I think I finally figured out what happens when you don't give Paznem first before its combo drug. Intuitively I could tell it was wrong but I was not clear in explaining why. Now I believe I have identified the problem.
The dose of Panzem was determined from animal experiments in order to find the correct dose of Panzem to give in humans. As a single agent the animal tumors shrank as the dose level of Panzem went up. They came up with the minimum dose to shrink tumors in humans at about 1000mg.
Now the problem the way I see it is when you add a combo drug like Taxol (paclitaxel) first, you just increased the HIF-1 levels as has been shown in the phase 1b test. "Paclitaxel causes an increase in tumor HIF-1alpha expression..." Since Panzem's HIF-1 inhibition is a dose dependent process and now the HIF-1 levels have just been increased, the Panzem dose of 1000mg or 1500mg is now too low.
If you give Panzem first then you avoid this complication, the dose as a mono-therapy is the same in the combo therapy. If you give Panzem first then cancer cells will not be able to cope with the effects of the second oxygen stressing drug. If you give it second then Panzem will not be able to catch up with the increased HIF-1 production caused by the first drug unless you give Panzem at a much higher dose. What that dose level should be is unknown at this point in time and may cause increased side effects.
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