Lecture 8: Chemotherapy and Drug Resistance Flashcards
What are the 4 conventional methods of treating cancer?
- SURGERY - removal of tumour, cure possible if remains local
- RADIOTHERAPY - variations: elimination of residual cancer cells following surgery (adjuvant therapy), pre-operatively (neo-adjuvant), as primary therapy, palliative
- CHEMOTHERAPY - cancers that have metastasized require systemic therapies
- Immunotherapy - 4th approach??
What is the “Therapeutic Window”?
Also known as “therapeutic index”.
The difference between the minimum effective does and maximum tolerated dose (MTD)
What are the 3 types of chemotherapy
- Alkylating agents and platinum-based drugs (eg cyclophosphamide;
cisplatin, carboplatin - all form bulky DNA adducts) - Antimetabolites (eg 5-Fluorouracil [5-FU] - inhibits thymidylate
synthase; Methotrexate - inhibits dihydrofolate reductase) - Organic drugs (eg Doxorubicin - inhibits topoisomerase 2;
Vincristine - prevents microtubule assembly, Paclitaxel (Taxol) -
block microtubule depolymerisation)
What does cisplatin do for cancer therapy and DNA damage
Many cancer therapies work by causing DNA damage (incl ionising radiation & alkylating agents), which affects ALL dividing cells
These results in apoptosis or mitotic catastrophe (if cells lack proper cell cycle check point controls) as cells are unable to repair such large DNA damage
How does cisplatin function?
- Administration: intravenously
- Upon entering the cell [Cl-] is low (~4mM), so Cl- ligands are removed, generating a positively charged species that reacts with nucleophilic sites on intracellular macromolecules to form protein, RNA, and DNA adducts
What are potential problems associated with conventional therapies?
- Deficient DNA repair systems in some cancers = problems with
some DNA damage inducing therapies
a. May not induce a response in some cancer cells and therefore
apoptosis
b. but would however lead to the death of healthy cells - This can lead to an increased ratio of cancerous cells
- Treatment itself is mutagenic, so, could kill the cancer but give rise to future tumours
How can individuals be resistant to cisplatin?
- Reduced intracellular accumulation (decreased uptake or increased efflux) or increased inactivation by intracellular proteins (eg glutathione)
- Increased repair of cisplatin adducts
- increased ability to replicate past cisplatin adducts
- defects in-apoptotic response pathway
What are the actions of 5-fluorouracil (5-FU) and methotrexate?
- 5-FU converted to F-dUMP, which competes with natural substrate dUMP of thymidylate synthase, which prod dTMP. Result: depletion of dTTP pool for DNA synthesis
- Methotrexate is an analogue of dihydrofolate, acting as a competitive inhibitor of dihydrofolate reductase (DHFR)
Why do some drugs fail?
- POOR PHARMOCOKINETICS - how well the drug is absorbed, how long it stays in the system (poor bioavailability)
- INSUFFICIENT THERAPEUTIC ACTIVITY
- TOXICITY
- RESISTANCE
What makes a good target for a new cancer drug?
Criteria A: uniquely or markedly over-expressed in the specific type of cancer (ie tumour specific)
Criteria B: essential for the survival of the cancer in question (ie rate limiting)
What is the “Gleevec” targeted tyrosine kinase therapy?
- Gleevec binds to BCR-ABL inactivating it, preventing the binding of ATP, which in-turn prevents the substrate of BCR-ABL becoming phosphorylated, which would lead to cell proliferation and survival & THEREFORE Leukemia
What is gleevec’s selectivity?
- Highly selective but also interacts with c-Kit and PDGFR
- Useful in Gastrointestinal Stromal Tumours (GIST)
What is the drug resistance phenomenon?
- A few cells: intrinsic resistance to chemotherapeutic agents
- All cells: acquired resistance when exposed to a drug (tumours become resistant to original drugs AND cross resistant to other drugs with other mechanisms of action)
Developing drug resistance during chemo is the leading cause of treatment failure
Elucidation of cellular resistance mechanisms holds promise for better cancer treatments
What are the models of tumour drug resistance?
- Conventional model: rare cell with MDR survive and proliferate after CT
- Cancer stem cell model: drug resistance mediated by stem cells
- Acquired resistance stem cell model
- intrinsic resistance model
What is “P-Glycoprotein (MDR1/ABCB1)”
Cells exposed to one drug can become resistant to not only that drug, but to structurally and functionally unrelated drugs
= MULTIDRUG RESISTANCE
Often due to ~1000x increase in P-glycoprotein gene amplification or increased transcription
170kDa transmembrane protein coded by MDR1 gene, chr 7
Normal function = Cl- ion efflux pump
Member of the ATP-binding cassette family (ABC) of transporters (48 total)
Drug binding activates ATP-binding domain; ATP hydrolysis results in conformational change and expulsion of drug restoration of shape by 2nd ATP hydrolysis
