Anti-cancer treatment

Question 1

What is the 1st line of cancer treatment?

Answer 1

1ST line cancer treatment: surgery (removal), then radiotherapy unless neoadjuvant setting (pre-operative treatment)

Question 2

What is the 2nd line of cancer treatment?

Answer 2

2nd line cancer treatment (adjuvant setting): Chemotherapy and hormonal therapy (if necessary breast etc.)

Question 3

Why is there 3 different types of therapy for cancer?

Answer 3

To reduce resistance to the therapy and to reduce exposure to the treatment.

Question 4

What is chemotherapy?

Answer 4

Chemotherapy
* Drugs that are toxic to cells (cytotoxic)
* Works on the whole system
* Active against highly proliferative cells (e.g. skin, intestinal epithelial, hair, blood)
* Used in metastatic growth (cancer at site different to original site)

Question 5

What is the objective of chemotherapy?

Answer 5

The objective of chemotherapy is to initiate apoptosis (caspase activation)

Question 6

What is an apoptosome?

Answer 6

An apoptosome:
Cytochrome C + APAF1
Activates caspase cascade

Question 7

Summary of the intrinsic apoptosis pathway

Answer 7

Intrinsic apoptosis pathway
* Damaged cell/cell stops receiving survival signals/ DNA damaged
* Antiapoptoiec proteins (BCL-2, BCL-X) are blocked
* P53 activates BAX
* Propapoptoiec proteins (BAX, BAK) create channels so mitochondrial substances such as cytochrome-c can leak into cytoplasm
* Cytochrome c bings to APAF1> Apoptosome formed
* Apoptosome activates caspase 9, initiating the caspase cascade and ending in apoptosis.

Question 8

Name the 5 types of chemotherapeutic agents

Answer 8

5 types of chemotherapeutic agents:
1. Antimetabolites (Disrupt DNA synthesis)
2. Alkylating agents (Damage DNA)
3. Platinum agents (Damage DNA)
4. Cytotoxic antibiotics (Damage DNA)
5. Plant derivatives (Disrupt mitosis)

Question 9

Thimidylate synthase needs a reduced ______ to convert dUMP to dTMP.

Answer 9

Thimidylate synthase needs a reduced folate to convert dUMP to dTMP.

Question 10

What happens if folate is restricted?

Answer 10

If folate is restricted, proliferation is reduced as reduced folate acts as a cofactor for dUMP when binding to thymidylate synthase. If reduced folate doesn’t bind allostearically and cause a conformotional change, dUMP can’t bind.

Question 11

What converts folate to FH2 (reduced folate)?

Answer 11

Dihydrofolate reductase converts folate to FH2 (reduced folate)

Question 12

What converts dUMP to dTTMP?

Answer 12

Thymidylate synthase converts dUMP to dTMP.

Question 13

dUMP is converted to dTMP which is converted to dTTP. What is dTTP for?

Answer 13

dTTP is a vital precursor for DNA replication and repair

Question 14

Thymidylate synthase converts dUMP to what?

Answer 14

Thymidylate synthase converts dUMP to dTMP.

Question 15

What does methotrexate inhibit?

Answer 15

Methotrexate inhibits dihydrofolate reductase (DHFR) which therefore inhibits thymidylate synthase.

Question 16

Apoptosis activates enzymes that ?

Answer 16

Apoptosis activates enzymes that activate nuclear matrix breakdown, cytoskeleton breakdown, endonuclease activation, RNA, DNA damage

Question 17

Chemotherapy apoptosis in one sentence

Answer 17

DNA damage activates P53, P53 activates BAX, BAX allows for cytochrome c release from mitochondria, apoptosome formed, caspase 9 activates caspase cascade, apoptosis activated.

Question 18

Anti-metabolites

Answer 18

Anti-metabolites
* Disrupt DNA synthesis
* Disrupt nucleic acid biosynthesis [target purines]
* Maybe incorporated into DNA [target pyrimidines] e.g 5FU, Tomudex
* Structurally similar to natural substances e.g vitamins, nucleosides.
* Inhibit important enzymes required in DNA/RNA synthesis.
Inhibit enzymes by:
Competing with a normal metabolite e.g., 5FU, Cytarabine
Competing with co-factors e.g., methotrexate
* Toxicity: bone marrow suppression, mucotosis, GI tox., nephrotoxicity.

