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PHAR2220 > L10 > Flashcards

L10 Flashcards

1
Q

Name the 7 hallmarks of cancer

A
  1. Self-sufficient in growth (+) signals
  2. Insensitive to growth-inhibitory (-) signals
  3. Can evade cell death – apoptosis
  4. Can proliferate indefinitely – immortalised
  5. Can promote blood vessel growth – angiogenesis
  6. Can spread away from primary tumour – invasion & metastasis
  7. Immune system evasion
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2
Q

metastasis

A

The spread of cancer cells from the place where they first formed to another part of the body.

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3
Q

Evolution of cancer treatments

Not too important

A
  • Originally surgical - excision or debulking
  • Radiotherapy - ~100 years old
  • Chemotherapy - since the 1940s
  • Biological therapies - e.g. B/M transplants
  • Targeted therapies - since 1990s
  • Immunotherapies - since 2010
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4
Q

Name the first chemotherapy drugs

A
  • Mustard gas -> nitrogen mustards -> Alkylating agents
  • Folate analogues acted as anti-folate -> anti-metabolites
  • periwinkle -> anto miotic chemotherapy
  • penicillin
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5
Q

Mustard gas used in WWI

A
  • WWII bombing of Allied ships carrying mustard gas →
    survivors had depleted bone marrow & lymph nodes
  • Nitrogen mustards → more stable derivatives
    developed (Goodman and Gilman) to treat lymph
    cancers (lymphomas) → alkylating agents
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6
Q

periwinkle drug development

A
  • 1950s - natural plant extracts (periwinkle) with cell killing activity (cytotoxicity) noted
  • Found to target microtubules in the cell division spindle → drugs stop spindle forming or stop it breaking up → anti mitotic chemotherapy
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7
Q

Classic mechanisms of anticancer drug action

A
  • Interferes with DNA synthesis/function
  • Chemical damage to DNA → cross linking of strands and damage to single strands
  • Impaired synthesis of DNA bases → pyrimidines & purines
  • Inhibition of transcription → DNA can’t uncoil
  • Anti-mitotics inhibit mitosis

  • Cancer proliferates uncontrollably
  • Replication of cancer DNA for cell division helps proliferation
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8
Q

Cancer proliferation is help by what?

A
  • Cancer proliferates uncontrollably
  • Replication of cancer DNA for cell division helps proliferation
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9
Q

chemical damage to DNA →

A

cross linking of strands and damage to single strands

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10
Q

impaired synthesis of DNA bases →

A

pyrimidines & purines

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11
Q

inhibition of transcription →

A

DNA can’t uncoil

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12
Q

anti-mitotics inhibit what?

A

mitosis

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13
Q

Principles governing the use of cancer chemotherapy

A

I. Specificity of cancer drugs
II. Kinetics of tumour growth & detection
III. Drug efficacy & fixed proportional killing
IV. Drug efficacy & tumour regrowth - cure
versus remission
V. Cell cycle & susceptibility to specific drugs
VI. Drug resistance

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14
Q

I. (Lack of) specificity of cancer drugs

And side effects

A
  • Tumours = uncontrolled growth
  • Traditional drugs are anti-proliferative and cytotoxic to decrease tumour growth
  • But also attack normal proliferative tissues (GI epithelial cells, hair follicles and bone marrow)
  • SE: GI toxicity, alopecia, myelosuppression and anaemia
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15
Q

II. Kinetics of tumour growth & detection

A
  • A tumour cell is usually relatively advanced when diagnosed.
  • BC they have slow growth for 15ish years then reach around 1g where it is detectable but its already been a while.
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16
Q

III. Chemotherapy drug efficacy &
proportional killing

A
  • A given dose of chemotherapy kills a fixed proportion of tumour cells (<100%), not a fixed number of cells.
  • To eradicate a tumour, drug kill % must be > cell number i.e. 99.999% kill rate is only effective with <105 cells
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17
Q

IV - Chemotherapy drug efficacy &
tumour regrowth

A
  • Initial treatments induce remission
  • Some go through 2nd course
  • Tumour is undetectable and its remaining cells are
  • Killer by immune system → cure
  • Still actively growing → minimal residual disease → reappears
  • Dormant → may lie quietly for manyyears before re-activation e.g. breast cancer metastases in the bone marrow
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18
Q

V - Cell cycle & susceptibility to
chemotherapy drugs

A
  • Cancer drugs target dividing cells
  • Cells in G0 are resistant to most chemotherapeutic drugs (i.e. cancer stem cells)
  • tumours with a higher proportion of dividing cells are more susceptible to drugs
  • different drugs act at specific stages of the cell cycle
  • some drugs can act on cells at any stage, including
    G0
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19
Q

Cell cycle specificity of drugs

A
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20
Q

Non-phase dependent drugs:

A

can target cells in G0:
* alkylating agents
* anthracyclines

21
Q

Phase specific drugs:

A

target cells in specific phases of the cell cycle

S: anti metabolites
G2: antibiotics and irinotecan
M: vinka alkaloids and taxanes
G1: Corticosteroids

