B33 CAN Pharmacology Flashcards
What is a cancer?
Cancer is a group of disease characterised by abnormal cell growth through which cells may acquire potential to metastasise from site of origin to secondary site
Tumour growth is dependent on….?
Tumour growth is depedent upon delivery of nutrients and oxygen via increased vascular supply (angiogenesis)
Types of tumours and descriptions
Benign
- Cells well-differentiated
- Slow growing
- Encapsulated & does not metastisize
Malignant
- Cells poorly differentiated
- Frequent cell divison
- Capable of intravastation at distant site and metastisi
Classification of Cancer Pathology
- Carcinoma - Most common type, ectoderm e.g. breast
- Sarcoma - Cancer of embryonic mesoderm e.g. bone
- Lymphoma - cancer in lymphnodes and tissue immune system
- Leukamia - Cancer of WBC in bone marrow
Properties of a metastatic cell
- Local invasion into vasculature
(loss of cell adhesion (cadherins) and gain of alternate adhesion (intergrins)
Survival in a vessel
(platelet-enhanced metastatic spread)
Arrest at Distant site
Extravasation
Growth of secondary tumour and angiogensis
Metastatic Cascade
1) primary tumour formation
2) localized invasion
3) intravasation
4) Transport through circulation
5) Arrest in microvessels of organs
6) Extravasation
7) formation of micrometastasis
8) colonisation
Vascularisation is essential for?
Vessel formation is essential for optimal;
Gas exchange, nutrient delivery, disposal of metabolic waste
Vasculogenisis: Differentiation and activation of ECs with prolfieration, alignment branching tube formation
Angiogenisis:
Formation of new vessels from pre-exisiting vasculature
Normal Vs pathological angiogensis
Controlled Vs Uncontrolled
Organisved Vs disorganized
Low interstital pressure vs High intersital pressure
Normal angiogenesis
In normal angiogenisism VEGF is the stimulus causing tip cells to grow and stalk elongation
Goals of cancer therapy
Curative
- Main goal is to cure the patient
Maintenance
- Secondary goal is maintenance to prolong progression-free survival
Pallitative
- Clear patient cannot be cured
- Focused on pain relief & comfort
General problems with anti-cancer drugs?
- Selectivity and specificity
- Off target side effects
- Tumour cell heterogeneity
- Drug resistance
Approaches to cancer treatment
Surgery
Radiotherapy: Damage DNA
Chemotherapy: Interfere with the cell cycle - Cytotoxic (S phase DNA rep, or M phase (mitosis)
Targeted Therapy : Interfere with specific pathway
Targeted Therapy examples
Inhibit the interaction of a growth factor/hormone with its receptor (e.g Bevacizumab and VEGF)
Bevacizumab and VEGF
VEGF binds to receptor
Phosphorylation occurs to tyrosine residues (autophosphorylation occurs T-arms coming together)
Stimulates series of downstream signalling processes
Leads to upregulation of signalling cascade molecules -ERK, PI3K
Bevacizumab inhibits interaction of Growth factor wirth receptor stopping the downstream signalling.
HER-2 Signalling & Trastuzumab
Breast cancers that express HER-2 receptor can be treated with Trastuzumab
Antibody shape Mab
- Binds to external domain receptor
-Stops signalling mechanism(RAS & PI3K)
History of chemotherapy
Era of modern chemotherapy during World War I - Soldiers exposed to mustard gas died because bone marrow destoyed -> compounds caused DNA alkylation, prevation cell divison -> APOPTOSIS
Chemotherapy
Drugs interfere with DNA synthesis and mitotic porcesses
These cytotoxic agents dont distinguish between normal cells and cancer cells
ADR to chemotherapy is the cytotoxicity of normal cells
Types of cytotoxic drugs (1-3 Sphase)
1) Alkylating-like agents
2) Antimetabolites
3) Topoisomerase Inhibitors
4) Microtubule poisons (M phase)
General ADR associated with chemotherapy
1) cytotoxic chemotherapy drugs target cells that are actively multiplying
2) common toxicities include myelosuppression
Increased risk infection
N & V & D
Sterility
Alkylating-like agents: Cisplatin
- Bind to DNA and cause cross-linking (prevent cell divison cause cell death)
Cause conformational change in DNA making DNA repair difficult
Impair DNA Replication and S
Link to DNA via Pt atom cross linking the strand
ADR:
Nephrotoxicity
Neurotoxicity
Peripheral neuropathy
Antimetabolites : Methotrextate MTX
Methotrexate is a DHFR inhibitor / Folate antagonist
MTX binds to DHFR preventing the production of thymidine (impairing nucleic acid synthesis therby inhibiting DNA RNA and protein production)
ADR:
Nephrotoxicity
Hepatic fibrosis and cirrhosis
Neurotoxicity
Topoisomerase I inhibitor: Topotecan
Topoisomerase I are enzymes that regulate DNA supercoiling, causing single strand breaks & religation
Topotcan intercalates between DNA bases, interfering with DNA structure (imparing DNA replication and synthesis and repair, leading to apoptosis)
Topoisomerase II inhibitor: Doxorubcin
Topoisomerase II are enzymes that regulate DNA supercoiiling causes cleavage of BOTH strands using hydroylsis and ATP
Doxorubicin inhibits activity TopoII
- Binds strongly to Duplex DNA by intercalation
- Generates free radicals
- Bind to cell membranes to alter fluidity and ion transport -> apoptosis
ADE:
Cardiotoxicity ; CHF can appear
Microtubule Poisons: Vincristine
Vincristine
- Binds to tubuli strucutres and prevents polymerisation into microtubules
- Blocks critcal step in M phase
ADE:
Cardiovascular
Peripheral Neuropathy (motor nerver damage long term)
GI : constipation
