High-Dose Metformin Plus Temozolomide Shows Increased Anti-tumor Effects in Glioblastoma In Vitro and In Vivo Compared with Monotherapy
Especially interesting was the finding that the higher dose of metformin + temozolomide eliminated the expression of fatty acid synthase in the tumor specimens.
Fatty acid synthase (FASN) may be an especially good target in IDH1-mutant gliomas, as FASN is one of the most differentially overexpressed transcripts in G-CIMP (for the most part IDH mutant) gliomas versus non G-CIMP (for the most part IDH wild-type).
As is usually the case, the devil is in the details.
The study states several times that the metformin doses used in this study are clinically relevant, and this is true, except for the fact that the mice were injected with metformin intraperitoneally, rather than fed the metformin orally the way humans would take it.
From a different study, we know that intraperitoneal injections of metformin can lead to peak plasma levels 150-fold higher than what can be achieved with oral dosing.
"Notably, HPLC-ESI-QTOF-MS pharmacokinetic analysis showed that the plasma levels of metformin immediately after the last i.p. injection were ~150-fold higher than those obtained with the oral dosing schedule. Thus, mice that were treated with the i.p. dosing schedule achieved 679 ± 16 µmol/L (~87 µg/mL) metformin, a circulating dose of metformin that is within the lower limit observed in an individual with metformin poisoning..."
Pharmacokinetic differences between the methods of drug administration used in mouse studies (often intraperitoneal) and the methods used in humans, may account for some of the failures of mouse studies to translate into clinical results.
It would be interesting to investigate the anti-diabetes drug phenformin, a much more potent biguanide which was removed from the market in the 1970s due to increased risk of lactic acidosis, for cancer treatment.
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