Abel explains, in the first part of a promised series.
This is a topic I've been meaning to write about for a long time but somehow never got around to it. Abel explains nicely the barriers to drug absorption, distribution, and activity and why it's very bad science for alties to try to extrapolate from studies of cells cultured in dishes to humans. In fact, toxicity to cultured cancer cells correlates only weakly with efficacy in an actual human, thanks to many of the factors Abel explains.
I would also point out that I'm involved as a coinvestigator in the evaluation of a drug that actually requires quite high concentrations inhibit tumor cell growth in a dish, levels higher than can be achieved in an experimental animal; yet this drug actually does inhibit tumor growth in xenografts implanted in nude mice. We suspect that it is because the drug disrupts a feedback loop wherein the tumor cells secrete a factor that stimulates themselves to grow and that this feedback loop doesn't exist in cell culture. In any case, by strict pharmacokinetics, our drug would be considered unlikely to work in vivo, but preliminary experiments suggest that it does. Another example is angiogenesis inhibition. Most angiogenesis inhibitors do little or nothing to tumor cells in a cell culture dish. That's because the tumor cells are not their target, but endothelial cells that form new blood vessels are. Angiogenesis inhibitors prevent these cells from forming new blood vessels for tumors, thus "starving" the tumor of nutrients and oxygen. These agents would never have been discovered if we relied on their activity against tumor cells in dishes to guide us.
I hear a lot of people complain about no useful science being done on the ISS, but one rather interesting experiment done already relates to this very problem: making cell cultures that would be more useful for cancer research. In addition to the angiogenesis problem, there's the fact that in a petri dish (unlike the human body), the colony is pretty much constrained to growing out in a flat blob along the bottom of the dish because there's nothing to support it. But giving it a three-dimensional matrix isn't useful either, because that also artificially constrains the colony's growth. So what if gravity were taken out of the equation? Ovarian cancer cells were brought to the ISS and grown in microgravity conditions. They ended up producing colonies remarkably similar in shape to actual tumors. While this is a rather expensive way to grow them, it might become very useful once the ISS is complete and can host more experiments.
Thank you, Orac, for your article illustrating that what happens in a Petri dish is not always what happens in vivo.
I would like to ask what the standard progression of testing is in a case like the example in your article. I am assuming that the normal sequence of testing if each phase is successful is: 1. Petri dish test 2. animal test 3. human trial
But what is the standard sequence of testing when one of the above steps is unsuccessful/unpromising?
In your example, the drug required quite high concentrations to inhibit tumor cell growth in a dish, levels higher than could be achieved in an experimental animal. And yet you went ahead and tried the drug on an animal (a mouse) - but is this usually the case? Or is research stopped at this point? How do you decide whether to go to the next step?
If they do try it in an animal, how do they figure out what dose to use (it has to be lower, right?). Do they just use the maximum dose the animal can handle?
and if the drug doesn't work in the animal, is the human trial automatically scratched? Does research stop at this point?