Biological Basis of Cancer Therapy Flashcards
5 most common cancers worldwide?
LUNG, BREAST, BOWEL, PROSTATE and STOMACH
MAIN ANTI-CANCER TREATMENT MODALITIES: (4)
- SURGERY
- RADIOTHERAPY
- CHEMOTHERAPY
- IMMUNOTHERAPY
What is cytotoxic therapy
Kills cancer cells by targeting their structures (mostly the DNA)
5 different types of cytotoxic therapy?
- Alkylating agents
- Antimetabolites
- Anthracyclines
- Vinca alkaloids and taxanes
- Topoisomerase inhibitors
2 types of targeted therapy?
There are 2 types:
- Small molecule inhibitors
- Monoclonal antibodies
2 types of systemic therapy?
cytotoxic and targeted therapy
how is cytotoxic chemotherapy administered (2+1)
- Given intravenously or by mouth (occasionally into CSF)
Selectivity of chemotherapy
not targeted, affects of all rapidly dividing cells of the body
What is post op chemotherapy known as
Adjuvant
What is post op chemotherapy known as
neoadjuvant
MoA of alkylating agents in cytotoxic therapy?
Add alkyl (CNH2N+1) groups to GUANINE residues in DNA
- Cross-link (intra, inter, DNA-protein) DNA strands and prevent DNA from uncoiling at replication
- Trigger apoptosis (via checkpoint pathway)
Examples of alkylating agents? (4)
chlorambucil, cyclophosphamide, dacarbazine, temozolomide
Peak side effect of alkylating agents?
- Can lead to secondary cancers because they encourage miss-pairing -> oncogenic
MoA pseudoalkylating agents?
- Add platinum to guanine residues in DNA
ross-link (intra, inter, DNA-protein) DNA strands and prevent DNA from uncoiling at replication - Trigger apoptosis (via checkpoint pathway)
Examples of pseudoalkylating agents (3)
carboplatin, cisplatin, oxaliplatin
chlorambucil is an example of…?
alkylating agent
cyclophosphamide is an example of…?
alkylating agent
dacarbazine is an example of…?
alkylating agent
temozolomide is an example of…?
alkylating agent
carboplatin is an example of…?
pseudoalkylating agent
cisplatin is an example of…?
pseudoalkylating agent
oxaliplatin is an example of…?
pseudoalkylating agent
Cisplatin MoA in detail starting with entry into cell via X channel:
1) Enters cells through copper channels CTR1/ATP7
2) Hydrolyses in a low chloride intracellular environment
3) Binds to guanine residues and cross-links DNA
4) DNA damage checkpoints detect damage
5) Cell tries to perform nucleotide excision repair
6) Mismatch repair pathway activated after many fruitless cycles of DNA repair attempts
Side effects of alkylating agents
- Cause hair loss (not carboplatin)
- Nephrotoxicity
- Neurotoxicity
- Ototoxicity (platinums)
- Nausea
- Vomiting
- Diarrhoea
- Immunosuppression -> Drop neutrophil count
- Tiredness
Which cytotoxic drug doesn’t cause hair loss
Carboplatin
Why is carboplatin special
Doesn’t cause hair loss
What are antimetabolites structurally and MOA
- Purine or pyrimidine analogues, or folate antagonists
- Lead to blocking of DNA synthesis, replication and transcription, DNA double strand breaks and apoptosis
- OR inhibit dihydrofolate reductase required to make folic acid, an important building block for all nucleic acids – especially thymine
Examples of antimetabolites
methotrexate (folate), 6-mercaptopurine, decarbazine and fludarabine (purine), 5-fluorouracil, capecitabine, gemcitabine (pyrimidine)
Side effects of antimetabolites? (7)
- Hair loss (alopecia) not 5FU or capecitabine
- Bone marrow suppression causing anaemia, neutropenia and thrombocytopenia
- Increased risk of neutropenic sepsis (and death) or bleeding
- Nausea and vomiting (dehydration)
- Mucositis and diarrhoea
- Palmar-plantar erythrodysesthesia (PPE)
- Fatigue
Gemcitabine mechanism:
1) Comes into cell via the hENT transporters
2) Deaminated to form dFdU which is toxic
3) Phosphorylated
4) Inhibits DNA replication
MoA of anthracyclines?
- Inhibit transcription and replication by intercalating (i.e. inserting between) nucleotides within the DNA/RNA strand
- Also block DNA repair mutagenic
- They create DNA/cell membrane damaging free oxygen radicals
Side effects of anthracyclins? (7)
- Cardiac toxicity (arrhythmias, heart failure) – probably due to damage induced by free radicals Anyone going on an anthracycline should first have an ECG/other cardiac examinations to check suitability
- Alopecia
- Neutropenia
- Nausea and Vomiting
- Fatigue
- Skin changes
- Red urine (doxorubicin “the red devil”)
MoA of vincalkaloids?
- Work by inhibiting assembly of mitotic microtubules causing dividing cells to undergo mitotic arrest Can’t replicate
MoA of taxanes?
