New Targets in Cancer Chemotherapy Flashcards
What are the new targets in cancer chemotherapy?
Potentiation of DNA damaging therapies.
Exploitation of the abnormal physiology of solid tumours
Inhibition of angiogenesis
Interference with signalling, especially cell cycle control
Interfere with management of DNA in the tumour cell
What are DNA damaging therapies?
Radiotherapy, mono alkylators, cross linkers, topoisomerase inhibitors, replication inhibitors, antimetabolites.
What is the mechanism of action of O-6-methylguanine DNA methyltransferase inhibition?
Alkylating agents alkylate at the N7 position, O6 guanine is a major carcinogenic lesion in the DNA. The adduct is removed by the repair protein and the protein is not a true enzyme as it is stoichiometric and is not regenerated.
What is temozolomide?
An oral prodrug which crosses the blood brain barrier to treat high grade glioma in adults and children.
What is poly(ADP-ribose)?
Nucleic acid in mammalian cell, a polyanionic polymer built from ADP ribose units derived from NAD+. Built onto the Glu side chains in target proteins. the MW varies with PARP isoform.
Can be linear or branched
How is tumour physiology exploited?
Tumours need supply of oxygen and other nutrients – angiogenesis
They have poor vascular structure – disorganised network, vessel walls not well formed, leaky, high interstitial pressure.
What are radiosensitising drugs?
Molecular oxygen is a potent chemical radiosensitiser because of its extreme electron affinity leading to participation in the chemical reactions which lead to DNA damage after absorption energy from ionising radiation.
Hypoxia is the reduced level of oxygen which has a knock on effect of reducing the efficacy of radiation.
Etanidazole is a nitromidazole drug with radiosensitising properties which reduces glutathione concentration and inhibits glutathione S transferase, the tissues become more sensitive to ionising radiation.
How do oxygen mimetic radiosensitisers work in hypoxic cells?
They replace oxygen in chemical reactions that lead to DNA damage.
What is PARP1 inhibitor and hypoxia inducible factor 2a?
Hypoxia inducible fatcors mediate the transcriptional adaptation of hypoxic cells. PARP1 is a nucelar protein which is involved in DNA repair and gene transcription.
PARP1 regulates HIF1 activity and interacts with HIF2a. The inhibition of PARP1 affects the formation of HIF2a/PARP1 complex.
What are hypoxia selective drugs?
They are prodrugs which have the potential to be metabolised by enzymatic reduction under hypoxic conditions – nitro groups, quinones, aromatic and aliphatic N oxides and transition metals.
Selectivity for hypoxic conditions rely on re-oxidation by oxygen of initial free radical intermediates formed by one electron reduction of the pro-drug. In oxic cells the prodrug radical is kept at low concentrations, but not in hypoxic conditions.
Inhibition of drug reduction by oxygen through the redox cycling was first shown in nirto compounds and shown to be responsible for the hypoxia selective cytotoxicity of nitroimidazoles.
Why do molecules of a certain size tend to accumulate more in tumour tissues than normal tissue?
Because of the need of tumour cells to grow quickly so the blood vessels are required. The newly formed vasculature is abnormal in form and architecture. The tumour tissues lack efficient lymphatic drainage.
This leads to abnromal molecular and fluid dynamcis – enhanced permeability and retention effect, of macromolecules in lipids in solid tumours.
This effect can be used to describe the delivery of nanoparticiles and liposomes to cancer tissue.
How can the inhibition of angiogenesis be targeted?
Complex regulatory pathway with many control systems. The VEGF binds to the VEGF receptor and signals for angiogenesis, PDGF binds to the PDGF receptor and signals for angiogenesis. They are both tyrosine kinase receptors.
Sunitinib inhibits both of these kinases. Bevacizumab is a neutralising antibody.
How is the cell cycle interfered with?
Inhibitors of cyclin dependent kinases,
Inhibitors of EGFR tyrosine kinase activity,
Inhibitors of Abl kinase
How is the management of DNA interfered with?
Inhibitors of elongation of telomerase activity – binding to G quadruplex.
Inhibition of tankyrase -1 – preventing telomerase from binding to telomere.
How is resistance to O-6 alkylators overcome?
MGMT depletion because there is a relationship between MGMT activity and resistance in tumour cells.