22
Q

Phase specific drugs
* S-phase dependent:

A

anti-metabolites

23
Q

Phase specific drugs
* G2-phase dependent:

A
  • Antibiotics
  • irinotecan
24
Q

Phase specific drugs
* M-phase dependent:

A
  • vinka alkaloids
  • taxanes
25
Q

Phase specific drugs
* G1-phase dependent:

A
  • corticosteroids
26
Q

Major classes of chemotherapy drugs

A
  1. Alkylating agents
  2. Anti-metabolites
  3. Mitotic inhibitors
  4. Cytotoxic antibiotics
27
Q

Alkylating agents

A
  • Mustard gas
  • Alkylate (methyl/ethyl) guanine bases to form DNA adducts (segment of DNA bound to a cancer-causing chemical) or cross linking of DNA strands
  • DNA damage/cell death is independent of cell cycle → alkylating agents kill cells in G0
  • Dose-dependent effects

Adducted and cross-linked DNA leads to:
– base excision repair of guanine adducts → strand breaks
– cross linked DNA cannot be replicated or transcribed

28
Q

Classical Alkylating agents drugs

A
  • Nitrogen Mustards: Cyclophosphamide
  • Nitrosoureas
  • Alkylsulphonates
29
Q

Alkylating agents: Platinum-Based Drugs:

A

Produce DNA adducts and X-links like classical agents: Cisplatin

30
Q

Alkylated DNA effects: Mono-functional agents

A

(temozolomide) → mono-adducts

31
Q

Alkylated DNA effects: * Bi-functional agents

A

cyclophosphamide, cisplatin) → cross-link DNA

32
Q

Alkylated DNA effects

Inter-strand X-links and lipid soluble agents

A
  • Inter-strand X-links → much more difficult to repair
  • Lipid soluble agents → cross blood-brain barrier - used in brain cancers (temozolomide)
33
Q

Anti-metabolites

A

Deprive cells of building blocks required for growth and division

34
Q

Anti-metabolites: Folic Acid Antagonists

A
  • Analogues - block dihydrofolate reductase (DHFR) required for purines synthesis
  • deplete cellular folates - needed for purine synthesis
  • Methotrexate, Pemetrexed
35
Q

Anti-metabolites: DNA Base Analogues

A
  • pyrimidine, purine & nucleoside analogues
  • disrupt DNA synthesis & function
  • 5-Fluorouracil (5FU),
36
Q

Mitotic inhibitors: Vinca Alkaloids:

Deprive cells of building blocks required for growth and division

A

Periwinkle
* Binds tubulin to prevent microtubule (MT) and mitotic spindle formation
* vinblastine

37
Q

Mitotic inhibitors: Taxanes

A

Pacific yew bark extract
* Binds MTs to prevent their disassembly at mitosis
* docetaxel

38
Q

Cytotoxic antibiotics: Anthracyclines

Naturally derived drugs, e.g. Streptomyces

A
  • Intercalate between base pairs
  • Also inhibit topoisomerase II
  • Both mechanisms prevent DNA replication
  • Cardiotoxic
  • Doxorubicin, Daunorubicin
39
Q

Cytotoxic antibiotics:Bleomycins

A
  • Produce Fe-mediated free oxygen radicals in nucleus
  • Induce single and double strand DNA breaks
  • Cause pulmonary fibrosis
  • Bleomycin A2 & B2
40
Q

Topoisomerase inhibitors:

A
  • Irinotecan (Topoisomerase I)
  • Etoposide (Topoisomerase II)
41
Q

Major side effects of classical chemotherapy drugs

Systemic agents/effects → affect rapidly proliferating normal tissues:

GI, Hairloss, Myelosuppression, secondary maglignancies

A
  • GI - mouth ulcers (mucositis - esp anti-metabolites), nausea & vomiting (esp alkylating agents), diarrhoea
  • Hair loss - severe with cyclophosphamide & platinum drugs
  • Myelosuppression - infections (↓WBCs), anaemia (↓RBCs) and bruising (↓platelets) (esp antimetabolites & mitotic inhibitors)
  • 2° Malignancies → myeloid neoplasms - Myelodysplastic syndrome & AML (esp alkylating agents)
42
Q

Drug-specific side effects

  • Haemorrhagic cystitis -
A

Cyclophosphamide (activated in the liver to phosphoramide mustard and acrolein)

43
Q

Pulmonary fibrosis -

A

Bleomycin (mechanism uncertain)

44
Q
  • Cardiomyopathy -
A

Doxorubicin & other anthracyclines

45
Q
  • Hepatic damage -
A

Methotrexate

46
Q
  • Skin pigmentation -
A

5-Fluorouracil

47
Q
  • Neurotoxicity -
A

Paclitaxel & other mitotic inhibitors - Cisplatin

48
Q
  • Nephrotoxicity & ototoxicity -
A

Cisplatin

PHAR2220 (20 decks)

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