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eMCD - Can > Cancer 9: Biological basis of cancer therapy > Flashcards

Cancer 9: Biological basis of cancer therapy Flashcards

1
Q

What are 4 Main anti-cancer treatment types ?

A
  1. Surgery
  2. Radiotherapy
  3. Chemotherapy
  4. Immunotherapy
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2
Q

Systemic therapy:

A
  • cytotoxic chemotherapy
  • -> alkylating agents
  • -> antimetabolites
  • -> anthracyclines
  • -> Vinca alkaloids and taxanes
  • -> Topoisomerase inhibitors
  • targeted therapies
    Small molecule inhibitors
    Monoclonal antibodies
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3
Q

How does cytotoxic chemotherapy work?

A
  • administrated IV / Oral
  • Cytotoxics target rapidly dividing cells by targeting their structures
  • Alkylating agents, Antimetabolites, Anthracyclines, Topoisomerase inhibitors target DNA
  • Taxanes + Vinca alkaloids target microtubules
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4
Q

What are alkylating agents?

How do they work?

A
  • Add alkyl groups to guanine residues in DNA
  • Cross-link DNA strands –> prevents uncoiling of DNA in replication
  • Trigger apoptosis (via checkpoint pathway)
    e. g Chlorambucil, cyclophosphamide, dacarbazine, temozolomide.
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5
Q

how do Pseudo-alkylating agent work?

A

o Same mechanism of cell death as alkylating agents

–> but Add platinum to guanine residues in DNA–> triggers apoptosis

o E.g: carboplatin, cisplatin, oxaliplatin

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6
Q

What are side effects of alkylating + pseudoalkylating agents?

A
  • hair loss (not carboplatin),
  • nephrotoxicity,
  • neurotoxicity,
  • ototoxicity (platinum),
  • nausea,
  • vomiting,
  • diarrhoea,
  • immunosuppression,
  • fatigue
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7
Q

What are Anti-metabolites?

How do they work?

A
  • they are purine/pyrimidine analogues
  • Masquerade as purine or pyrimidine residues–> inhibition of DNA synthesis, DNA ds-breaks, and apoptosis
  • Block DNA replication + transcription
  • Can be purine (A/G), pyrimidine (C/T/U) or folate antagonists
    e. g methotrexate, 6-mercaptopurine, dacarbazine, and fludarabine, 5-fluorouracil, capecitabine, gemcitabine
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8
Q

What are side effects of Anti-metabolites?

A

o Hair loss (alopecia) – not 5FU or capecitabine

o Bone marrow suppression à anaemia, neutropenia, and thrombocytopenia

o Increased risk of neutropenic sepsis (and death) or bleeding

o Nausea/vomiting (dehydration)

o Mucositis + diarrhoea

o Palmar-plantar erythrodysesthesia (PPE) – red hands/feet

o Fatigue

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9
Q

What are Anthracyclines?

How do they work?

A
  • Inhibit transcription + replication by intercalating (i.e. inserting between) nucleotides in DNA/RNA strand.

–> Also block DNA repair - mutagenic

–> They create free oxygen radicals –> damage DNA + cell membrane

e.g doxorubicin, epirubicin

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10
Q

what are side effects of Anthracyclines?

A

o Cardiac toxicity (arrythmias, HF) – due to free radical damage(?) –> due ECHO before starting treatment

o Alopecia/hair loss

o Neutropenia

o Nausea/Vomiting

o Fatigue

o Skin changes

o Red urine

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11
Q

What are vinca alkaloids + taxanes?

How do they work?

A
  • they re Originally derived from natural sources
  • -> Works by inhibiting assembly (vinca alkaloids) or disassembly (taxanes) of mitotic microtubules –> cause dividing cells to undergo mitotic arrest
  • -> microtubule targeting drugs
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12
Q

What are side effects vince alkaloids + taxanes?

A

o Nerve damage: peripheral neuropathy (tingling), autonomic neuropathy

o Hair loss

o Nausea + Vomiting

o Bone marrow suppression (neutropenia, anaemia etc)

o Arthralgia

o Allergy

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13
Q

What are topoisomerase inhibitors?

How do they work?

A

Normally = Topoisomerases prevent DNA torsional strain in replication + transcription

o They induce temporary single strand (topo1) or double strand (topo2) breaks in phosphodiester backbone

  • They protect free ends of DNA from aberrant recombination events
  • Drugs e.g. anthracyclines –> also have anti-topoisomerase effects
    e. g Topotecan and irinotecan (topo I) + etoposide (topo II) alter binding of topoisomerase complex to DNA –> allow permanent DNA breaks
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14
Q

What are side effects of topoisomerase inhibitors?

A

o (irinotecan): Acute cholinergic type syndrome – diarrhoea, abdominal cramps, and diaphoresis (sweating). Therefore, given with atropine

o Hair loss

o Nausea, vomiting

o Fatigue

o Bone marrow suppression

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15
Q

What are some resistance mechanisms ?

A
  1. Drug effluxed from cell by ATP-binding cassette (ABC) transporters
  2. DNA adducts replaced by Base Excision repair (using PARP)
  3. DNA repair mechanisms upregulated –> damage repaired –> prevents DNA ds-breaks
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16
Q

What are targeted therapies?

