Biological Basis of Cancer Therapy Flashcards
6 most common cancers worldwide?
Lung Breast Bowel Prostate Stomach
What is included in ‘western cancers’?
Breast
Colorectal
Lung
Prostate
Main anti-cancer treatment modalities?
- Immunotherapy
- Chemotherapy
- Radiotherapy
- Surgery
What is cancer?
Disease of the genome
Types of genetic mutations causing cancer?
• Chromosome translocation
• Gene amplification
- copy no. variations
• Point mutations
- in promoter/enhancer regions of genes
- Deletions/insertions
- Epigenetic alterations
- Heritable mutations
Broadly the 2 types of Systemic Therpay?
- Cytotoxic chemotherapy
* Targeted therpaies
What is included in Cytotoxic chemotherapy
(1) Alkylating agents
(2) Antimetabolites
(3) Anthracyclines
(4) Vinca alkaloids & taxanes
(5) Topoisomerase inhibitors
What is included in Targeted therapies?
(2) Small molecule inhibitors
(1) Monoclonal antibodies
Generally, how do cytotoxic agents work?
Select rapidly DIVIDING CELLS by targeting their structures
• i.e. their DNA
• target ALL rapidly dividing cells
Generally, how can cytotoxic agents be given?
Given via.
• IV
or
• Orally
Functions SYSTEMICALLY
How are cytotoxic agents administered?
Post-operatively
• adjuvant
Pre-operatively
• neoadjuvant
Monotherapy/combinantion
With curative or pallative intent
Explain the MOA of the (1) of cytotoxic chemotherapy
Alkylating agents
- add alkyl (CnH2n+1) groups to G residues
- cross-link DNA strands (intra, inter, DNA-protein) = prevents it from uncoiling @ replication
- triggers APOPTOSIS (via. checkpoint pathway)
- encourages miss-pairing (oncogenic)
Pseudoalkylating agents
• add PLATINUM to G residues
• SAME other effects as above
Example agents of (1) of cytotoxic chemotherapy
Alkylating agents • Chlorambucil • Cyclophosphamide • Dacarbazine • Temozolomide
Pseudoalkylating agents
• Carboplatin
• Cisplatin
• Oxaliplatin
Side effects associated with (1) of cytotoxic chemotherapy
Hair loss
• NOT carboplatin
Nephrotoxicity Neurotoxicity Ototoxicity (ear) Nausea Vomiting Diarrhoea Immunosuppresion Tiredness
Explain the MOA of (2) of the cytotoxic chemotherapy?
ANTI-METABOLITES
Analogues of • PURINE or • PYRIMIDINE residues
BLOCK DNA replication & transcription
• inhibit DNA synthesis, double strand breaks = APOPTOSIS
Examples of potential metabolites (2) can be for cytotoxic chemotherapy
Can be:
- Purine (A, G)
- Pyrimidine (C, T/U)
• Folate antagonists
- inhibit DIHYDROFOLATE REDUCTASE needed to make folic acid = needed to make nucleic acids
Drug examples of (2) for cytotoxic chemotherapy
Folate
• Methotrexate
Purine
• 6-mercaptopurine
• Decarbazine
• Fludarabine
Pyrimidine
• 5-flurouracil
• Capecitabine
• Gemcitabine
SEs associated with (2) of cytotoxic chemotherapy?
Alopecia (hair loss)
• NOT 5FU or Capectiabine
Bone marrow suppression
• causes anaemia, neutropenia & thrombocytopenia
Sepsis Nausea/vomiting (dehydration) Mucositis/diarrohea Palmar-plantar erythrodysethesia (PPE) Fatigue
MOA of (3) of cytotoxic chemotherapy
ANTHRACYCLINES
Inhibit transcription & replication
• by intercalating nucleotides within the DNA/RNA strand
Block DNA repair (mutagenic) & create free radicals
• DNA/membrane damaging
Example drugs of (3) of cytotoxic chemotherapy
Docorubicin
Epirubicin
SEs of (3) of cytotoxic chemotherapy
Alopecia (HAIR LOSS)
Cardiac problems
• due to free radicals
Neutropenia Nausea/vomiting Fatigue Skin changes Red urine • Doxorubicin
MOA of (4) of cytotoxic chemotherapy?
VINCA ALKALOIDS & TAXANES
Inhibit either
• Assembly - VA
OR
• Disassembly -T
of mitotic microtubules CAUSING mitotic arrest
SEs of (4) of cytotoxic chemotherapy?
Nerve damage
• peripheral neuropathy
Alopecia
Nausea/vomiting
Bone marrow suppression
• neutropenia/anaemia
Arthralgia (joint pain)
Allergy
MOA of (5) of cytotoxic chemotherapy
TOPOISOMERASE INHIBITORS
Topoisomerases:
• are required to PREVENT DNA torsional strain during DNA replication & transcription
- SO inhibitors allow for this
• induce temporary single (topo1) OR double (topo2) strand breaks in the DNA backbone
- allowing for uncoiling
- induce apoptosis in checkpoints
• protect the free ends from aberrant recombination
Which drugs have anti-topoisomerase effects?
Anthracyclines
• through their action on DNA
Examples drugs of (5) of cytotoxic chemotherapy
Topotecan
Irinotecan (topo1)
Etoposide (topo2)
Alter binding of complex to DNA
AND
induce PERMANENT DNA BREAKS
SEs of (5) of cytotoxic chemotherapy
Acute cholinergic type syndrome (Irinotecan)
• diarrhoea, abdo cramps & diaphoresis (sweating)
• SO given w. ATROPINE
Alopecia
Nausa/vomiting
Fatigue
Bone marrow suppression
Summary of the routes to apoptosis?
