Drug resistance Flashcards
What are the two major types of resistance that cancer cells have to chemotherapy?
Intrinsic resistance which exists prior to receiving therapy and makes the therapy ineffective
Acquired resistance which can develop during the treatment of tumours which were initially sensitive to the drug this may be caused by drug resistance minor subpopulations of cells which existed before treatment and are capable of repopulating the tumour
Additional mutations which arise during treatment
Adaptive responses such as the upregualtion of target proteins or activation of alternative signalling pathways
What are the different facets of drug resistance?
The drug doesn’t reach the cancer cell from the blood supply
The drug gets into the cell but is prevented from reaching a high enough concentration to be effective
The drug gets into the cell and induces a response but this is not sufficient to induce death
The drug induces cell death but surviving tumour cells escape host immune mechanisms and repopulate the tumour
The drug induces cell damage but the tumour cells upregulate cell survival signalling pathways, survive and repopulate the tumour
What are the problems with delivering chemotherapeutics to tumour tissue?
Tumour cells lie in a sea of stromal cells containing the blood vessels
Individual cells may be distant from blood vessels creating a large distance for the drug to transverse
The tumour blood supply may be intermittent in some areas
The poor blood supply may create pharmacological sanctuaries with reduced drug access
Some tumour areas may be hypoxic affect the action of some drugs
What are the cellular mechanisms of drug resistance?
Failure of cell death pathways Compartmentalisation Altered drug export or import Altered metabolism Increased or altered drug targets Altered cell cycle checkpoints and induction of emergency response genes and signal transduction pathways Tumour suppressor gene inactivating mutations Oncogene activating mutations Increased levels of DNA repair
What are the mechanisms which prevent the build up of adequate intracellular drug concentration in tumour cells?
Many drugs require inward transporters to get them past the plasma membrane which may be absent or inactive in resistant cells
Drug outward transporters may remove the drug
Some drugs require enzymatic activation in the cell, these enzymes might not be present in the tumour cell
Drug degradation or conjugation enzymes may remove effective drug
What are drug transport proteins?
There are many subfamilies of transport proteins associated with the plasma membrane, mitochondrial membrane and membranes of cytoplasmic vesicles
These have normal physiological functions such as the uptake of amino acids, vitamins and the other components and the efflux of toxins and unwanted metabolites
Transport is driven by ATP for some transporters and by an ion gradient
Some transporters are selectively expressed in organs involved in secretion
Tumours may over express these to scavenge nutrients
How can multi-drug resistance involve outward transporters?
Early observations showed that cell lines developing resistance to a drug like doxorubicin simultaneously developed resistance to drugs with widely differing structures like paclitaxel
Measurement of cellular drug levels demonstrated that the cells were able to lower their internal drug concentration in a time and energy dependent mechanism
What is the ABC Drug transporter family?
This is composed of 49 genes with three main classes that are concerned with drug transport including subfamily ABCB, ABCC and ABCG
What is the P-glycoprotein transporter?
This is a member of the ABCB subfamily which is found mainly in the plasma membrane and is extensively glycosylated on its external face
It has 2 ATP binding domains on the cytoplasmic side
Its natural function is probably to remove potential toxins (reflected by high levels of expression in the intestinal epithelium) however in tumour cells it can also act to reduce cellular concentrations of drugs such asdoxorubicin and paclitaxel
It acts via an ATP catalysed change in confirmation
What are the current strategies used to overcome multidrug resistance provided by drug efflux pumps?
Co-administration of pump-inhibitors and cytotoxic agents
Use of cytotixc agents that bypass MDR-mediated efflux
Look for collateral sensitivity of MDR cells
How can multi drug resistance occur through loss of a target protein?
Some cancer cells have been found to have multidrug resistance without a drug efflux pump, this is most likely due to their lowered concentrations of topoisomerase II so a different therapy must be used to overcome this form of resistance
How can multidrug resistance be mediated by increased DNA repair?
DNA damage activates the S phase checkpoint and induces apoptosis
A variety of enzymes are involved in DNA repair and deficiency in these enzymes can lead to increased drug sensitivity for instance MGMT deficiency can lead temozolomide sensitivity
Conversely cells which have increased DNA repair are resistant to drugs which cause DNA damage
This can sometimes be circumvented through using an inhibitor of DNA repair
How might resistance to apoptosis be a property of cancer stem cells?
Tumour cells in a human tumour have a high rate of turnover and therefore a high rate of apoptosis however resistance to apoptosis is considered a hallmark of cancer with many therapeutic approaches aiming to induce this process
To resolve this paradox the majority of the cells in the cancer tissue are undergoing apoptosis but it is the stem cell population which is resistant to apoptosis
What are the therapeutic approaches which aim to overcome resistance to apoptosis?
Changing the balance of pro and anti apoptotic family members in favour of apoptosis
Developing small molecules that modify function by directly binding to Bcl-2 proteins such as ABT-263 and obatoclax which are their initial development stages
Gene therapy or siRNA approaches to reducing the expression of proteins that are driving tumour cell survival
How do cancer cells become resistant to cisplatin?
There is pretarget resistance where there is down regulation of the CTR1 transporter involved in the uptake of cisplatin
Increased expression of efflux pumps like MRP2 and ATP7A
Increased sequestration/inactivation in the cytoplasm by reduced glutathione and other cytoplasmic scavengers
There is on-target resistance with increased DNA damage repair (ERCC1, BRACA 1&2) and defects in mismatch repair components
There is post-target resistance with up regulation of pro-survival factors to prevent apoptosis as well as down regulation of pro apoptotic factors and upregulation of the MAP Kinase pathway