A

Cancer cells have wiring, but can cut wiring in monogenic cancers

  • But if cut one path –> parallel pathways or feedback cascades may be activated
  • Dual kinase inhibitors being developed – prevent feedback loops but increase toxicities
17
Q

What are the 10 hallmarks of cancer cells ?

A
  1. Self –sufficient: survives with minimal stimulation
  2. Insensitive to anti-growth signals: grows regardless of intake
  3. Anti-apoptotic
  4. Pro-invasive + metastatic
  5. Pro-angiogenic
  6. Non-senescent
  7. Dysregulated metabolism
  8. Evades immune system
  9. Unstable DNA
  10. Inflammation
18
Q

Over expression of receptor causes:

a) HER2
b) EGFR
c) PDGFR

Over expression of ligand causes:

d) VEGF

A

Over expression of receptor causes:
a) HER2 – breast cancer

b) EGFR – breast + colorectal cancer
c) PDGFR- glioma (brain cancer)

Over expression of ligand causes:
d) VEGF - prostate, kidney, breast cancer

–> over expression causes increase in kinase cascade and signal amplification

19
Q

Constitutive (ligand-independent) receptor activation:

  • EGFR (lung cancer)
  • FGFR (head + neck cancers, myeloma)
A

-

20
Q

Monoclonal antibodies:

how do humanized vs chimeric antibodies differ?

A 
Humanized monoclonal antibody, 
murine regions (black) interspersed within the light (light gray) and heavy (dark gray) chains of the Fab portion. 
Chimeric antibody 
murine component (black) of the variable region of the Fab section is maintained integrally.
21
Q

Monoclonal antibodies target extracellular component of receptor. They act by which 4 mechanisms?

A
  1. Neutralise ligand
  2. Prevent dimerization of receptors
  3. Internalisation of receptor
  4. Also, activate Fcγ-receptor-dependent phagocytosis or cytolysis induces complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC)
22
Q

What do Small molecule inhibitors (SMIs) do?

A
  • they Bind to kinase domain of tyrosine kinase in cytoplasm –> block autophosphorylation + downstream signalling
  • E.g. glivec (imatinib) for CML targeted BCR-ABL fusion protein – specifically targets ATP-binding region in kinase domain –> inhibits kinase activity of ABL1

–> also acts on intracellular kinases –> ca affect cell signalling pathways

23
Q

Small molecule inhibitors (SMIs) 2 different modes of action

A
  1. Receptor-inhibiting examples: erlotinib (EGFR), gefitinib (EGFR), lapatinib (EGFR/HER2), sorafinib (VEGFR)
  2. Intracellular kinase-inhibiting examples: Sorafinib (Raf kinase), Dasatinib (Src kinase), Torcinibs (mTOR inhibitors)
24
Q

What are 4 main resistance mechanisms to targeted therapies?

A
  1. Mutations in ATP-binding domain (BCR-Abl fusion gene/ALK gene, Glivec + crizotinib respectively)
  2. Intrinsic resistance (herceptin effective only in 85% HER2+ breast cancers, suggesting other driving pathways)
  3. Intragenic mutations
  4. Upregulation of downstream or parallel pathways
25
Q

What are antisense oligonucleotides?

A

antisense oligonucleotides = single-stranded, chemically modified DNA-like molecule 17-22 nucleotides in length

–> causes complementary nucleic acid hybridisation of targets gene, hindering translation of specific mRNA

–> Recruits RNase H to cleave target mRNA

26
Q

What is RNA interference

A

SS-complementary RNA

  • Compounds needs to be packaged to prevent degradation - nanotherapeutics
27
Q

What are downsides of targeted therapy?

A
  • treatments are very expensive

- Tumour heterogeneity –> difficult to target

28
Q

how can Immune modulation occur via programmed cell death 1 (PD-1)

A

o PD1 ligand found on surface of cancer cells

o PD1 required to maintain T cell activation

o When T cells bind PDL1 –> no longer recognise tumour cells as foreign

o If either blocked, immune system stimulated e.g. Nivolumab (anti-PD1) used in:

  • Treatment-refractory melanoma, non-small cell lung cancer, renal cell carcinoma (median survival of 16 months in phase I trial)
29
Q

Note: Future of Cancer Treatment

- sequence tumors prior to starting therapy 
(treatment + prognosis identified) 
- nano therapies 
- immunotherapies 
- targeting cancer metbolism
A

-

30
Q

6 most common cancer world wide are:

A 
lung 
breast 
liver 
stomach 
colon
cervix
31
Q

how do cisplatin work as cancer treatment

????

A

hydrolyses
binds to guanine
–> damages DNA check points –> nucleotide excision repair occurs
–>

32
Q

How do gemcitabine work as cancer treatment ? ?????

A

gemcitabine –> comes into cell
undergoes deamination
produce toxic inhibits DNA synthesis

33
Q

patients undergoing chemotherapy = at high risk of neutropenic sepsis
–> give dose of anti viral

A

-

34
Q

note :

Glivec = small molecule inhibitor and targets the ATP binding region within the kinase domain

A

-

eMCD - Can (15 decks)

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