Question 19

Alkylating agents

Answer 19

Alkylating agents
* Damages DNA: via inter strand cross links by binding to guanine
* Target proliferating cells
* Causes DNA fragmentation
* Most widely used treatment
* Covalently interact with DNA base residues e.g melphalan.
* Add CH2CH2
* Most are cycle specific: cell must be dividing
* Form highly reactive charged species which covalently binds to DNA (alkylation)
* Most are bifunctional (two alkylating groups): Has two arms to interact with both DNA strands
* Side effects: immunosuppression, nausea, vomiting, infertility

Question 20

What does 5FU target?

Answer 20

5FU targets and inhibits thymidylate synthase

Question 21

Anthrocyclins

Answer 21

Anthrocyclins:
Most useful antibiotic anti cancer drugs
- Daunorubicin (red/orange) was first to be isolated. It’s metabolite is responsible for action

Doxorubicin: most useful in clinic
- Mechanisms:
- Binds to DNA and inhibits synthesis of DNA and RNA
- Inhibits (in direction) of the action of topoisomerase II (DNA gyrase)
- Generates free radicals through CytP450 action: further damage to DNA

Question 22

Cisplatin

Answer 22

Cisplatin
- Causes DNA inter strand crosslinks
• most active single drug against ovarian
cancer
• Used in combination with Vinblastin and
Bleomycin (PVB) refractory cancers of
bladder and head & neck • Very nephron toxic, nausea

Question 23

Response to platinum based therapy and p53 status (ovarian cancer)

Answer 23

Response to platinum based therapy and p53 status (ovarian cancer)
- p53 can affect cancer outcome
- 178 biopsies: 99 mutant or over expressed mP53
- Faster disease progression
- Shorter overall survival compared to p53wt

-178 biopsies: 110 wild type p53
- Slower disease progression
- Longer overall survival compared to mutated p53

Question 24

Plant derivatives – anticancer drugs

Answer 24

Plant derivatives – anticancer drugs
- Four main types:
* Vinca alkaloids (vincristine and vinblastine), derived from periwinkle plant.
• Etoposide (VP-16) derived from mandrake root.
• Taxanes (paclitaxel, taxol) derived from yew of tree bark.
• Camptothecins (topotecan)
• Side effects: Toxicity: Nausea and vomiting and bone marrow suppression with alopecia.

Question 25

Overview of plant derivatives: Taxanes and Vinca Alkaloids

Answer 25

Overview of plant derivatives: Taxanes and Vinca Alkaloids Taxanes: Derived from Yee Tree Bark - Bind to substructure in microtubules (stabilises microtubules) - Prevents microtubles from pulling chromosomes apart - Results in incomplete mitosis Vina alkaloids Derived from Periwinkle plant - Binds to tubulin inhibiting polymerisation - Prevents microtubles from pulling chromosomes apart - Results in incomplete mitosis - Used in all cancers Side effects: Toxicity: nausea and vomiting and bone marrow suppression with alopecia

Question 26

Taxanes mechanism of action

Answer 26

Taxanes mechanism of action: - Inhibits tubule DISASSEMBLY - Binds subunit of the β tubulin heterodimer within microtubule interior - hyperstabilisation of microtubules & no shortening or progression from metaphase to anaphase - stabilises microtubules - prevents mitosis

Question 27

Name a cancer treatment that can affect cells at any stage

Answer 27

Bleomycin in is a cancer treatment that can affect cells at any stage

Question 28

Phase specific drugs

Answer 28

Phase specific drugs: Drug acts at specific phase of cell cycle – e.g antimetabolites in S phase, vinca alkaloids in M phase

Question 29

Antimetabolites work in which phase?

Answer 29

Antimetabolites work in S phase

Question 30

Vinca alkaloids work in which phase?

