Safety and Tolerance of D,L-Methadone in Combination with Chemotherapy in Patients with Glioma

Onken, Julia; Friesen, Claudia; Vajkoczy, Peter; Misch, Martin

doi:10.21873/anticanres.11438

Cited by 32 publications

(15 citation statements)

References 24 publications

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“…Therefore, a first trial was conducted with glioma patients (grade II-IV) that received standard therapy, including TMZ, together with MTD. Although no final conclusions can be drawn from this retrospective study of small group size [ 6 ], the regime based on MTD as therapeutic has been widely discussed and propagated in social media. It, thus, became obvious that there is a strong need for more background data on MTD and its impact on TMZ-induced responses.…”

Section: Discussionmentioning

confidence: 99%

“…This was explained by assuming that MTD impacts doxorubicin uptake and attenuates its efflux, which would enhance the intracellular level of doxorubicin and, consequently, its cytotoxic activity [ 5 ]. Based on this work, a trial has been initiated treating glioma patients (grade II–IV) with MTD, which occurred independent of their neuro-oncological treatment [ 6 ]. In view of the patient heterogeneity, small group size and lacking stratification of the control group, a conclusion as to the therapeutic benefit of MTD in mono- or combined therapy could not be drawn.…”

Section: Introductionmentioning

confidence: 99%

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Cytotoxic and Senolytic Effects of Methadone in Combination with Temozolomide in Glioblastoma Cells

Kaina

Beltzig

Piée-Staffa

et al. 2020

IJMS

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Methadone is an analgesic drug used for pain treatment and heroin substitution. Recently, methadone has been proposed to be useful also for cancer therapy, including glioblastoma multiforme (GBM), the most severe form of brain cancer, because experiments on cultured glioma cells treated with doxorubicin showed promising results. Doxorubicin, however, is not used first-line in GBM therapy. Therefore, we analyzed the cytotoxic effect of methadone alone and in combination with temozolomide, a DNA-alkylating drug that is first-line used in GBM treatment, utilizing GBM-derived cell lines and a human fibroblast cell line. We show that methadone is cytotoxic on its own, inducing apoptosis and necrosis, which was observed at a concentration above 20 µg/mL. Methadone was similar toxic in isogenic MGMT expressing and non-expressing cells, and in LN229 glioblastoma and VH10T human fibroblasts. The apoptosis-inducing activity of methadone is not bound on the opioid receptor (OR), since naloxone, a competitive inhibitor of OR, did not attenuate methadone-induced apoptosis/necrosis. Administrating methadone and temozolomide together, temozolomide had no impact on methadone-induced apoptosis (which occurred 3 days after treatment), while temozolomide-induced apoptosis (which occurred 5 days after treatment) was unaffected at low (non-toxic) methadone concentration (5 µg/mL), and at high (toxic) methadone concentration (20 µg/mL) the cytotoxic effects of methadone and temozolomide were additive. Methadone is not genotoxic, as revealed by comet and γH2AX assay, and did not ameliorate the genotoxic effect of temozolomide. Further, methadone did not induce cellular senescence and had no effect on temozolomide-induced senescence. Although methadone was toxic on senescent cells, it cannot be considered a senolytic drug since cytotoxicity was not specific for senescent cells. Finally, we show that methadone had no impact on the MGMT promoter methylation. Overall, the data show that methadone on glioblastoma cells in vitro is cytotoxic and induces apoptosis/necrosis at doses that are above the level that can be achieved in vivo. It is not genotoxic, and does not ameliorate the cell killing or the senescence-inducing effect of temozolomide (no synergistic effect), indicating it has no impact on temozolomide-induced signaling pathways. The data do not support the notion that concomitant methadone treatment supports temozolomide-based chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cytotoxic and Senolytic Effects of Methadone in Combination with Temozolomide in Glioblastoma Cells

