Resistance to chemotherapy drugs Flashcards
What is intrinsic resistance?
When a tumour shows little reponse to an anticancer
agent from the very start.
This can be due to a variety of possible reasons/mechanisms:
Slow growth rate.
Poor uptake of the drug.
Biochemical/genetic properties of the cell.
Tumour cells in the centre of the tumour may be in the resting state and be intrinsically resistant as a result.
What is accquired resistance?
When a tumour is initially susceptible to a drug but becomes resistant.
This is due to the presence of a mixture of drug-resistant and drug-sensitive cells within the tumour.
The drug wipes out the drug-sensitive cells. This only serves to select out and enrich the drug-resistant cells.
The survival of even one such cell can lead to failure of the treatment, since the single survivor can spawn a newer drug resistant tumour.
Why does a single tumour contain both drug-resistant and drug-sensitive cells?
Because cancer cells, by their very nature, are genetically unstable and so mutations are bound to have occurred during tumour growth which will result in resistant cells.
How do tumour cells evolve mechanisms of resistance?
Production of a drug-resistant variant of the target protein - new target.
Substitution of its cellular function by up-regulating other pathways - can be exploited.
Enhanced expression and function of drug efflux transporters.
What is the MDR phenotype?
The MDR phenotype is mostly associated with the over-expression of P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1).
Both proteins are members of the superfamily of membrane transport carriers known as ATP-binding cassette (ABC) proteins - these hydrolyse ATP as an energy source to drive the outwardly directed transport of substrates against a concentration gradient and therefore reduce their intracellular concentration.
What are the general features of ABC transporters?
ABC transporters are “pump” proteins found in the membranes of bacteria and human cells.
They are present in organs related to digestion and excretion. A protective mechanism that eliminates toxic chemicals.
They have a great importance in drug absorption through biological membranes like those found in the intestinal wall.
These transporters are the biggest single cause for failure of anticancer chemotherapy.
The genes responsible for their synthesis are activated by environmental stress (e.g. foreign chemicals or heat).
They act by removing the anticancer drugs from the cell, and much effort has been placed in developing compounds that block the transport protein thus restoring sensitivity to the anticancer drug.
What is the P-glycoprotein?
A membrane-associated 170 kDa glycoprotein that effluxes ~50% of all anticancer agents used clinically today without chemically modifying them.
It is over-expressed in many intrinsically resistant tumours and in others that acquire resistance during chemotherapy treatment.
When the gene which encodes P-gp (mdr) was transfected into drug-sensitive cells they became resistant to those drugs.
Most MDR modulators act by binding to P-gp and MRP, inhibiting their drug-efflux activity. Others inhibit expression of the mdr1 gene.
What is the structure of the P-glycoprotein?
P-gp contains two transmembrane domains that form a single barrel with a central pore that is open to the extracellular surface and spans much of the membrane depth.
After ATP binding, a major conformational change opens the pore, allowing access of hydrophobic substrates from the membrane and their ejection out of the cell.
Chemosensitisers (P-gp modulators) are able to reverse this activity through direct binding to the transporter.
What are P-gp inhibitors?
P-gp inhibitors are non-cytotoxic agents that, when used in combination with drugs pumped by P-gp, restore the sensitivity to these drugs by maintaining their intracellular concentration.
What is important about the (R)-enantiomer of verapamil?
The (R)-enantiomer of verapamil (dexverapamil) lacks the cardiac effects of verapamil, but retains the ability to inhibit P-gp.
Unfortunately, it is non-selective and inhibits more than one protein of the ABC family.
What are MGMT inhibitors?
The MGMT gene encodes a DNA damage repair protein that removes alkylating agents resulting in resistance to chemotherapy. Because DNA methylation can inhibit transcription, methylation of MGMT promoter increases sensitivity to alkylating agents.
MGMT inhibitors are used in combination with alkylating agents.
What is O6-Benzylguanine?
It is a MGMT inhibitor.
It exerts its effect by covalent transfer of the benzyl group to the active site cysteine.
It can enhance the toxicity of many alkylating chemotherapeutic agents.
What is Glutathione (GSH)?
Glutathione (GSH) is a ubiquitous cysteine-containing tripeptide that is the predominant cellular thiol.
GSH is nucleophilic and reacts with electrophiles to form deactivated conjugates readily excreted by a glutathione synthase (GS)-conjugated export pump.
Reaction may occur spontaneously or with the help of the enzyme glutathione-S-transferase (GST).
What is γ-Glutamylcysteine synthetase (γ-GCS)?
γ-Glutamylcysteine synthetase (γ-GCS) is the enzyme involved in the rate-limiting step of GSH synthesis.
This makes it an ideal target for enabling depletion of intracellular GSH levels by designing inhibitors of it.
What are glutathione-S-transferases (GSTs)?
Glutathione-S-transferases (GSTs) are a family of phase II metabolic enzymes that catalyse the conjugation of glutathione to a large variety of electrophilic compounds.
GSTs have been implicated in the resistance towards electrophilic antitumour agents, especially alkylating agents, such as nitrogen mustards and nitrosoureas, because they catalyse their conjugation with glutathione.
They are then expelled from the cell, and subsequently, the body.