Answer 30

Vinca alkaloids work in M phase

Question 31

Cycle specific drugs

Answer 31

 Cycle Specific: – Drug acts in any phase of cycle, cell MUST be cycling – e.g alkylating agents, doxorubin, dactinomycin, cisplatin

Question 32

Non-phase specific drugs

Answer 32

Non-Phase Specific: – Drug acts on non-cycling and cycling cells – e.g bleomycins nitrosureas

Question 33

Non-phase specific drugs:

Answer 33

Non-phase specific drugs: Bleomycins Nitrosureas

Question 34

Are alkylating agents cycle specific?

Answer 34

Yes alkylating agents are specific the cell must be cycling for them to work

Question 35

Name 3 cycle specific drugs

Answer 35

3 cycle specific drugs: - Alkylating agents - Doxorubin - Dactinomycin - Cisplatin

Question 36

Tamoxifen

Answer 36

Tamoxifen: - Anti-oestrogen hormone - Dose: 20mg day: oral - Use: Breast cancer, only works in receptor positive - Not a steroid - Competitive oestrogen inhibitor - Oestrogenic action on endometrium and bone - Anti-oestrogenic action on breast tissue - Prevents cancer proliferation - Binds to oestrogen receptor in nucleus: little or no stimulation of transcription occurs - Increases TGF-B- inhibits proliferation Side effects: (Nolvadex) - Hot flashes - Nausea - Fluid retention - 3 to 4 fold increased risk of endometrial cancer (promotes oestrogenic action in endometrium) New analog: Raloxifene

Question 37

Arimidex

Answer 37

Arimidex - Prevents oestrogen synthesis - Arimidex is an aromatase inhibitor, hence reduces eostrogen • For postmenopausal, early invasive tumour patients. Also used for ovarian cancer. • Switching from standard therapy to Arimidex reduced death by 29%, re-occurance fell by 26%

Question 38

Challenges of cancer chemotherapy: drug resistance

Answer 38

Challenges of cancer chemotherapy: drug resistance 1. Decreased drug uptake 2. Increased drug efflux (multi drug resistance) 3. Insufficient drug activation e.g. 5FU 4. Increased repair enzymes e.g. alkylating agents 5. Enzyme amplification (increase that inhibits drug)

Question 39

Pharmaceutical challenges in cancer: Drug toxicity

Answer 39

Pharmaceutical challenges in cancer: Drug toxicity • Inflammation of oral mucosa • Alopecia • Bone marrow suppression (neutropenia, thrombocytopenia, anaemias • GI tox (nausea, vomiting diarrhoea) • Neurotoxicity (confusion/headaches

Question 40

Pharmaceutical challenges in cancer: drug resistance inherent or acquired

Answer 40

Pharmaceutical challenges in cancer: drug resistance inherent or acquired Decreased accumulation of drug (MDR  p-glycoprotein) • Insufficient drug activation e.g., 5-FU • Decrease drug uptake e.g., MTX • Increase in inactivation e.g., cytarabine by cytidine deaminase • Enhanced DNA repair • Alteration of drug targets & pathways • Change in tumour suppressors

Question 41

CAR- T Cell therapy

Answer 41

CAR- T Cell therapy: - aim to restore: restoring T- cell–mediated antitumor immunity. - • T-cell–mediated immunity includes multiple sequential steps: clonal selection of antigen-specific cells, activation, proliferation, trafficking, and execution of direct effector function. CAR T-cell therapy: T cells are removed from cancer patients, genetically modified so they express receptors specific to the patient’s particular cancer. They are re- infused into patients, now able to recognise and kill the cancer cells. - Expensive

Question 42

What is tyrosine kinase?

Answer 42

Tyrosine kinase: - enzyme that phosphorylates tyrosine - important in signal transduction and proliferation

Question 43

Tyrosine kinase inhibitor: HERCEPTIN

Answer 43

Tyrosine kinase inhibitor: HERCEPTIN Drug inhibits Human Epidermal growth factor Receptors HER2 and HER3. • HER2:HER3 dimerization (Fig A) is believed to produce the strongest mitogenic signalling • Herceptin (an antibody) binds to HER2 subdomain IV (Fig B) and disrupts ligand‑independent HER2 signalling. • This prevents interaction of EGF ligand with HER2 and therefore stops downstream MAPK and PI3K signalling. • Herceptin also triggers antibody‑dependent cell-mediated cytotoxicity (ADCC)