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PPI > Anti-cancer treatment > Flashcards

Anti-cancer treatment Flashcards

1
Q

What is the 1st line of cancer treatment?

A

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

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2
Q

What is the 2nd line of cancer treatment?

A

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

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3
Q

Why is there 3 different types of therapy for cancer?

A

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

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4
Q

What is chemotherapy?

A

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)

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5
Q

What is the objective of chemotherapy?

A

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

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6
Q

What is an apoptosome?

A

An apoptosome:
Cytochrome C + APAF1
Activates caspase cascade

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7
Q

Summary of the intrinsic apoptosis pathway

A

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.

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8
Q

Name the 5 types of chemotherapeutic agents

A

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)

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9
Q

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

A

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

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10
Q

What happens if folate is restricted?

A

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.

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11
Q

What converts folate to FH2 (reduced folate)?

A

Dihydrofolate reductase converts folate to FH2 (reduced folate)

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12
Q

What converts dUMP to dTTMP?

A

Thymidylate synthase converts dUMP to dTMP.

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13
Q

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

A

dTTP is a vital precursor for DNA replication and repair

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14
Q

Thymidylate synthase converts dUMP to what?

A

Thymidylate synthase converts dUMP to dTMP.

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15
Q

What does methotrexate inhibit?

A

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

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16
Q

Apoptosis activates enzymes that ?

A

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

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17
Q

Chemotherapy apoptosis in one sentence

A

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

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18
Q

Anti-metabolites

A

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.

19
Q

Alkylating agents

A

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

20
Q

What does 5FU target?

A

5FU targets and inhibits thymidylate synthase

21
Q

Anthrocyclins

A

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

22
Q

Cisplatin

A

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

23
Q

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

A

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

24
Q

Plant derivatives – anticancer drugs

A

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.

25
Q

Overview of plant derivatives: Taxanes and Vinca Alkaloids

A

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

26
Q

Taxanes mechanism of action

A

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

27
Q

Name a cancer treatment that can affect cells at any stage

A

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

28
Q

Phase specific drugs

A

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

29
Q

Antimetabolites work in which phase?

A

Antimetabolites work in S phase

30
Q

Vinca alkaloids work in which phase?

A

Vinca alkaloids work in M phase

31
Q

Cycle specific drugs

A

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

32
Q

Non-phase specific drugs

A

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

33
Q

Non-phase specific drugs:

A

Non-phase specific drugs:
Bleomycins
Nitrosureas

34
Q

Are alkylating agents cycle specific?

A

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

35
Q

Name 3 cycle specific drugs

A

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

36
Q

Tamoxifen

A

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

37
Q

Arimidex

A

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%

38
Q

Challenges of cancer chemotherapy: drug resistance

A

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)

39
Q

Pharmaceutical challenges in cancer: Drug toxicity

A

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

40
Q

Pharmaceutical challenges in cancer: drug resistance inherent or acquired

A

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

41
Q

CAR- T Cell therapy

A

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

42
Q

What is tyrosine kinase?

A

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

43
Q

Tyrosine kinase inhibitor: HERCEPTIN

A

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)

PPI (23 decks)

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