vivo. Die Forscher schlagen diese kombinatorische Behandlung nun als einen möglichen Ansatz für weitere klinische Studien bei Glioblastompatienten vor.

https://www.hirntumorhilfe.de/projekte/newsroom/news-16042021/

Quelle:
Jiménez-Alcázar M, Curiel-García Á, Nogales P, Perales-Patón J, Schuhmacher AJ, Galán-Ganga M, Zhu L, Lowe SW, Al-Shahrour F, Squatrito M. Dianhydrogalactitol overcomes multiple temozolomide resistance mechanisms in glioblastoma. Mol Cancer Ther. 2021 Apr 12:molcanther.0319.2020. doi: 10.1158/1535-7163.MCT-20-0319.
Epub ahead of print. PMID: 33846235.

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Das gleiche schafft Hydroxyurea seit 17 Jahren, wenn man es zu Tmz nimmt.

@buttkreis "Das gleiche schafft Hydroxyurea..."
Hast Du eine Quelle dazu?

Gibt etliche seit Jahrzehnten.
Hier eine Studio in vivo und in vitro von Teng:

https://pubmed.ncbi.nlm.nih.gov/29099956/

Hydroxyurea und metronomische Tmz hilft oft dort, wo Stupp und Pcv versagt.



Recycling drug screen repurposes hydroxyurea as a sensitizer of glioblastomas to temozolomide targeting de novo DNA synthesis, irrespective of molecular subtype
Jian Teng 1 2 , Seyedali Hejazi 1 2 , Lotte Hiddingh 3 4 , Litia Carvalho 1 2 , Mark C de Gooijer 1 3 , Hiroaki Wakimoto 5 , Marco Barazas 1 3 , Marie Tannous 6 , Andrew S Chi 7 , David P Noske 3 8 , Pieter Wesseling 8 9 10 , Thomas Wurdinger 1 2 3 8 , Tracy T Batchelor 1 11 , Bakhos A Tannous 1 2
Affiliations

PMID: 29099956 PMCID: PMC5892145 DOI: 10.1093/neuonc/nox198

Free PMC article
Erratum in

Corrigendum to: Recycling drug screen repurposes hydroxyurea as a sensitizer of glioblastomas to temozolomide targeting de novo DNA synthesis, irrespective of molecular subtype.
Teng J, Hejazi S, Hiddingh L, Carvalho L, de Gooijer M, Wakimoto H, Barazas M, Tannous M, Chi AS, Noske DP, Wesseling P, Wurdinger T, Batchelor TT, Tannous BA. Neuro Oncol. 2020 Dec 18;22(12):1894. doi: 10.1093/neuonc/noaa166. PMID: 33112953 Free PMC article. No abstract available.

Abstract

Background: Glioblastoma (GBM) is the most common and most aggressive primary malignant brain tumor. Standard-of-care treatment involves maximal surgical resection of the tumor followed by radiation and chemotherapy (temozolomide [TMZ]). The 5-year survival rate of patients with GBM is <10%, a colossal failure that has been partially attributed to intrinsic and/or acquired resistance to TMZ through O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status in the tumor.

Methods: A drug screening aimed at evaluating the potential recycling and repurposing of known drugs was conducted in TMZ-resistant GBM cell lines and primary cultures of newly diagnosed GBM with different MGMT promoter methylation status, phenotypic/genotypic background and subtype, and validated with sphere formation, cell migration assays, and quantitative invasive orthotopic in vivo models.

Results: We identified hydroxyurea (HU) to synergize with TMZ in GBM cells in culture and in vivo, irrespective of MGMT promoter methylation status, subtype, and/or stemness. HU acts specifically on the S-phase of the cell cycle by inhibiting the M2 unit of enzyme ribonucleotide reductase. Knockdown of this enzyme using RNA interference and other known chemical inhibitors exerted a similar effect to HU in combination with TMZ both in culture and in vivo.

Conclusions: We demonstrate preclinical efficacy of repurposing hydroxyurea in combination with TMZ for adjuvant GBM therapy. This combination benefit is of direct clinical interest given the extensive use of TMZ and the associated problems with TMZ-related resistance and treatment failure.

dianhydrogalctitol ist auch eine alte und bekannte substanz. Vor ca. 30 Jahre hat die Wirksamkeit in Glioblastoma gezeigt. Man hat die halt nicht weiterentwickelt.

Korrektur: die Substanz war vor ca. 45 Jahre !! bei Glioblastom Patienten angewendet:


May 11, 1979
Dianhydrogalactitol and Radiation TherapyTreatment of Supratentorial Glioma

Robert T. Eagan, MD; Donald S. Childs Jr, MD; Donald D. Layton Jr, MD; et al Edward R. Laws Jr, MD; Harry F. Bisel, MD; Margaret A. Holbrook, MD; Thomas R. Fleming, PhD


JAMA. 1979;241(19):2046-2050. doi:10.1001/jama.1979.03290450044023

Abstract

Dianhydrogalactitol was the most active of 177 agents tested against a mouse ependymoblastoma tumor. We conducted a prospectively randonized trial comparing whole-brain irradiation alone vs identical irradiation plus dianhydrogalactitol in 42 patients with grade 3 and 4 supratentorial astrocytomas. Patients receiving dianhydrogalactitol in addition to irradiation had a significantly longer median survival time (67 vs 35 weeks) than did patients receiving only irradiation. The major toxic effect of dianhydrogalactitol is hematologic suppression of a cumulative nature. Dianhydrogalactitol may play an important role (in conjunction with radiation therapy) in the initial treatment of patients with supratentorial glioma. Our data may indicate that the mouse ependymoblastoma system is a useful screen for agents to be used in the treatment of human glioma.

(JAMA 241:2046-2050, 1979)


https://jamanetwork.com/journals/jama/article-abstract/364774