anti cancer agent ii Flashcards
classical chemotherapy agent contradiction:
- Very advanced disease
- Existing bone marrow depression
- Presence of active infection
limitation of classical chemotherapy:
* Most target cell — but not— and —
* Lack of — ( — on marrow, etc)
* Lack of —
* — of tumour may not be possible
* Development of —
cell proliferation
invasion
metastasis
selectivity
toxic effects
sensitivity
elimination
resistance
types of anticancer therapy :
1- classical anticancer ( cytotoxic agents ) as :
2- — therapy
3- — therapy
- Antimetabolites
- Alkylating agents
- Cytotoxic antibiotics
- Plant alkaloids/microtubule inhibitors
- hormone
- targeted
hormones as anti cancer targets:
* Tumours derived from hormone sensitive tissue can be — (breast, endometrium,
testes).
* Hormone dependency related to presence of — receptors in tumour cells.
* No. of receptors can be estimated by — , provides guide to potential efficacy of hormone therapy.
* In patients with hormone-sensitive advanced breast cancer, endocrine therapy is — tolerated than
cytotoxic chemotherapy, while being equally effective
hormone dependent
stereiod
biopsy/immunohistochemistry
better
tumour growth can be inhibited by:
(a) Hormone —
– Mechanism of action: these hormone analogues bind the – and — its normal action
– Tamoxifen which is —
– Flutamide which is —
(b) Agents that inhibit — of the relevant hormone e.g. — inhibitors
receptors
block
anti oestrogen
anti androgen
sythesis
aromatase inhibitors
- Selective estrogen receptor modulator (SERM)
- Antagonist of the oestrogen receptor (ER) in breast ( (but partial agonist at some other sites e.g. uterus, bone)
is —-
tamoxifen
tamoxifen competes w natural — for binding to —
- adverse effects:
- effective in — and advanced ER+ breast cancer and both in — and — women
- mechanism of action :
* Prodrug converted to active metabolite —
* Binds to —
* Binding of — to — inhibits
transcription of — genes
* The complex does not readily dissociate, interfering with
the recycling of receptors
oestrogen
ER ( osterogen recepor )
early and advanced
pre n post menopausal women
4-hydroxytamoxifen
ER
ER/tamoxifen-complex
ERE ( oestrogeen response element )
oestrogen-responsive
- — enzyme (CYP19) responsible for key steps in the biosynthesis of oestrogens:
1. conversion of — to — in the – - predominant method for oestrogen synthesis in —
women
2. conversion of — to — in — tissue - predominant method for oestrogen synthesis in —
women - Because oestrogens promote some cancers, — are frequently used in ER+ breast & ovarian cancer in — women.
- When AIs are used in — women they must be combined with surgical or medical ovarian ablation.
Aromatase
testosterone
estradiol
ovary
premenopausal
androstenedione
estrione
adipose
postmenopasual
aromatase inhibitors
post meno women
pre meno women
mode of action of aromatase inhibitor :
- inhibition of —- aka the converision of — to —
2 classes:
1. – analogues of androstenedione: Exemestane
* — inhibit —
2. — inhibitors: Anastrozole, Letrozole
* compete — for the — binding site on the aromatase enzyme
peripheral aromatisation
androgen to oestrogen
steroid
irreversibly
aromatase enzyme
non steriodal
reversibily
androestendione
targeted agents vs cytotoxic agents:
- less —
- more – to each particular cancer
- causes disease – and — further growth rather than —
- emerging therapies aimed at new molecular targets :
- Target specific — pathways e.g.
– — over —
– Over/underactive — pathways
– New — growth
toxic
specific
stabilisation
decrease
tumour regression
cellular
receptor over expression
cell control pathways
blood vessels
1-target therapy HER2 and breast cancer :
Normal cells - — copies of gene coding for HER2, produces small amounts of –
*HER2 plays a role in transmission of – that ensure controlled — with regulated rate of —
*Excess HER2 protein leads to sustained — , growth-promoting signals are — transmitted
to nucleus
*Results in uncontrolled — & ↑ rate of–
*HER2 over-expression by tumour cells found in ~15% of women with breast cancer
*Approved for treatment of HER2+ breast, stomach & oesophagus cancers
2
human epidermal growth
factor receptor 2 (HER2 protein)
signals
cell growth
divison
activation
permanently
growth
division
( check slide 18,11 )
trastusumab ( Herceptin ) is a — antibody against —
* Blocks—
* Also acts by – (antibody-dependent cell- mediated cytotoxicity), flags the tumour cell for – by the body’s immune system
* Inhibits —- of cancer cells which overexpress the HER2 receptor
* — therapy – important to – tumours over-expressing HER2
* Associated with — in 2-7% of cases, regular cardiac screening before/during treatment
– blocks HER2 signalling required for the growth, repair, and
survival of cardiac cells
monoclonal
HER2
HER2/receptor dimerzation
ADCC
destruction
proliferation
expensive identify
cardiac dysfunction
( check slide 20 )
2- target therapy - tyrosine kinase:
* Many molecular pathways controlling malignant progression depend on expression of — or — with — activity
* A tyrosine kinase is an enzyme that can transfer a — group from – to – on — proteins in a cell
* Function as a molecular — in many cellular pathways
* Regulate pathways controlling — , — , —
* Tyrosine kinases:
1. — tyrosine kinase e.g. VEGFR, EGFR/HER2, PDGFR
* Most are activated by ligand binding to extracellular domain
2. — tyrosine kinase e.g. Abl, Rb
receptor
intermediate proteins
tyrosine kinase activity
phosphate
ATP
tyrosine residue
effector protein
a molecular on/off switch
proliferation survival and angiogenesis
receptor
non receptor
Chronic Myeloid Leukaemia
(CML) and the Philadelphia
Chromosome:
- A shortened chromosome 22
resulting from the
translocation between
chromosome 9 and 22. - Produces BCR-ABL oncogene
and fusion protein - Constitutively active tyrosine
kinase - 95% of CML patients have this
translocation (Ph+ : positive for
Philadelphia chromosome) - See also FUN42
imatinib ( Gleevec or glivec ) is a — and the known targets are:
- highly — and – side effects
- used to treat: —– and the target is –
and —- and the target is —
- —- can occur
selective tyrosine kinase inhibitor
Bcr/Abl, PDGFR and c-kit
specific
few
treats:
* Ph+ chronic myeloid leukemia (CML) – Target: ABL protein
* Gastrointestinal stromal tumors (GISTs) – Target: KIT protein
resistance mutation
