Tumour Necrosis Factor Flashcards
TNF family
Two regulatory factors:
- TNF-α (cachectin)
- TNF-β (lymphotoxin).
Where are TNF-α & TNF-β located
Next to each other on human chromosome 6
Most significant cellular source of TNF-α
Activated macrophages
Biological responses induced by TNF-α include:
- Activation of specific and non-specific immunity to gram-negative bacteria
- induction/regulation of inflammation
- Selective cytotoxicity against a range of tumour cells
- Mediation of various pathological conditions - e.g. septic shock and anorexia
What is the biologically inactive form of TNF?
Monomer
What is the active form of TNF?
Homotrimer
What is the function of metalloprotease in TNF synthesis?
To cleave the pro-peptide
How is TNF biosynthesis regulated?
Both at the transcriptional and post-translational levels
What is the reason for constitutive expression of TNF-α mRNA in macrophages?
To be always ready as a first responder
What is the origin of the interest in TNF-α and its naming?
Its anti-tumour activity
Who was the American doctor who noted tumour regression in some cancer patients after they suffered a severe bacterial infection?
William Coley
What was the approach to treating cancer that involved injecting bacteria into the tumour?
Direct bacterial injection
Why was the approach of directly injecting bacteria into the tumour to treat cancer abandoned?
More often than not, the patient succumbed to the bacterial infection before being ‘cured’ of their cancer.
How does TNF-α mediate death of sensitive cells
Apoptosis
- cellular shrinking, formation of dense ‘apoptoic’ masses and DNA fragmentaion
Necrosis
- Clumping of the nuclear chromatin, cellular swelling, disintrigation of intracellular organelles and cell lysis.
Why has the initial interest in TNF as a general anti-cancer agent diminished?
- many tumours are not susceptible to destruction mediated by TNF
- tumour cell necrosis is not TNF’s major biological activity
- severe side effects accompany systemic administration of therapeutically relevant doses.
What is Beromun?
A therapeutic agent based on TNF-α.
How is Beromun produced?
It is human TNF-α-1a heterologously expressed by E. coli.
What is the indication for the use of Beromun?
Treatment of soft-tissue sarcoma (STS) in the limbs, mainly to prevent or delay amputation.
What is the usual combination therapy for Beromun?
The chemotherapeutic drug melphalan.
What do clinical trials reveal about Beromun?
It delays/prevents the need for whole limb amputation in a majority of patients.
What is the clinical interest in TNF at present?
- Neutralizing its biological effects.
- This is achieved through the administration of anti-TNF monoclonal antibodies or soluble forms of the TNF receptor.
What is Enbrel?
- Enbrel is an engineered hybrid protein used in the treatment of rheumatoid arthritis.
- It consists of the extracellular domain of the TNF receptor fused to the Fc (constant) region of human IgG.
How is Enbrel produced?
Enbrel is produced in a Chinese hamster ovary (CHO) cell line, from which it is extracted as a dimeric soluble protein.
