D,L-Methadone also down-regulates expression of anti-apoptotic molecules such as B-cell lymphoma-extra large (BCL-xL) or X-linked inhibitor of apoptosis protein (XIAP) ( 2, 3, 7). This effect is most pronounced with D,L-methadone since D-methadone stabilizes the opioid receptors and thus facilitates more binding of L-methadone. Down-regulation of cAMP sensitizes tumor cells for anticancer treatment and leads to increased rates of apoptosis of human glioma cells and glioma stem cells in cell culture ( 2). Simultaneous administration of the μ-opioid receptor agonist D,L-methadone and doxorubicin led to an increased antitumor effect via reducing second messenger cAMP ( 2, 3). Opioid receptor stimulation can activate inhibitory G i-proteins, which in turn block adenylyl cyclase activity, reducing cyclic adenosine monophosphate (cAMP) ( Figure 1) ( 8). Opioid receptor activation initiates a cascade of events resulting in a diversity of biological effects such as analgesia and sedation but also has effects on cell survival and proliferation ( 4- 7). Opioids are substances that act on opioid receptors. Recently it has been shown that the opioid D,L-methadone increases sensitivity toward chemotherapy of different tumor cell populations ( 2, 3). One possible way to overcome chemoresistance and tumor progression might be reached with the use of additional agents sensitizing tumor cells to applied therapies. Glioblastoma multiforme (GBM) is the most frequent and malignant type of human brain tumor, which quickly recurs despite standard therapy ( 1). PFS-6 in patients with primary glioblastoma treated this way seems to be at least comparable to that of historic controls. Conclusion: D,L-methadone can be safely combined with standard glioma chemotherapy without increasing the risk of toxicity or vegetative symptoms such as tachycardia, sweating and restlessness. PFS-6 of patients with glioblastoma was 80% in those with non-methylated O 6-methylguanine-DNA methyltransferase (MGMT) (n=5) and 100% in those with MGMT methylation (n=7).
Four patients reported persistent side-effects of nausea (CTC Grade 2, n=1) and obstipation (CTC grade 2-3, n=3). Results: A total of 13 patients reported grade 1-3 nausea at the beginning of the D,L-methadone therapy. Progression-free survival at 6 months (PFS-6) was assessed.
Toxicity was assessed accordingly to the Common Toxicity Criteria (CTC) of the National Cancer Institute. Patients and Methods: The dosage, duration of therapy and side-effects related to D,L-methadone were recorded in 27 patients. We evaluated the safety and tolerance of additional use of D,L-methadone in patients with glioma in combination with chemotherapy. Background/Aim: D,L-Methadone increases sensitivity toward chemotherapy of different tumor cell populations.
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