Block C Lecture 2 - Classical Chemotherapy Flashcards
What are 3 examples of cancer therapies?
Surgery
Radiation Therapy
Chemotherapy
(Slide 3)
What does the choice of cancer therapy depend on?
The location, grade, stage and molecular profile of the disease, as well as the general health of the patient
(Slide 3)
What are the 3 aims of cancer therapy? - outline these
To cure - ensure there is no evidence of the disease
To control - prolong length and quality of life, and to prevent distant and possible unknown metastases
Palliation - Symptom management (to improve comfort and quality of life). Appropriate when curing and controlling aren’t feasible
(Slide 4)
What are 5 examples of classes of chemotherapy agents?
Answers Include:
Classical chemotherapy
Hormonal therapy
Immunotherapy
Therapeutic antibodies
Antibody-drug conjugates
Kinase inhibitors
Note: All of these except classical chemotherapy are targeted cancer therapy drugs, which means they exclusively target cancer cells rather than all cells like classical chemotherapy does
(Slide 5)
What does classical chemotherapy target?
Rapidly dividing cells
(Slide 6)
What are 4 examples of drugs which can be used as classical chemotherapy agents?
Answers Include:
Alkylating agents
Platinum-based compounds
Anthracyclines (antitumour antibiotics)
Antitumour antibiotics (non-anthracyclines)
Anti-Microtubule agents
Antimetabolites
Topoisomerase inhibitors
(Slide 6)
What 2 categories can classical chemotherapy agents be divided into (briefly outline)?
Cell Cycle-Specific - target cells in specific phases of the cell cycle (such as antimetabolites targeting cells in the S phase)
Cell Cycle-Nonspecific - can act on cells in any phase of the cell cycle
(Slide 6)
What is alkylation?
The transfer of an alkyl (CnH2n+1) group from one molecule to another
(Slide 7)
What do alkylating agents do?
Attach an alkyl (CnH2n+1) group to the guanine base of DNA, at the number 7 nitrogen atom of the purine ring
(Slide 7)
What are 3 examples of types of alkylating agents?
Nitrogen mustards
Nitrosoureas
Triazines
Others (Such as thiotepa or altretamine)
(Slide 8)
State an example of a nitrogen mustard, nitrosoureas and triazine used as alkylating agents.
Nitrogen mustards: Cyclophosphamide, Ifosfamide, Melphalan or Chlorambucil
Nitrosoureas: Carmustine, Lomustine or Streptozocin
Triazines: Dacarbazine or Temozolomide
(Slide 8)
What is the mechanism of action of alkylating DNA stopping tumour growth?
They cross-link guanine nucleobases in the DNA double helix, which results in the DNA double helix distorting, interfering with its ability to unwind for replication or transcription.
This initiates the DNA damage repair pathway, with DNA which cannot be repaired leading to apoptosis
(Slide 10)
Why are cancer cells often more sensitive to alkylating agents than normal cells?
As they are often defective in their DNA repair proteins
(Slide 10)
Are the effects of alkylating agents and platinum based compounds cell cycle specific or non-specific?
Cell cycle non-specific
(Slide 10)
Give an example of a platinum based compound used in classical chemotherapy, and state which cancers it can be used on.
Answers Include:
Cisplatin - used for testicular, ovarian, bladder and lung cancers
Carboplatin - Used for ovarian, lung, head and neck cancers
Oxaliplatin - Used for colorectal cancer
(Slide 11)
What is a significant limit of cisplatin’s effect?
Many tumours have inherent insensitivity or can develop resistance to it
(Slide 11)
What is the mechanism of action of platinum based compounds?
They act in a similar war to alkylating agents, causing DNA damage, but by intercalating (inserting itself) between DNA bases.
This prevents DNA synthesis and transcription and again activates the DNA damage repair pathway, leading to cell with unrepairable DNA undergoing apoptosis.
(Slide 12)
What are the side effects of cisplatin treatment?
It has a small therapeutic window which makes it hard to dose right.
Neurotoxic - can lead to abnormalities in visual perception, and hearing disorders
Nephrotoxic - can damage the kidneys - this is dose limiting
Myelotoxicity - can cause serious bone marrow suppression
Can also cause nausea and vomiting
(Slide 13)
What drugs are given to treat nausea and vomiting?
Anti-emetics
(Slide 13)
What is an example of an anthracycline based drug?
Answers Include:
Doxorubicin
Daunorubicin
Epirubicin
Idarubicin
(Slide 16)
What is the structure of anthracycline based drugs?
A 4 ring structure which is glysosidically bound to daunosamine - a type of amino sugar
(Slide 16)
How do the uses for doxorubicin differ from those of daunorubicin / idarubicin?
