L10 Flashcards
Name the 7 hallmarks of cancer
- 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
metastasis
The spread of cancer cells from the place where they first formed to another part of the body.
Evolution of cancer treatments
Not too important
- 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
Name the first chemotherapy drugs
- Mustard gas -> nitrogen mustards -> Alkylating agents
- Folate analogues acted as anti-folate -> anti-metabolites
- periwinkle -> anto miotic chemotherapy
- penicillin
Mustard gas used in WWI
- 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
periwinkle drug development
- 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
Classic mechanisms of anticancer drug action
- 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
Cancer proliferation is help by what?
- Cancer proliferates uncontrollably
- Replication of cancer DNA for cell division helps proliferation
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 what?
mitosis
Principles governing the use of cancer chemotherapy
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
I. (Lack of) specificity of cancer drugs
And side effects
- 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
II. Kinetics of tumour growth & detection
- 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.
III. Chemotherapy drug efficacy &
proportional killing
- 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
IV - Chemotherapy drug efficacy &
tumour regrowth
- 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
V - Cell cycle & susceptibility to
chemotherapy drugs
- 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
Cell cycle specificity of drugs
Non-phase dependent drugs:
can target cells in G0:
* alkylating agents
* anthracyclines
Phase specific drugs:
target cells in specific phases of the cell cycle
S: anti metabolites
G2: antibiotics and irinotecan
M: vinka alkaloids and taxanes
G1: Corticosteroids
Phase specific drugs
* S-phase dependent:
anti-metabolites
Phase specific drugs
* G2-phase dependent:
- Antibiotics
- irinotecan
Phase specific drugs
* M-phase dependent:
- vinka alkaloids
- taxanes
Phase specific drugs
* G1-phase dependent:
- corticosteroids
Major classes of chemotherapy drugs
- Alkylating agents
- Anti-metabolites
- Mitotic inhibitors
- Cytotoxic antibiotics
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
Adducted and cross-linked DNA leads to:
– base excision repair of guanine adducts → strand breaks
– cross linked DNA cannot be replicated or transcribed
Classical Alkylating agents drugs
- Nitrogen Mustards: Cyclophosphamide
- Nitrosoureas
- Alkylsulphonates
Alkylating agents: Platinum-Based Drugs:
Produce DNA adducts and X-links like classical agents: Cisplatin
Alkylated DNA effects: Mono-functional agents
(temozolomide) → mono-adducts
Alkylated DNA effects: * Bi-functional agents
cyclophosphamide, cisplatin) → cross-link DNA
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)
Anti-metabolites
Deprive cells of building blocks required for growth and division
Anti-metabolites: Folic Acid Antagonists
- Analogues - block dihydrofolate reductase (DHFR) required for purines synthesis
- deplete cellular folates - needed for purine synthesis
- Methotrexate, Pemetrexed
Anti-metabolites: DNA Base Analogues
- pyrimidine, purine & nucleoside analogues
- disrupt DNA synthesis & function
- 5-Fluorouracil (5FU),
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
Mitotic inhibitors: Taxanes
Pacific yew bark extract
* Binds MTs to prevent their disassembly at mitosis
* docetaxel
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
Cytotoxic antibiotics:Bleomycins
- Produce Fe-mediated free oxygen radicals in nucleus
- Induce single and double strand DNA breaks
- Cause pulmonary fibrosis
- Bleomycin A2 & B2
Topoisomerase inhibitors:
- Irinotecan (Topoisomerase I)
- Etoposide (Topoisomerase II)
Major side effects of classical chemotherapy drugs
Systemic agents/effects → affect rapidly proliferating normal tissues:
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)
Drug-specific side effects
- Haemorrhagic cystitis -
Cyclophosphamide (activated in the liver to phosphoramide mustard and acrolein)
Pulmonary fibrosis -
Bleomycin (mechanism uncertain)
- Cardiomyopathy -
Doxorubicin & other anthracyclines
- Hepatic damage -
Methotrexate
- Skin pigmentation -
5-Fluorouracil
- Neurotoxicity -
Paclitaxel & other mitotic inhibitors - Cisplatin
- Nephrotoxicity & ototoxicity -
Cisplatin
