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.