Doxorubicin is used for solid tumours whereas daunorubicin and idarubicin are used for acute nonlymphocytic leukaemia
(Slide 16)
What is the mechanism of action of doxorubicin?
It intercalates between nucleotides along the DNA molecule, disrupting DNA synthesis and transcription - same as alkylating agents and platinum based compounds
It also binds to topoisomerase II, the enzyme which is responsible for cutting both strands of the DNA helix and uncoiling / re-ligating (re-joining) of the DNA strands. disrupting its activity.
Doxorubicin binds to the enzyme-DNA cleavage complex which prevents re-ligation
They also create ROS
(Slides 17 and 18)
What does the redox recycling of the quinone group in anthracyclines lead to?
Reactive Oxygen Species (ROS)
(Slide 18)
How does the redox recycling of the quinone ground in anthracyclines lead to ROS being produced?
- The quinone group accepts electron (reducing it) to form the semiquinone radical.
- The semiquinone radical donates electrons to oxygen, which forms superoxide (O2-)
- The ROS produced then leads to hydroxyl radicals (OH·) through interactions with iron
(Slide 18)
Why does anthracyclines creating ROS and hydroxyl radicals contribute to an anti-cancer effect, and what other effect does the creating of ROS contribute to?
Critical mechanism as the hydroxyl radicals damage DNA, lipids, and proteins, contributing to the anticancer effect, however these also contribute to cardiotoxicity
(Slide 18)
What kind of monitoring do patients which take anthracycline based drugs need to undergo?
Cardiac monitoring - via an ECG, and patients should also have their cardiac function assessed before use
(Slide 18)
On top of causing cardiotoxicity, what is one other adverse side effects which anthracycline based drugs can cause (and what can this lead to)?
Myelosuppression - which can cause diarrhoea, nausea, vomiting and hair loss
(Slide 18)
Is doxorubicin cell cycle specific or non-specific?
Non-Specific, however it has a greater effect during certain phases of the cell cycle, namely the S and G2/M phases
(Slide 18)
What are microtubules made out of?
Subunits called tubulin, which themselves are made up of 1 α and 1 β tubulin, which are attached to each other
(Slide 20)
What are microtubules essential for?
Cell shape, cell movement, movement of cargo within a cell and mitosis.
(Slide 20)
What is the mechanism of action of vincristine?
It binds to tubulin, preventing microtubule polymerisation.
The inability of microtubules to assemble properly then leads to the spindle fibres being unable to form, leading to the cell undergoing cell cycle arrest, usually in the M phase.
This then causes a anti-cancer effect as cells in cell cycle arrest lose the ability to replicate, thus preventing the tumour from growing as cells contained in it cannot undergo cell replication
(Slide 21)
What kind of drugs are vincristine, and taxanes?
Spindle poisons
(Slide 21 and 22)
What are 2 adverse side effects of vincristine?
Peripheral neuropathy (when the nerves outside of the brain and spinal cord are damaged) and myelosuppression
(Slide 21)
What are the mechanisms of taxanes?
They bind to the taxane-binding site on β-tubulin within the assembled microtubule. This occurs on the inner surface of the microtubule wall
Taxanes binding to tubulin prevents microtubule polymerization, which means spindle fibres can’t form properly, which ends up putting the cell into cell cycle arrest.
This then causes a anti-cancer effect as cells in cell cycle arrest lose the ability to replicate, thus preventing the tumour from growing as cells contained in it cannot undergo cell replication.
(Slide 23)
What are 2 examples of taxanes?
Paclitaxel and Docetaxel
(Slide 23)
What are the differences between paclitaxel and docetaxel?
They have different C13 side chains and C10 substitutions
Paclitaxel has a lower water solubility whereas docetaxel has a higher water solubility
Paclitaxel has a lower microtubule binding affinity whereas docetaxel has a higher affinity
Paclitaxel is used for ovarian and breast cancers whereas docetaxel has a much broader use
(Slide 24)
What are 3 different toxicities which paclitaxel can cause?
Answers Include:
Peripheral neuropathy (dose-limiting toxicity)
Hypersensitivity Reactions
Myelosuppression (though less severe than docetaxel)
Alopecia
Nausea and vomiting
Fatigue
(Slide 24)
What are 3 possible toxicities that docetaxel can cause?
Answers Include:
Neutropenia (dose-limiting toxicity)
Fluid retention
Myelosuppression (more severe neutropenia)
Nausea and vomiting
Fatigue
(Slide 24)
What are antimetabolites?
Chemotherapeutic drugs which are structurally related to normal metabolites found in the body
(Slide 25)
What are the 2 mechanisms of action of antimetabolites?
