Tutorial Questions Flashcards
Identify the different classes/categories of drugs used to treat cancer
Cytotoxic drugs - Alkylating agents - Antimetabolites - Cytotoxic antibiotics - Plant derivatives Hormones/antagonists Monoclonal antibodies Protein kinase inhibitors Others
Cytotoxic Drugs can be subdivided into, Alkylating agents, Antimetabolites, Cytotoxic antibiotics and Plant derivatives.
Describe the mechanism of action of the anti-metabolite methotrexate
Methotrexate is a folate inhibitor
Folates are essential for the synthesis of purine nucleotides and thymidylate, which in turn are essential for DNA synthesis
Folates act as coenzymes, with thymidylate synthetase to produce thymidylate
Folate are actively taken up into cells, where are converted to polyglutamates
In order to act as coenzymes for thymidylate synthetase, folates must be reduced to FH4
This 2 step reaction is catalysed by dihydrofolate reductase, which converts the substrate first to FH2 and then to FH4
Methotextrate has a higher affinity for dihyrdofolate reductase than FH2, and thus competes with FH2, inhibits the enzyme and depletes intracellular FH4
Describe the mechanisms of antimetabolites
Most current anti-cancer drugs, particularly cytotoxic agents, affect only one characteristic aspect of cancer cell biology - cell division and progression through the cell cycle
The antimetabolites are structurally similar to naturally occuring metabolites which are required for the synthesis of DNA and RNA
Thus, they act on the S phase. More specifically, they exert their effects by competing with or substituting for normal metabolites
Methrotexate is one of the most widely used antimetabolites for cancer chemotherapy
Describe the mechanisms of antimetabolites
Most current anti-cancer drugs, particularly cytotoxic agents, affect only one characteristic aspect of cancer cell biology - cell division and progression through the cell cycle
The antimetabolites are structurally similar to naturally occuring metabolites which are required for the synthesis of DNA and RNA
Thus, they act on the S phase. More specifically, they exert their effects by competing with or substituting for normal metabolites
Methrotexate is one of the most widely used antimetabolites for cancer chemotherapy
Tumours arising in hormone-sensitive tissue (breast, uterus, prostate gland) may be hormone-dependent, an effect related to the presence of hormone receptors in the malignant cells
Describe the mechanisms of action of endocrine therapies used to treat hormone receptor-positive metastatic breast cancer (MBC).
Selective Oestrogen receptor modulators (SERMs) compete with oestrogen for binding to the oestrogen receptor, and reduce signalling within the tumour, however oestrogen receptors bound by SERMs can still form dimers and have some residual agonist activity
Aromatose inhibitors disrupt oestrogen signalling in breast cancer tumour by reducing the amount of oestrogen circulating in the blood stream. These targeted agents inhibit the aromatization of circulating androgens into oestrogen
Selective Oestrogen Receptor Downregulators (SERDs) bind to, and accelerater the degradation of the oestrogen receptor, diminishing the signal. Oestrogen receptors bound by SERDs cannot form dimers with other oestrogen receptor, and so cannot translocate to the nucleus.
