Chemotherapy Drug Resistance
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1
What is clonal selection?
As cancer is treated with a drug, many of the cancer cells die off. However, the drug resistant cells remain. Now the tumor is much smaller, possibly even undetectable, but it is made of drug resistant cells.
2
What is stable resistance?
The remaining drug resistant cells from clonal selection multiply, growing and eventually creating and entire full size tumor that is drug resistant.
3
What is darwinian (pre-existing)/intrinsic resistance?
Drug resistant cells are already present in the tumor, just at a lower percentage, and after a drug wipes out the non resistant cells, they take over and become the whole tumor.
4
What is lamarckian/aquired resistance?
The tumor starts with no resistant cells, but in response to the drug develops resistance, through something like upregulation of drug efflux pumps. These resistances are passed on to offspring until eventually the whole tumor is drug resistant.
5
What are some common methods of drug resistance?
Decreased uptake of drug (lowered permeability of membrane or less expression of active transporters)
Failure to activate drugs
Enhanced conversion to inactive species
Increased transport of drug out of cells
Increased levels of intracellular scavengers
Increased levels of DNA repair mechanisms
Failure to activate drugs
Enhanced conversion to inactive species
Increased transport of drug out of cells
Increased levels of intracellular scavengers
Increased levels of DNA repair mechanisms
6
What are ABC transporters?
ATP-Binding Cassette transporters, use ATP to pump things out of the cell, such as drugs. Major component of multi-drug resistance, where a cancer cell will become resistant to one type of drug, and then also have resistance against another completely unrelated drug class, because upregulation of these transporters will pump both drugs out of the cell.
7
What are the parts of ABC transporters?
TMD, the transmembrane domain, made of 6 alpha helices. This sits across the membrane and recognizes / binds to the drugs, effluxing them out of the cell.
NBD, the nucleotide binding domain. This sits inside of the cell and binds ATP for energy
NBD, the nucleotide binding domain. This sits inside of the cell and binds ATP for energy
8
What are the most common ABC transporters?
P-GP (ABCB1) - P-glycoprotein pump
BCRP (ABCG2) - Breast cancer resistance protein
MRP1 (ABCC1) - multi-drug resistance associated protein
BCRP (ABCG2) - Breast cancer resistance protein
MRP1 (ABCC1) - multi-drug resistance associated protein
9
He stated in the lecture that he wanted us to know two types of transporters, one of which was the ABC transporters mentioned above. He never mentioned a second type, and at the end of lecturing about ABC transporters, he said he just wanted us to know those two. So idk what the deal is, did he just forget to talk about the second type, he only wants us to know ABC?? Idk. Maybe he was just referring to active transport into the cell required for some drugs? He never mentioned a specific type of transporter for that though.
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