Seminar 10 - Biological Basis of Cancer Chemotherapy Flashcards
What are the main ways in which tumours can spread?
- Local
- Blood
- Lymphatics
- Implantation
What is implantation?
Mechanical spread of detached clumps of tumour cells - peritoneum, ureters, CSF
Which types of tumour spread by lymphatics?
- Carcinomas
2. Melanomas
Which types of tumour spread via the bloodstream?
- Sarcomas
2. Carcinomas - later
If there is an abnormal connection between the bladder and bowel due to malignancy, what type of urine is formed?
- Fizzy urine - gas passed through
2. Possible feces in the urine
Where is the first site where secondaries from rectal cancer are observed? Why?
Lung - direct connection from the rectum to the lung via lymphatics
State the treatment options for cancer.
- Surgery
- Radiotherapy
- Chemotherapy
- Biological targeted therapy
- Hormones
State the options for chemotherapy.
- Primary treatment - radical
- Adjuvant
- Neoadjuvant
- Advanced disease - palliative
What is radical chemotherapy often used for?
Relatively rare but often used for haematological malignancies rather than solid tumours:
- Lymphomas
- Leukaemias
Define adjuvant therapy.
Post-operative treatment in a patient at high risk of microscopic metastases after removal of the primary tumour
What is neoadjuvant therapy?
Primary treatment of patients with a clinically localised tumour - it can be used to assess the biological responsiveness of the tumour
What is transcription?
DNA conversion to RNA
What is translation?
RNA conversion to amino acids which code for protein
Outline the sites of action of cytotoxic agents.
- Intercalating agents- DNA duplication and transcription
- Antimetabolites - DNA synthesis
- Alkylating agents - DNA
- Spindle poisons - mitosis
How do platinum compounds inhibit DNA synthesis?
Lead to formation of platinated inter- and intrastrand adducts leading to inhibition of DNA synthesis
State the percentage of platinated intrastrand adducts formed by Eloxatin (a platinum compound).
- G-G: 55%
2. G-A: 31%
How does topoisomerase-1 work?
Transient single strand cleavage: passage of the intact strand through the nick
What can be used to inhibit topoisomerase-1?
CPT-11
How does CPT-11 inhibit topoisomerase 1?
- CPT-11 binds to the Topo-I-DNA complex without affecting cleavage reaction
- Stabilisation of the cleavable complex = inhibition of the religation step
State 2 examples of anti-metabolite drugs.
- 5-Fluorouracil
2. Methotrexate
Which enzyme does 5-fluoracil act on?
Thymidylate synthase (TS)
Which enzyme does methotrexate act on?
Dihydrofolate reductase
Which enzyme converts 5’-DUFR to 5-FU?
Thymidine phosphorylase - TP
What are the 2 main ways microtubule binding agents affect microtubule dynamics?
- Inhibit polymerisation
2. Stimulate polymerisation and prevent depolymerisation
What is the aim of combination therapy?
- Increased efficacy
- Activity - different mechanisms of action and mechanisms of resistance
- Safety - compatible side effects
What is P-glycoprotein?
An ATP-powered efflux pump
Pumps cytotoxic agents out of the cell against the concentration gradient
Outline the mechanisms of resistance to alkylating agents.
- Increased exit or decreased entry of agent
- Inactivation of agent in cell
- Enhanced repair of DNA lesions produced by alkylation
Outline how double stranded breaks are repaired.
Recombinational repair:
- HR - ATM
- NHEJ - DNA-PK
Outline how single strand breaks are repaired.
Base excision repair: PARP
Outline how bulky adducts are repaired.
Nucleotide excision repair: XP, polymerases
Outline how insertions and deletions are repaired.
Mismatch repair: MSH2, MLH1
Outline how O6-alkylguanine is repaired.
Direct reversal by AGT enzyme
What is the key enzyme involved in repair of SSBs?
PARP-1
Outline the current endocrine therapies for prostate cancer.
- LHRH agonists: Goserelin
- Oestrogen: stilboestrol
- Castration
- Anti-androgens: cyproterone acetate, flutamide, bicalutamide
State the mechanism of action of abiraterone in treatment of prostate cancer.
Inhibits CYP17A1 - enzyme crucial in conversion of pregnenolone and progesterone to testosterone
What is the target for anti-cancer therapy in CML?
STI 571
What is the mechanism of action of imatinib?
Magic bullet: bcr-abl tyrosine kinase inhibitor –> tumour selective, rationally designed targets and inhibitors
What is trastuzumab?
A recombinant humanised IgG1 monoclonal antibody against the human epidermal growth factor receptor 2 (HER2)
Outline the mechanism of action of herceptin (trastuzumab)
- Binds to HER2 positive tumour cells and flags them for destruction by the immune system
- Antibody-dependent cell-mediated cytotoxicity (ADCC)
Which type of cancers is EGFR generally overexpressed in?
- Colorectal
- Breast
- NSCLC
- Prostate
- Ovarian
- Pancreatic
- Gastric
What is high EGFR expression generally associated with?
- Invasion
- Metastasis
- Late stage disease
- Chemotherapy resistance
- Hormone-therapy resistance
- Poor outcome
Why may EGFR-targeted therapies not work in patients with KRAS mutations?
When the KRAS gene is mutated, KRAS protein (p21 ras) is active regardless of EGFR activation
KRAS mutations associated with a poor prognosis - need to analyse NRAS
Describe the biological role of VEGF.
- Involved in the migration and proliferation of endothelial cells
- Promotes angiogenesis in vivo by inducing endothelial cells to invade collagen gels and proliferate to form capillary-like structures
- New blood vessel formation
Outline the process of angiogenesis.
- Endothelial cells migrate into the perivascular space towards angiogenic stimuli
- They proliferate, follow each other and adhere to create a lumen
- Blood vessel sprouts fuse to build new circulatory systems
Outline the classes of drugs that can be used to target the VEGF pathway.
- Anti-VEGF antibodies
- Ribozymes - VEGFR1
- Anti-VEGFR antibodies
- Small molecule VEGFR inhibitors - tyrosine kinase inhibitors
- Soluble VEGFRs
State an example of a CTLA-4 inhibitor.
Ipilimumab
State an example of a PD-1 inhibitor.
Nivolumab
Outline the routes of administration of cancer chemotherapy.
- IM: Rarely
- PO: convenient, dependent on oral bioavailability
- IV: most common, bolus, continuous pump infusion, infusional bag
- Subcutaneous: convenient in community setting
- Into a body cavity: bladder, pleural effusion
- Intrathecal - into the CSF: via lumbar puncture or omaya reservoir (directly into the ventricles)
- Intralesional: directly into the cancerous area- consider pH
- Topical: medication is applied onto the skin
