Chapter 19 Flashcards
Explain 9 cellular mechanisms associated with resistance to anticancer drugs - with examples of drugs in each cathegory
- Decerased uptake - antimetabolites (methotrexate, cytarabine, 5-fu), melphalan, cisplatin, nitrogen mustard
- Increased efflux - Antraycyclines, vinca alkaloids, epotoposide, TKI, taxanes, methotrexate, 5-FU
- Decreased drug activation - antimetabolites,
- Increased drug catabolism - antimetabolites
- Increased or decrease in target enzyme levels - topoisomerase inhibitor, antimetabolites, TKI
- Alteration in target protein - topoisomerase inihibitors, antimetabolites, TKI
- Inactivation by binding to sulfhydryls - alkylating agents, cisplatin
- Increased DNA repair- Alkylating agents, cisplatin, anthracycline,
- Decreased ability to undergo apoptosis - alkylating agents, anthracyclines, etoposide
Why do we consider many types of drug resistance genetic in origin?
- Characteristics of drug-resistant cells are inherited in the absence of the selecting drug
- Drug resistant cells develop at a rate consistent with genetic mutations
- It is increased by exposure to drugs that cause mutations in genes or facilitate gene amplification
- Altered drug-target protein that are the products of mutated genes
- Drug resistant phenotypes have been transferred to drug-sensitive cells by transfer of genes
What does the Goldie- Coldman model imply?
There is a greater chance to cure cancer if therapy is begun early with only microscopic foci present, and it predicts a better outcome when 2 equally effective drugs are alternated rather than given sequentially??
What is the underlying mechanism causing unstable drug resistance?
Epigenetic mechanisms (transient gene amplification, changes in patterns of DNA methylation)
Give exampled of epigenetic mechanisms which can influence drug resistance?
Methylation of promotor regions of genes
Acetylation or deacetylation of of histones - which will allow transcription of genes
Name 2 ways we can treat or restore drug resistance in cancer cells?
- The histone deacetylase (HDAC) inhibitor together with inhibitors of DNA methylation can restore drug sensitivity (experimental models)
- RNA interference- use microRNA to silence genes, by binding to the untranslated messenger RNA.
- Combine cytotoxic drug with autophagy inhibitors such as proton pump inhibitors
How can cancer cells develop resistance through impaired drug uptake?
- Point mutation causing altered carrier protein - ex. methotrexate and reduced folate carrier FRC1 is an example
What is the name of the carrier group which is responsible for cellular uptake of most hydrophilic drugs?
The solute carrier superfamily (SLC)
Which drugs depend on cellular uptake via membrane transport carriers?
Gemcitabine, cytarabine, methotrexate enter the cells through carriers in the SLC family
What is P-glycoprotein
A multidrug efflux pump encoded by the ABCB1 gene
Which drugs are substrates for P-glycoprotein efflux pump?
Doxorubicin, epirubicin, mitoxantrone, viblastine, vincristine, etoposide, methtotrexate, paclitaxel
Which other multi-drug efflux pumps have been described?
MRP 1/2/4 (ABCC1 gene), ABCG2
Which drugs may be affected by MRP2 efflux pump?
Cisplatin, anthracyclins, vinca alkaloids, etoposide, camptothecin, methotrexate
Which drugs may be affected by MRP4?
Methotrexate
Which ABC- transporter has the lowest specificity and is able to transport the most drugs?
MRP1
Which drugs can be transported by the MRP1-transporter?
Doxo, epi, vin, vinb, etoposide, methotrexate, paclitaxel (same so far as for MDR1), but can in addition transport camtothecin, SN-38, topotecan, flutamide, hydroxyflutamide
By which mechanisms does the ABC-transporters affect drug effect?
They influence absorption, tissue distribution and elimination, in addition to being over expressed on the plasma membrane of tumour cells increasing efflux of the chemotherapeutic drug
How can cells protect themselves from damage caused by reactive agents (ROS)?
By up regulating synthesis of sulfhydryl-containing molecules such as GSH. It binds tothe electrophilic metabolites and render them less reactive and nontoxic. The enzymes forming GSH (GST) play a role in the development of cellular resistance to some antineoplastic drugs
Upregulation of the enzyme GSH S-transferase (GST) has most commonly been associated with resistance against which two groups of antineoplastic drugs?
Alkylating agents and platinums
By which mechanism other than through drug detoxification can GST contribute to drug resistance?
It is an inhibitor of the MAP kinase pathway
By which methods may resistance occur due to altered level or modification of the drug target?
It is usually a result from genetic mutation altering the target of an important enzyme/target protein. Example is mutation in thymidylate synthase which is the target for the active metabolite of 5-FU (5 FdUMP) which result in reduced affinity for the drug. Another mechanism is gene amplification, where the cell produce more of the target protein. Example is DHFR which is the target for methotrexate where gene amplification result in increased DHFr production reducing the effect of the drug.
Name two topoisomerase 1 inhibitors
camptothecin and topotecan
How can cells become resistant to topoisomerase 1 inhibitors?
By downregulate and produce mutant forms of topoisomerase 1
How can cells become resistant agains topoisomerase 2?
They can change transcription resulting in reduced production of the enzyme, or alter the enzymes ability to bind to DNA. This is usually due to mutation in the gene TOP2A.
How can resistance develop against drugs targeting microtubules?
By changing the target - ie change the structure of the tubulin target or produce more of the microtubule associated molecules which bind to the outer side of the tubule wall and prevent chemotherapeutic access to the target.
By which method can cancer cells repair DNA adducts inter strand crosslinks?
By nucleotide excision repair
Non-homologeous or homology-directed repair pathways
How can tumour cells develop resistance to targeted therapy?
Through point mutations that lead to reduced interaction between drug and the target
Through amplification of oncogenes such as BCR-ABL in CML
Increase expression of P-glycoprotein and ABCG2/BCRP expression reducing intracellular levels of the drug
Activation of parallel signalling pathway
What is the mechanism of resistance against monoclonal antibodies?
Not well understood
How does contact with the cellular matrix impact responsiveness to chemotherapy?
It can provide protection of the tumour cells agains cell death mediated by anticancer drugs = cell adhesion mediated drug resistance
By which 3 mechanisms can drug transported have an impact on drug sensitivity and resistance?
They influence absorption, metabolism, distribution and elimination ( both APC and MRP transporters)
What is the target substrate for 5-FU?
Thymidylate synthase
explain some important factors of in vivo pathophysiology which impact in vivo drug resistance?
- Variable cell proliferation rates due to hypoxia and variable nutrient access
- Cells in extracellular matrix may be protected agains cell death mediated by cancer drugs
- Integrin cell to cell signalling impact cell proliferation and therefore sensitivity
- Vasculature is immature and leaky- reduced concentration, may not reach therapeutic levels
- Hypoxia- less ROS formation, select for p53 deficient cells - therefore less likely to undergo apoptosis, may increase expression of genes which increase resistance such as dihydrofolate reductase for metotherexate
- Recovery - intervals between treatment leaves room for repopulation and may go faster