- They act as competitive substrates in place of an actual metabolite that incorporates itself into DNA/RNA. This incorporating occurs during replication or transcription and results in errors or breaks in the genetic material which leads to cell cycle arrest, preventing tumours from growing as their cells can’t replicate.
- They also inhibit the enzyme which is involved in the synthesis or uptake of a metabolite. This contributes to the synthesis of nucleotides and without this there is a depletion of nucleotides. This again leads to cell cycle arrest and apoptosis.
(Slide 25)
During what cell cycle phase does the maximal cytotoxic effects of antimetabolites occur?
S-phase
(Slide 25)
What is the difference between the de novo and salvage pathways of nucleotide synthesis?
The de novo pathway is when nucleotides are synthesised from scratch whereas the salvage pathway involves the recycling of previously used bases and nucleosides to form nucleotides
(Slide 26)
How does the balance of the de novo and salvage pathways of nucleotide synthesis differ between normal cells and cancer cells?
In normal cells, the de novo pathway is less activate and the salvage pathway is dominant, whereas in cancer cells the salvage pathway is less active and the de novo pathway is dominant
(Slide 26)
What are 2 examples of purine analogues which are also antimetabolites?
6-mercaptopurine (6-MP) and 6-thioguanine (6-TG)
(Slide 27)
What is the mechanism of action of 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG)?
They are converted into their active forms; 6-thioinosine monophosphate (6-TIMP) and 6-thioguanosine-triphosphate (6-TGTP) by the enzyme hypoxanthine-guanine. It then inhibits purine biosynthesis which results in the disruption of the formation of DNA and RNA as it reduces the availability of purine nucleotides. Since the body doesn’t have enough purines, it instead incorporates 6-TIMP into newly synthesised DNA and RNA.
This causes DNA structural distortions and replication errors, which can activate the DNA damage response which exists within the cell.
If the damage cannot be repaired, this leads to cell apoptosis, killing the tumorous cells
(Slide 27)
What is thiopurine S-methyltransferase (TPMT)?
A cytoplasmic enzyme which methylates aromatic compounds such as the thiopurine drugs 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG).
This results in them being inactivated
(Slide 28)
What are some possible side effects of thiopurine S-methyltransferase (TPMT)?
Myelosuppression
Nausea
Vomiting
Diarrhoea
Hair loss
(Slide 28)
What is TPMT used to treat?
Hematologic malignancies - such as leukaemia and lymphomas
(Slide 28)
What are haematologic malignancies?
Cancers that affect blood-forming tissues or immune system cells
(Slide 28)
What are the 2 main challenges of classical chemotherapy, and what can these result in?
Chemotherapy cannot distinguish between cancer cells and normal, rapidly dividing cells, which can result in a range of side effects due to different cell types being killed.
Cancers are heterogenous - which is a challenge as it can lead to variable drug responses and resistance development.
(Slides 29 and 30)
What are 4 examples of side effects which chemotherapy killing non-cancerous cells can lead to?
Answers Include:
Myelosuppression
Nausea and vomiting
Hair loss (alopecia)
Mucositis (mouth sores)
Peripheral neuropathy
Fatigue
Diarrhea
Infections (due to low white blood cell count)
(Slide 29)
What are 3 examples of drug resistance mechanisms related to classical chemotherapy?
Drug efflux - overexpression of efflux pumps reduces intracellular drug levels
Drug inactivation - enzymatic detoxification neutralises the drug
Altered drug targets - mutations or changes in the expression of drug targets reduce binding affinity
Increased DNA repair - enhanced repair of chemotherapy induced DNA damage
Apoptosis evasion - upregulation of anti-apoptotic proteins and downregulation of pro-apoptotic proteins, or p53 mutations
Altered cell cycle checkpoints - mutations in checkpoint proteins like p53 allow cells to bypass damaged induced arrest
(Slide 30)
What is combination therapy in cancer?
When 2 or more drugs with different mechanisms of action are combined to treat cancer more effectively
(Slide 31)
What are 4 advantages of combination therapy?
It helps overcome drug resistance as combining drugs with different mechanisms reduces the likelihood of cancer cells developing resistance mechanisms
Different drugs target different subpopulations, increasing the likelihood of eradicating the entire tumour
Combining agents with synergistic effects increases their effectiveness compared to a single-agent, potentially enhancing each other’s activity
Lower doses of each drug can be used in combination. reducing the risk of severe side effects associated with high doses of the drugs. Each drug can be used at its optimal dose without intolerable side effects (as long as the side effect profiles don’t overlap)
(Slide 31)
What are 2 ways which the efficacy of anticancer drugs can be measured in clinical trials?
Overall survival (OS) - the time from the start of treatment to death from any cause
Progression-Free Survival (PFS) - the time during and after treatment that the patient lives without tumour progression
(Slide 32)
