Treatment of Cancer (chemo, radiotherapy and targeted biological therapies) Flashcards
what consists of ionising radiation?
high energy sources are gamma rays and x-rays
gamma rays = originate in cell nucleus of radioactive isotopes
x -rays = originate in electron fields or artificially produced by bombarding accelerating electrons to a target
(above no mass only packets of energy)
alpha and beta particles (mass and energy)
difference between photoelectric effect and compton scattering
photoelectric effect = lower energy radiation (like seen in x rays and CT) is all absorbed by the atom based and is based on atomic number. the higher the atomic number the greater the absorption is.
with compton scattering in higher energy such as radiotherapy the incoming photon is scattered and reflected out. is independent of atomic number
the mechanism of radiotherapy:
when radiation targets a molecule such as water/oxygen a free radical is formed. A free radical is a molecule with an unpaired electron that is highly reactive and can damage DNA by causing a single, double strand break or base mutation.
types of radiotherapy
- external beam radiotherapy Dose per fraction 2-3 Gy
- stereotactic body RT or stereo active ablative RT (6-11 Gy) much higher dose)
- brachytherapy (pellets directly into a tumour) (follows inverse square law in which the tissues further away from the pellet receive inversely less radiation thus non-cancerous tissue is more protected
- brachytherapy in unsealed sources such as radioactive iodine which is taken as a pill and accumulates in certain places eg thyroid
what is Gray
radiation dose
1 Gy is 1 J of energy absorbed per kg of matter
radiotherapy can be split into..
radical treatment = curative
palliative treatment = alleviate symptoms
fractionated RT = given over several days
applications of radical treatment
local and loco-regional treatment and early disease as with surgery
can be used alone, with surgery or with chemo
advantages of radical radiotherapy
organ preservation
function preservation
cosmesis
other applications of radiotherapy:
palliative =
pain: bone metastasis
bleeding = haemoptysis, tumour bleed
relief of obstruction in SVC, bronchial obstruction or spinal cord compression
adjuvant RT: to treat microscopic disease that is not seen on a imaging modality/macroscopic disease
acute side effects of RT
skin = erythema, pruritus, desquamation
mucosa = mucositis
oesophagitis + dysphagia
lung = pneumonitis - cough and dyspnoea
liver - hepatitis
rectum = proctitis
haematopoietic = anaemia and leucopenia
systemic = lethargy
nerve = myelitis
late/chronic side effects of RT
fibrosis occurring in many sites of body, telangiectasia, stricture + fistula,
radiation necrosis, growth retardation and asymmetry in bone
myelofibrosis
tumorigenesis
permanent nerve damage
4 types of chemotherapy
- curative = cures the cancer permanently
- adjuvant = given after a local treatment such as surgery or radiotherapy
- neoadjuvant = given prior to a local treatment (shrinks the tumour)
- palliative = providing relief from symptoms
4 classes of chemotherapy drugs
- Alkylating agents cause cross linking of DNA, damaging it and thus preventing protein synthesis. Examples include cyclophosphamide, cisplatin and dacarbazine
- anti-metabolites are designed to block DNA synthesis. Have similar structure but altered chemical groups —> errors —> apoptosis. Examples are 5 fluorouracil and methotrexate
- topoisomerase inhibitors inhibit enzymes from unwinding DNA, can’t be replicated. Example = etoposide
- anti-microtubule agents = hyper-stabilisation of microtubules = inflexible = blocks cell division. Example paclitaxel and vinblastine
How can cancers become resistant to therapies
- change in sensitivity or binding affinity of target enzymes or receptors
- decreased drug accumulation due to increased expression of glycoprotein transporters or decreased permeability
- formation of drug-inactivating enzymes
- formation of reactive chemicals that trap anti cancer drug
- increased nucleic acid repair mechanisms
- reduced activation of pro-drugs
Point two: MDR-1 gene is responsible for glycoprotein that is involved in drug efflux
Difference between primary and secondary drug resistance
Primary = tumour shows resistance from the start, never responds to treatment
Secondary = occurs later in tumour development
What other cells with a high growth fraction are affected by chemotherapy
Bone marrow
Hair follicles
GI mucosa
skin
Nails
Common side effects of chemotherapy:
- decreased WBC, RBC and platelets
- alopecia
- stomatitis or mucositis
- nausea or vomiting
- extravasation = leakage of intravenous drugs into surrounding tissues
What are some of the limitations of conventional cytotoxic therapies
Lack of specificity
Toxicity of chemotherapeutic agent
Lack of effectiveness
Lack of individualisation
Normal role of EGFR and pathway under normal conditions and what happens in cancer
Epidermal growth factor receptor is activated by ligands such as EGF and transforming growth factor. This causes it to form a homodimer or heterodimer that are now active. Dimerisation stimulates intrinsic auto phosphorylation of tyrosine residues. This elicits downstream activation of other proteins. Cascade of signal transduction begins leading to DNA synthesis and proliferation.
In cancer mutations (somatic) lead to over expression of EGFR or over activity —> uncontrolled cell division
Seen in squamous cell carcinoma of lung, anal cancers, glioblastoma and epithelial tumours of head and neck
What drugs can be used to target EGFR
- monoclonal antibody inhibitors. Cetuximab is a monoclonal antibody that blocks the extracellular ligand binding domain so pathway is not initiated
- small molecule kinase inhibitors such as gefitinib which inhibit tyrosine kinase which is not able to activate itself and signalling cascade is halted
How do immune checkpoint inhibitors work and examples of PD-1 inhibitors and PD L1 inhibitors
Immune checkpoints are molecules that turn up a signal or turn down a signal in the immune system
Programmed cell death 1 protein and its ligand PD L1.
PD1 is located on immune cells such as T cells, NK, B lymphocytes, macrophages, dendritic cells and monocytes. When PD L1 binds to PD1 activity of immune cells is inhibited. In cancer PD L1 is upregulated so cancer cells are able to evade immune system
PD1 inhibitors = permbrolizumab
PD L1 inhibitors = atexolizumab
What is an example of another protein located on T cells that inhibits its activity in cancer + example of an inhibitor of this protein
Cytotoxic T. Lymphocyte associated protein 4 (CTLA-4)
Monoclonal antibodies can attach to protein and stop it from working thus boosting immune response to cancer cells
CTLA-4 inhibitor = ipilimumab
What stimuli any turn on an angiogenic switch in tumour cells
Oxygen deprivation
Inflammation
Oncogenic mutations
Mechanical stress
What pro-angiogenic paracrine factors do tumour cells secrete
Angiogenin
VEGF
Fibroblast growth factor FGF
Transforming growth factor
What strategies can be used to prevent angiogenesis in tumour cells
Antibodies directed against VEGF, or VEGFR
Soluble VEGF/VEGFR hybrids
Tyrosine kinase inhibitors
Major adverse effects cell signalling therapy (EGFR inhibitors)
Papulopustular rash across face and torso
Diarrhoea
Vomiting
Nausea
Fatigue
Dehydration
How do many patients develop resistance to EGFR inhibitors
Through mutation of T790M
MET oncogene
Common SE of immune checkpoint inhibitors
Can allow Immune system to attack some normal body organs
Fatigue
Nausea
Loss of appetite
Skin rash
Itching
Common side effects of angiogenic inhibitors
Bleeding
Hypertension
Rash or itchy skin
Diarrhoea
Fatigue
Low blood count
