gms | German Medical Science

Objective: Glioblastoma (GBM) is the most common and most lethal primary malignant tumor of the central nervous system. Standard therapy consisting of surgery and adjuvant radio-chemotherapy using temozolomide (TMZ) results in median survival of only 14.6 months. Recently, the opioid D,L-methadone emerged as a potential drug for treatment of GBM, since it was shown that cultured GBM cells exposed to both D,L-methadone and doxorubicin displayed reduced cell viability. Despite the lack of further evidence that the opioid will be of clinical value, an increasing number of cancer patients requests treatment with D,L-methadone due to its presence in media. Here, we investigate whether D,L-methadone in combination with standard therapy may be beneficial for GBM treatment.

Methods: Following standard surgery, primary cell cultures of six tumor patients were established from GBM tissue and galea-fibroblasts, respectively. Cultures were treated with increasing concentrations of D,L-methadone in combination with either x-irradiation, TMZ or both. Cell viability was determined by measuring ATP concentrations in cell lysates (ACL) and dehydrogenase activity in living cells (DHA). In addition, µ-opioid receptor expression was detected by western blot.

Results: µ-opioid receptor was detected in all GBM cultures and interestingly expression levels varied between different isoforms in the respective cell lines. Concentrations of D,L-methadone up to 1 µM did neither significantly reduce viability of GBM cells nor show synergistic effects in combination with TMZ and/or irradiation. However, a concentration of 1 µM D,L-methadone reduced fibroblasts viability significantly (p<0.05) to 87.5%±6.1% (DHA) compared to the untreated control. At concentrations of 10 µM and 30 µM of the opioid – which are known to be toxic plasma concentrations in humans – GBM cell viability was significantly diminished to 82.4%±8.4%; p<0.05 and 53.4±6.8%; p<0.005 (DHA), respectively. As observed at low concentrations, no significant synergistic effect on treatment with 10 µM and 30 µM of the opioid in combination with TMZ and/or irradiation was observed.

Conclusion: D,L-methadone reduces glioblastoma cell viability in culture only at physiologically toxic concentrations. Moreover, no synergistic effect in combination with TMZ and/or irradiation was observed. Therefore, recommending the use of D,L-methadone for glioblastoma treatment does not seem plausible, according to our data.