Drug combinations - (Jun/02/2009 )

Hello!

I'm trying to assess the effect of some drug combinations in some cancer cell lines. I'm new in this world of pharmacology.

Can someone tell me how can I quantify the degree of synergism/additivism/antagonism that I obtain with my combinations? I only know the "combination index" method and the CalcuSyn software. However, I'm getting some nonsense values.

Also, is there any expert in this "combination index" method?

Thanks!!

I’ve found this review to be the most helpful that I’ve encountered, though it’s heavy going at times.

Ting-Chao Chou, “Theoretical Basis. Experimental Design. and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies,” Pharmacological Reviews 58, no. 3 (2006): 621-681.

Good luck!

DRT on Jun 3 2009, 12:01 AM said:

Thank you for your answer. I've already read that paper. I was looking for alternatives to that method or find someone who is an expert in that method.

cardosopedro on Jun 3 2009, 09:37 PM said:

Your main consideration with alternate calculations/methods will be how they handle the Hill equation slope. If your compounds have cytotoxic curves which vary only in their IC50s (same slopes) any of the isobologram or CI based calculations will probably serve you well enough. However, (and this is possibly the reason you are getting strange results), if your compounds have disparate slopes then I think you might be stuck with an approach similar to Chou.
I tend to do all my calculations on my own spreadsheets so I’m sorry I can’t offer any recommendations for alternate software.

Thanks DRT.

Yes, you're right, the drugs that I use in the combinations have different slopes.

So, I'll have to use the CI approach.

Another controversy that I found out is whether you can classify by "synergism" when two drugs have a higher % inhibition compared with the sum of the % inhibition of the drugs alone. I believe this is too simplistic and also it's impossible to sum, for instance, 2 drugs that have 60% inhibition alone. Nevertheless, I think this is a reasonable method for sums < 100%.

What do you think?

And what's the best strategy? Constant-ratio or non-constant ratio combinations?

Yeah; that term ‘sum’ can be very misleading when working with %s. At the very least use the fractional products ie for two 60% inhibiting drugs:
100% - ((100% - 60%) x (100% - 60%)) = 84%


I tend to use constant ratios, but only because I’m usually asked to deconstruct an existing drug/herbal combination so the ratios are predetermined. I’ll have to have a longer think about this and post back in a couple of weeks (hectic exam time here).

Thanks a lot!

Thank you for interesting post ..
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