- DNA double strand breaks
• Apoptosis - DNA damage checkpoint
• Apoptosis (using p53, bcl-2)
Resistance mechanisms that allow the cell to survive the damage by cytotoxic drugs?
• DNA repair mechanisms upregulated
- so DNA does NOT break
• DNA adducts replaced by Base Excision repair
- using PARP
• Drug efflux from cell
- via. ATP-binding cassettes (ABC) transporters
ALL may lead to lower chance of relapse/cure
What is the opposite no cytotoxic chemotherapy that can be used instead?
TARGETED (i.e. non-cytotoxic) therapy
How can targeted chemotherapy be used?
Cancer cells have INTERNAL PATHWAYS which can be targeted in treatment
• in monogenic cancers, this is useful
BUT
• in other cancers, parallel pathways OR feedback cascades are often activated
How can the problem with targeted chemotherapy for other cancers be tackled?
Dual kinase inhibitors
• prevent the feedback loops
BUT
• increase toxicities (so new therapeutic strategies required)
The six hallmarks of cancer cells?
SPINAP
S - self-sufficient P - pro-invasive and metastatic I - insensitive to anti-growth signals N - non-senescent A - anti-apoptotic P - pro-angiogenic
Another 4 hallmarks have been added to cancer cells - what are they?
DIE U
D - dysregulated metabolism
I - inflammation (tumour-promoting)
E - evades immune systme
U - unstable DNA
Relationship between GF and the cancer cell?
Normal cells need GROWTH SIGNALS to move from
quiescent –> active
These signals are trasmitted by the GF receptor pathway (another lecture!!)
• e.g. Receptor TYROSINE KINASE
- responsible for >50% of human malignancies
- results in increase in kinase cascade & signal amplification
Outline common over-expression of receptors?
Her2 ; EGFR
- Her2 - 25% of breast cancer
- EGFR - breast & colorectal cancer
- PDGFR - glioma (brain cancer)
results in increase in kinase cascade & signal amplification
Outline common over-expression of ligands
VEGF
• VEGF - prostate, kidney & breast cancer
results in increase in kinase cascade & signal amplification
Outline common constitutive receptor activation
Constitutive (ligand independent)
- EGFR - lung cancer
- FGFR - head/neck cancer, myeloma
results in increase in kinase cascade & signal amplification
Common suffix of (1) of targeted chemotherapy?
-momab
• derived from mouse Abs
-ximab
• chimeric
• fusing the antigen binding region (variable domains of the heavy and light chains, VH and VL ) from one species with the constant domain (effector region) from another species
-zumab
• humanised
• a type of Ab made by combining a human antibody + a small part of a mouse/rat monoclonal antibody
-mumab
• fully human
Explain the MOA of (1) of targeted chemotherapy
Monoclonal Abs
Target the EC component of the receptor
• the Ab can bind to one of the two receptors and PREVENT receptor dimerization
• this causes internalisation of the receptor
• and this NEUTRALISES the ligand
What else can (1) of targeted chemotherapy activate?
Monoclonal Abs can also activate
• Fcy-receptor-dependent phagocytosis
• cytolysis induced complement-dependent cytotoxicity (CDC)
• Ab-dependent cellular cytotoxicity (ADCC)
Examples drugs of (1) of targeted therapy?
Monoclonal Abs
Bevacizumab
• humanised
• binds & neutralises VEGF (ligand)
• improves survival in colorectal cancer
Cetuximab
• chimeric
• targets EGFR
• prevents receptor dimerization
Explain the general MOA of (2) of targeted chemotherapy
Small molecule inhibitors
These bind to the KINASE DOMAIN and inhibit auto-phosphorylation and thus downstream signalling
Give an example drug of (2) of targeted chemotherapy
Glivec
• first SMI
• targets BCR-ABL fusion protein made in CML
Explain the function of the first (2) drug of targeted chemotherapy
BCR-Abl translocation in CML was discovered
• created its own fusion protein - BCR-Abl
• it drove the over-production of WBCs
Gilvec (SMI) was made
• targeted the ATP-binding region within the kinase domain
• inhibited the kinase activity of ABL1
(2) of targeted chemotherapy work on TK receptors but also on something else - what is this?
Also on IC kinases
• SO can affect cell signalling pathways (e.g. kinase cascade)
i.e. they bind not just to TK but also to Raf, MEK, Akt etc. proteins
(2) drugs of targeted chemotherapy that work on TK receptors?
- Erlotibib - EGFR
- Gefitinib - EGFR
- Lapatinib - EGFR/HER2
- Sorafinib - VEGFR
(2) drugs of targeted chemotherapy that work on IC kinases?
- Sorafinib - Raf kinase
- Dasatinib - Src kinase
- Torcinibs - mTOR inhibitors
What is an advantage of targeted therapy?
By acting on receptors (IC/EC), targeted therapies BLOCK CANCER HALLMARKS
• e.g. VEGF inhibitors alter blood flow to a tumour
Advantages and disadvantages of (1) and (2) of targeted chemotherapy?
ONENOTE!!
What is one of the largest disadvantages of targeted chemotherapy and explain how?
RESISTANCE!!
The mechanisms are
• Mutation in ATP-binding domain (e.g. BCR-Abl fusion gene)
- Intrinsic resistance
- Intragenic mutations
- Upregulation of downregulation or parallel pathways
Explain anti-sense oligonucleotides
Single-stranded, chemically modified, DNA-like molecule
• 17-22 nucleotides in length
The complementary nucleic acid hybridisation to target genes HINDERS translation of specific mRNA
It recruits RNase H
• to cleave target mRNA
• good choice for un-druggable targets
BUT £££
RNAi?
RNA Interference
• single-stranded complementary RNA
• has to be packaged to avoid degradation
