L10 Flashcards
(48 cards)
1
Q
Name the 7 hallmarks of cancer
A
- Self-sufficient in growth (+) signals
- Insensitive to growth-inhibitory (-) signals
- Can evade cell death – apoptosis
- Can proliferate indefinitely – immortalised
- Can promote blood vessel growth – angiogenesis
- Can spread away from primary tumour – invasion & metastasis
- Immune system evasion
2
Q
metastasis
A
The spread of cancer cells from the place where they first formed to another part of the body.
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
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
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
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
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
8
Q
Cancer proliferation is help by what?
A
- Cancer proliferates uncontrollably
- Replication of cancer DNA for cell division helps proliferation
9
Q
chemical damage to DNA →
A
cross linking of strands and damage to single strands
10
Q
impaired synthesis of DNA bases →
A
pyrimidines & purines
11
Q
inhibition of transcription →
A
DNA can’t uncoil
12
Q
anti-mitotics inhibit what?
A
mitosis
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
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
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.
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
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
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
19
Q
Cell cycle specificity of drugs
A
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
Phase specific drugs
* G1-phase dependent:
* corticosteroids
26
Major classes of chemotherapy drugs
1. Alkylating agents
2. Anti-metabolites
3. Mitotic inhibitors
4. Cytotoxic antibiotics
27
Alkylating agents
* 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
## Footnote
Adducted and cross-linked DNA leads to:
-- base excision repair of guanine adducts → strand breaks
-- cross linked DNA cannot be replicated or transcribed
28
Classical Alkylating agents drugs
* Nitrogen Mustards: Cyclophosphamide
* Nitrosoureas
* Alkylsulphonates
29
Alkylating agents: Platinum-Based Drugs:
Produce DNA adducts and X-links like classical agents: **Cisplatin**
30
Alkylated DNA effects: Mono-functional agents
(**temozolomide**) → mono-adducts
31
Alkylated DNA effects: * Bi-functional agents
cyclophosphamide, **cisplatin**) → cross-link DNA
32
Alkylated DNA effects
| Inter-strand X-links and lipid soluble agents
* Inter-strand X-links → much more difficult to repair
* Lipid soluble agents → cross blood-brain barrier - used in brain cancers (temozolomide)
33
Anti-metabolites
Deprive cells of building blocks required for growth and division
34
Anti-metabolites: Folic Acid Antagonists
* Analogues - block dihydrofolate reductase (DHFR) required for purines synthesis
* deplete cellular folates - needed for purine synthesis
* **Methotrexate**, Pemetrexed
35
Anti-metabolites: DNA Base Analogues
* pyrimidine, purine & nucleoside analogues
* disrupt DNA synthesis & function
* **5-Fluorouracil** (5FU),
36
Mitotic inhibitors: Vinca Alkaloids:
| Deprive cells of building blocks required for growth and division
Periwinkle
* Binds tubulin to prevent microtubule (MT) and mitotic spindle formation
* vinblastine
37
Mitotic inhibitors: Taxanes
Pacific yew bark extract
* Binds MTs to prevent their disassembly at mitosis
* **docetaxel**
38
Cytotoxic antibiotics: Anthracyclines
| Naturally derived drugs, e.g. Streptomyces
* Intercalate between base pairs
* Also inhibit topoisomerase II
* Both mechanisms prevent DNA replication
* Cardiotoxic
* **Doxorubicin**, Daunorubicin
39
Cytotoxic antibiotics:Bleomycins
* Produce Fe-mediated free oxygen radicals in nucleus
* Induce single and double strand DNA breaks
* Cause pulmonary fibrosis
* **Bleomycin** A2 & B2
40
Topoisomerase inhibitors:
* Irinotecan (Topoisomerase I)
* Etoposide (Topoisomerase II)
41
Major side effects of classical chemotherapy drugs
| Systemic agents/effects → affect rapidly proliferating normal tissues:
## Footnote
GI, Hairloss, Myelosuppression, secondary maglignancies
* **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
# Drug-specific side effects
* Haemorrhagic cystitis -
Cyclophosphamide (activated in the liver to phosphoramide mustard and acrolein)
43
Pulmonary fibrosis -
Bleomycin (mechanism uncertain)
44
* Cardiomyopathy -
Doxorubicin & other anthracyclines
45
* Hepatic damage -
Methotrexate
46
* Skin pigmentation -
5-Fluorouracil
47
* Neurotoxicity -
Paclitaxel & other mitotic inhibitors - Cisplatin
48
* Nephrotoxicity & ototoxicity -
Cisplatin