Kaina

Beltzig

Piée-Staffa

et al. 2020

IJMS

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“…It is therefore conceivable that the in vivo concentrations of methadone are even lower in GBM patients compared with nontumorous brain tissue, which was the subject of recent forensic studies investigating tissue concentrations of D and L methadone in the human brain [ 44 ]. A first study on the clinical feasibility of D,L-methadone in patients with recurrent GBM has used an ascending dosing protocol of D,L-methadone up to a maximum of 20–35 mg/day [ 10 ], which is about half of the dosage used in opioid addicts. Although in this study, the observed D,L-methadone-related toxicity was rather moderate and the 6-month progression free survival was found comparable to historic controls, the putative concentrations of D,L-methadone in the brain with this dose regimen are presumably significantly lower compared with the concentrations found effective in the in vitro study on GBM cells by Friesen and co-workers [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

“…[ 9 ] showed that D,L-methadone mediates enhanced apoptosis and increased sensitivity toward doxorubicin in established GBM cell lines by reversing deficient caspase activation and reducing intracellular cAMP levels. Furthermore, a recent retrospective report from 27 recurrent GBM patients treated with increasing D,L-methadone concentrations implies a moderate toxicity, while no efficacy data were reported due to the absence of a control arm in this study [ 10 ]. D,L-methadone is a μ-opioid receptor agonist, stimulating inhibitory G i -proteins, which in turn block adenylyl cyclase activity, followed by an decrease of cAMP levels [ 11 ].…”

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confidence: 95%

Efficacy of D,L-methadone in the treatment of glioblastoma in vitro

et al. 2018

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Aim:Recently, D,L-methadone has been put forward as adjuvant treatment in glioblastoma (GBM).Methods:We analyzed the μ-opioid receptor expression in a set of GBM cell lines and investigated the efficacy of D,L-methadone alone and in combination with temozolomide (TMZ).Results & conclusion:Expression of the μ-opioid receptor was similar in the tested cell lines. High concentrations of D,L-methadone induced apoptosis in all cell lines and showed treatment interaction with TMZ. However, in lower dosages, reflecting clinically attainable concentrations, D,L-methadone alone showed no efficacy, and induced even higher proliferation in one specific cell line. Also, no interaction with TMZ was observed. These results suggest caution to the premature use of D,L-methadone in the treatment of GBM patients.

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“…After reaching the maximal methadone dosage, the adverse side effects remained in four patients with mild to moderate obstipation (CTC grade 2–3; n = 3) and nausea (CTC grade 2; n = 1). The comparison of the progression free survival at 6 months (PFS-6) between the intervention group and a historic control group was not significant; however, mean overall survival was not reached ( Onken et al, 2017 ). This study gives a hint that methadone can be safely combined with standard tumor treatment.…”

Section: Antitumor Activities Of Methadonementioning

confidence: 86%

Methadone as a “Tumor Theralgesic” against Cancer

2017

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Methadone has beneficial characteristics as an analgesic against cancer pain, including high bioavailability, multiple receptor affinities, and lack of active metabolites that might induce adverse side effects. However, methadone has an own pharmacological profile that should be considered in the treatment of cancer patients. There is evidence from preclinical studies that methadone could also elicit antitumor activity by downregulating the threshold of apoptosis and to enhance the effects of different chemotherapeutic agents. This confirms the concept of using methadone as a chemosensitizer in the future treatment of cancer. Our article discusses major issues about the role of methadone as a possible “tumor theralgesic,” combining tumor therapeutic and analgesic activities.

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Safety and Tolerance of D,L-Methadone in Combination with Chemotherapy in Patients with Glioma

Abstract: Abstract. Background

Cited by 32 publications

References 24 publications

Cytotoxic and Senolytic Effects of Methadone in Combination with Temozolomide in Glioblastoma Cells

Cytotoxic and Senolytic Effects of Methadone in Combination with Temozolomide in Glioblastoma Cells

Efficacy of D,L-methadone in the treatment of glioblastoma in vitro

Methadone as a “Tumor Theralgesic” against Cancer

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