- Work by inhibiting disassembly of mitotic microtubules causing dividing cells to undergo mitotic arrest Can’t replicate
Side effects of vinca alkaloids and taxanes?
- Nerve damage: peripheral neuropathy (tingling in hands and feet), autonomic neuropathy
- Hair loss
- Nausea
- Vomiting
- Bone marrow suppression (neutropenia, anaemia etc.)
- Arthralgia joint pain
- Allergy
What is the purpose of topoisomerase
required to prevent DNA torsional strain during DNA replication and transcription
They induce temporary single strand (topo1) or double strand (topo2) breaks in the phosphodiester backbone of DNA
They protect the free ends of DNA from aberrant recombination events
What drugs have an indirect anti-topoisomerase effect
Anthracyclins
What is topotecan an example of
anti-topoisomerase
What is irinotecan an example of
anti-topoisomerase
How do anti-topoisomerases work
- Specific topoisomerase inhibitors include Topotecan and irinotecan (topo1) and etoposide (topo2) alter binding of the complex to DNA and allow permanent DNA breaks
Side effects of topoisomerase (5)
- Irinotecan causes acute cholinergic type syndrome diarrhoea, abdominal cramps and diaphoresis (sweating) therefore given with (anti-cholinergic) atropine
- Hair loss
- Nausea, vomiting
- Fatigue
- Bone marrow suppression
MECHANISMS OF RESISTANCE TO CYTOTOXIC THERAPIES:
- DNA repair mechanisms upregulated and DNA damage is repaired This would cause resistance to DNA double strand breaks
- DNA adducts replaced by Base Excision repair (using PARP)
- Drug effluxed from the cell by ATP-binding cassette (ABC) transporters
Problem with dual kinase inhibitors?
Increased toxicity
10 hallmarks of a cancer cell?
- Self-sufficient
- Insensitive to anti-growth signals
- Anti-apoptotic
- Pro-invasive and metastatic
- Pro-angiogenic
- Non-senescent
- Dysregulated metabolism
- Evades the immune system
- Unstable DNA
- Inflammation
Examples of cancers with over expressed RPTK
- HER2 – amplified and over-expressed in 25% breast cancer
- EGFR – over-expressed in breast and colorectal cancer
- PDGFR- glioma (brain cancer)
Examples of cancers with over expressed ligands
- VEGF – prostate cancer, kidney cancer, breast cancer
Examples of cancers with constitutive ligand independent receptor activation
- EGFR (lung cancer)
- FGFR (head and neck cancers, myeloma)
Three ways cancers can cause an increase in the kinase cascade?
- Constitutive ligand independent receptor activation
- Over expressed ligands
- Over expressed RPTK
What’re - -momab antibodies
derived from mouse
What’re - -mumab antibodies
(fully human
What’re - -ximab antibodies
chimeric
What’re - -zumab antibodies
humanised
What suffix is a chimeric Ab
-ximab
What suffix is a (fully human Ab
-mumab
What suffix is a humanised Ab
-zuman
What suffix is a derived from mouse Ab
-momab
What do monoclonal antibodies do to the ligand and receptors in cancer therapy (3)
- Neutralise the ligand
- Prevent receptor dimerization
- Cause internalisation of receptor
What do small molecule inhibitors do in cancer therapy
- Bind to the kinase domain of the tyrosine kinase within the cytoplasm
- Block autophosphorylation and downstream signalling
IMATINIB is an e.g. of?
Small molecule inhibitor
Do targeted therapies have toxicity and why
by acting on receptors, targeted therapies don’t have cytotoxicity
Resistance to targeted therapies? (4)
- Mutations in ATP-binding domain (e.g BCR-Abl fusion gene and ALK gene, targeted by Glivec and crizotinib respectively)
- Intrinsic resistance (herceptin effective in 85% HER2+ breast cancers, suggesting other driving pathways)
- Intragenic mutations
- Upregulation of downstream or parallel pathways
What are anti-sense oligonucleotides
- Single stranded, chemically modified DNA-like molecule 17-22 nucleotides in length
- Complementary nucleic acid hybridisation to target gene hindering translation of specific mRNA
- Recruits RNase H to cleave target mRNA
- Good for “undruggable” targets
2 cancer treatments still in development?
Anti-sense oligonucleotides
RNA interference
Advantages of monoclonal Antibodies? (3)
High target specificity
Long half life so lower dosing frequency
Cause target receptor internalisation
Advantages of small molecule inhibitors? (4)
Oral admin
Cheap
Good tissue penetration
Can target TK without an extracellular domain
Disadvantages of monoclonal Antibodies? (3)
Expensive
Less useful against bulky tumours
Only works on targets with EC domains
Disadvantages of small molecule inhibitors? (3)
Short half life so have admin more frequently
Pleiotropic targets so more unexpected toxicity
The future for cancer therapies? (2)
- SEQUENCING TUMOURS PRIOR TO STARTING THERAPY:
2. NEW THERAPEUTIC AVENUES:
