I have some questions about the main principles in drug resistant cell models development.
After determination of IC50 whatever cytotoxic assay is used. I knew there are 2 schools; those who prefer to do a dose-escalation of anti-cancer drug concentrations, and this consumed a lot of time to develop (increase the drug concentration gradually.)
The second, those who prefer to start with a high dose (higher than IC50) and then keep changing the media (drug-free) every week/ 2 weeks.
So how can the one be sure in these weeks (while putting a drug-free media), all cells won't lose the resistance they develop or in other words, why we didn't keep putting drug to cells every week? In order not to kill them all or just mimics what happened in the clinic?
In drug resistant models development, Is there transient vs stable phenotype of drug resistance? How can we really distinguish?
And also there are any methods except for what I said?
Thank you!
I think these two methods are designed to do two different things.
In the first method, in which the cytotoxic drug concentration is gradually increased from a level that permits substantial cell survival, the purpose is to allow time for resistance mutations to occur, and even to accumulate, during the course of the treatment. An example might be the gradual amplification of the gene for a multidrug resistance transporter.
In the second method, in which the cells are treated for a short time with a high concentration of the cytotoxic drug that kills nearly all the cells, then grown in medium without the drug, the purpose is to select for a rare, stable, preexisting mutation in the cell population that confers high-level resistance. An example might be a mutation in the drug target (such as topoisomerase) that reduces the binding affinity of the drug.
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