Thursday, 17 January 2019

Temozolomide + mifepristone in rat glioma model

  • Mifepristone, an FDA and Health Canada approved antiprogestogen, used to induce abortion.
  • C6 rat glioma cells implanted into brains of male Wistar rats
  • temozolomide applied to the rats at a dose of 5 mg/kg/day intraperitoneally
  • mifepristone applied to the rats at a dose of 10 mg/kd/day subcutaneous injection
  • rat survival as show below ("sham" refers to rats undergoing sham surgery with no glioma cells implanted)
  • combination of temozolomide + mifepristone was effective where either single agent alone was  ineffective


  1. "Western blot data and band intensity showed the protein expression of MGMT to be strikingly downregulated in the mifepristone/temozolomide group"

    Perhaps this combo would be particularly useful in MGMT unmethylated GBM?

    1. Thank you for the new interesting research!

      Very interesting, what should be the dose of oral intake of mifepristone by a human in order to repeat the dose of subcutaneous injection to a rat?

    2. It's always hazardous trying to convert rodent doses into human doses. But a rough approximation would be 10 mg/kg x 0.16 (allometric scaling conversion factor from rat to human) = ~ 1.6 mg/kg = ~ 100 mg for a 60 kg human.

      The subcutaneous injection would probably lead to a higher plasma spike compared to oral dosing though.

      The recommended dose of mifepristone for Cushing syndrome is 300 mg orally once per day, with dose increases every two to four weeks.

      If the sensitization to TMZ seen in the rat study was primarily due to downregulation of MGMT protein (this isn't certain though), I wonder if it would be possible to take it a few days before and during TMZ cycles, rather than all 28 days of a cycle.

    3. Thank you very much for answering the question! I think this question was interesting for many readers of the blog.

  2. Did a little sleuthing and found this interesting case report which suggests it crosses the BBB and may be beneficial in some humans:
    Realize it's an n of 1, but patient had very advanced disease.

  3. Stephen, thank you heartily for such information and your help!
    I read the full study, but unfortunately, I don't understand some things. Sorry for taking your time, but could you please explain:
    1) Is it possible somehow to measure the level of expression of MGMT, and not just to determine if MGMT is methylated or not methylated? As far as I understand, this is an important prognostic factor.
    2) The answer to mephiristone / TMZ therapy should be better if a MGMT is methylated?
    3) What mutations or indicators may have prognostic value in mefipristone / TMZ treatment? Some abbreviations (P53 and Ki (67) in this study were familiar for me, but I didn't understand the correlation between them and effectiveness of such treatment.
    4) How do you think is it possible that incorrectly chosen dosage or schedule of taking mefipristone (together with TMZ) can cause the opposite effect (tumor growth) ?
    5) I read instruction to mefipriston where indicated that use with NSAIDs (including acetylsalicylic acid) should be avoided due to possible changes in efficacy of mefipriston. How do you think, if there any other medicines or supplements in "cocktail approach" which should be avoided during mefipristone, because they may affect its effectiveness or for some other reasons?
    6) Could you at least try to guess should a person starts mefipristone much in advance next TMZ course (not 2 days but 2 weeks for excample)?

    Thank you!