Block C Lecture 2 - Classical Chemotherapy Flashcards

Question

What is the mechanism of action of doxorubicin?

Answer 1

It intercalates between nucleotides along the DNA molecule, disrupting DNA synthesis and transcription - same as 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 These all cause damage to DNA / disrupt DNA replication and activate the DNA repair system, with cells with DNA that can't be repaired being killed via apoptsos (Slides 17 and 18)

Answer 2

Reactive Oxygen Species (ROS) (Slide 18)

Answer 3

1. The quinone group accepts an electron (reducing it) to form the semiquinone radical. 2. The semiquinone radical donates electrons to oxygen, which forms superoxide (O2-) 3. The ROS produced then leads to hydroxyl radicals (OH·) through interactions with iron (Slide 18)

Answer 4

As the hydroxyl radicals damage DNA, lipids, and proteins, contributing to the anticancer effect, however these also contribute to cardiotoxicity (Slide 18)

Answer 5

Cardiac monitoring - via an ECG, and patients should also have their cardiac function assessed before use (Slide 18)

Answer 6

Myelosuppression - which can cause diarrhoea, nausea, vomiting and hair loss (Slide 18)

Answer 7

Non-Specific, however it has a greater effect during certain phases of the cell cycle, namely the S and G2/M phases (Slide 18)

Answer 8

Subunits called tubulin, which themselves are made up of 1 α and 1 β tubulin, which are attached to each other (Slide 20)

Answer 9

Cell shape, cell movement, movement of cargo within a cell and mitosis. (Slide 20)

Answer 10

Vincristine (Slide 21)

Answer 11

Spindle poisons (Slide 21 and 22)

Answer 12

It binds to β-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, and it may result in apoptosis if the arrest cannot be resolved. (Slide 21)

Answer 13

Peripheral neuropathy (when the nerves outside of the brain and spinal cord are damaged) and myelosuppression (Slide 21)

Answer 14

Acute leukaemias Hodgkin's lymphoma Non-Hodgkin's lymphomas Small cell lung cancer (Slide 21)

Answer 15

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 **depolymerization**, which locks microtubules in place, meaning they can't form spindle fibres properly, leading to 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, and it may result in apoptosis if the arrest cannot be resolved. (Slide 23)

Answer 16

Paclitaxel or Docetaxel (Slide 23)

Answer 17

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)

Answer 18

Answers Include: Peripheral neuropathy (dose-limiting toxicity) Hypersensitivity Reactions Myelosuppression (though less severe than docetaxel) Alopecia Nausea and vomiting Fatigue (Slide 24)

Answer 19

Answers Include: Neutropenia (dose-limiting toxicity) Fluid retention Myelosuppression (more severe neutropenia) Nausea and vomiting Fatigue (Slide 24)

Answer 20

Chemotherapeutic drugs which are structurally related to normal metabolites found in the body (Slide 25)

Answer 21

1. 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. 2. 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)

Answer 22

S-phase (Slide 25)

Answer 23

The de novo pathway is when nucleotides are synthesised from scratch whereas the salvage pathway involves the recycling of previously used bases and / or nucleosides to form nucleotides Note: A nucleoside is a base plus a deoxyribose sugar (Slide 26)

Answer 24

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)

Answer 25

6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) (Slide 27)

Answer 26

They are both converted into 6-TGMP and then 6-TGDP intermediates before being converted into 6-TGTP. These can incorporate themselves into DNA, leading to DNA damage, which activates the repair system with cells containing DNA which cannot be repaired undergoing apoptosis. They also inhibit de novo purine synthesis, reducing the availability of purines for DNA replication, slowing cell growth and division, slowing growth of a tumour (Slide 27)

Answer 27

A endogenous 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 activated, controlling their activity Patients with low TPMT may have to be given TPMT supplements to prevent 6-MP and 6-TG from doing too much damage (Slide 28)

Answer 28

Answers Include: Myelosuppression Nausea Vomiting Diarrhoea Hair loss Hematologic malignancies - such as leukaemia and lymphomas (long term use) Having low TPMT makes these side effects worse and more likely to occur (Slide 28)

Answer 29

Cancers that affect blood-forming tissues or immune system cells (Slide 28)

Answer 30

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)

Answer 31

Answers Include: Myelosuppression - killing bone marrow cells Nausea and vomiting - irritation of GI lining Hair loss (alopecia) - killing cells in hair follicles Mucositis (mouth sores) - killing epithelial cells in GI tract Peripheral neuropathy - direct damage to peripheral nerves Fatigue - anaemia, inflammation or body response to cellular damage and repair Diarrhea - damage to cells lining intestinal tracts Infections - due to low white blood cell count (Slide 29)

Answer 32

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)

Answer 33

When 2 or more drugs with different mechanisms of action are combined to treat cancer more effectively (Slide 31)

Answer 34

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)

Answer 35

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 Note: yeah PFS ends if the patient dies, don't know how I didn't fucking figure that one out (Slide 32)

Answer 36

Overall survival provides a direct measure of survival benefit whereas progression-free survival indicates how long a treatment can control the cancer. (Slide 32)

Answer 37

Answers Include: FOLFOX (Folinic acid, Fluorouracil and Oxaliplatin) - used for colorectal cancer FOLFIRI (Folinic acid, Fluorouracil and Irinotecan) - also used for colorectal cancer (if FOLFOX fails) FOLFIRINOX (Folinic acid, Fluorouracil, Irinotecan and Oxaliplatin) - used for pancreatic cancer CHOP (Cyclophosphamide, Hydroxydaunorubicin (Aka doxorubicin), Oncovin (AKA vincristine) and prednisone) - used for Non-Hodgkin lymphoma (Slides 32 and 33)