Monoclonal antibodies are a relatively recent addition to the arsenal of anti-cancer drugs. Describe their general mechanisms of action
Either bind to its target and activates the host immune response and the cancer cell is killed by complement-mediated lysis or by recruitment of NK cells
Or attach to and inactivate growth factor receptors on cancer cells (e.g. by inhibiting binding of he endogenous agonist), thus inhibiting the survival pathway and promoting apoptosis
Or more recent advances have lead to the design of mABs which bind to growth factor receptors to specifically prevent receptor dimerization, thus preventing receptor activation, tumour cell survival, and proliferation
- Unlike the majority of cytotoxic drugs, they offer the prospect of highly targeted therapy, without many of the side effects associated with conventional chemotherapy
- This advantage is offset by the fact that they are given in combination with more traditional therapies
Monoclonal antibodies are a relatively recent addition to the arsenal of anti-cancer drugs. Describe their general mechanisms of action
Either bind to its target and activates the host immune response and the cancer cell is killed by complement-mediated lysis or by recruitment of NK cells
Or attach to and inactivate growth factor receptors on cancer cells (e.g. by inhibiting binding of he endogenous agonist), thus inhibiting the survival pathway and promoting apoptosis
Or more recent advances have lead to the design of mABs which bind to growth factor receptors to specifically prevent receptor dimerization, thus preventing receptor activation, tumour cell survival, and proliferation
- Unlike the majority of cytotoxic drugs, they offer the prospect of highly targeted therapy, without many of the side effects associated with conventional chemotherapy
- This advantage is offset by the fact that they are given in combination with more traditional therapies
Identify and describe the proposed mechanisms of action for the mAb Tratstuzuab/Herceptin
HER2 internalisation and degradation
Antibody dependent cellular cytotoxicity (mAB attracts/recruits immune cellls, such as NK cells, to the tumour site which overexpresses HER2)
Interference with HER2 dimerisation and inhibition of downstream pathways (p42/44 MAPK and PI3-kinase)
Describe the mechanism of action of the protein kinase inhibitor Gefitinib
Gefitinib is a small molecule inhibitor selective for EGFR intrinsic tyrosine kinase activity
Inhibits EGFR tyrosine kinase by binding to the ATP-binding site of the enzyme
Tyrosine residues on the intracellular component of the EGFR are NOT phosphorylated therefore are unable to act as docking sites for proteins integral to cellular proliferation pathways (MAPK) and cell survival/anti-apoptotic pathways (PI3-kinase)
Describe the mechanism of action of the anti-sense oligonucleotide Augmerosen
Augmerosen is an antisense oligonucleotide which downregulates the anti-apoptotic protein Bcl-2
It is a synthetic sequence of single stranded DNA complementary to the specific coding region of the mRNA for the anti-apoptotic Bcl-2 protein. Once bound to its targeted region of mRNA, mRNA can no longer be translated and inhibition of Bcl-2 gene expression is achieved
An early clinical trial demonstrated that Augmerosen sensitized malignant melanoma to standard anti-cancer therapy (Genta)
Identify the 4 major pathways which are poignant to the pathophysiology and treatment of schizophrenia
- Mesocortical DA system
- Mesolimbic DA system
- Tuberoinfundibular system
- Nigrostriatal DA system
How may dopaminergic neurotransmission contribute to both positive and negative symptoms of schizophrenia?
Mesolimbic pathway: Increase in dopamine causes positive symptoms of schizophrenia
Mesocortical pathway: Deficit in dopamine causes negative and cognitive symptoms of schizophrenia
First generation anti-psychotics (D2 antagonists) are often characterised by debilitating side effects
Explain how these occur:
Dopaminergic neurons of the nigrostriatal pathway have their cell bodies in the substantia nigra of the midbrain and extend axon terminals to the striatum
These dopaminergic neurons are involved in the control of motor function.
Unfortunately, first generation antipsychotics block dopamine receptors (D2) within the nigrostriatal pathways and give rise to debilitating neurological side effects referred to Extra Pyramidal Side Effects.
What are Extra Pyramidal Side Effects?
Tremor Rigidity Akinesia Akathisia Acute dystonic reactions Neuroleptic malignant syndrome (fatal in 10%) Tardive dyskinesia Oculogyric crisis
Explain how the pharmacology of second generation anti-psychotics attempts to overcome these Extrapyramidal Side Effects
- FGA show some preference for D2 over D1 (negative symptoms-mesocortical)
- Some of the newer agents are highly selective for D2 (eg. the benzamides, sulpiride and amisulpiride)
- More recently, D2 antagonists which dissociate rapidly from their cognate receptor have been introduced in an attempt to overcome EPS (clozapine, olanzapine, amisulpiride)
