Chemo Chemistry Flashcards
Why is a combination of cytotoxic agents used rather than single agents?
Different agents target different areas of the cell cycle in order to kill as much cancer as possible.
What are the 8 classes of cytotoxic agents?
- Drugs acting directly on nucleic acids
- Drugs acting on enzymes
- Hormone-based therapies
- drugs acting on structural proteins
- drugs inhibiting signalling pathways
- miscellaneous enzyme inhibitors
- antibodies, antibody conjugates, gene therapy
- miscellaneous
Which drugs act on nucleic acids?
alkylating agents, intercalating agents, non intercalating topoisomerase inhibitors, groove binders, 06 methylators, bulsulfan, platinum agents
Give an example of an alkylating agent
Cyclophosphomide
How do alkylating agents work?
Alkylating agents form a highly reactive aziridium ion, by kicking out leaving groups, that can be attacked by nucleophilic DNA bases such as guanine. Alkyl groups are transferred to nucleophilic sites of DNA bases. This can occur twice, leading to cross-linked DNA. This damage cannot be undone and cancer cells can no longer proliferate.
What are the limitations of alkylating agents?
They are unstable structures that decompose in the aqueous environment of cells. The formation of the aziridium ion is a fast reaction that has no tissue or cell specificity leading to side effects and toxicity. Water can inactivate the aziridium ion
What is the significance of the r group on alkylating agents?
If it is aromatic, this stabilises the lone pair, the nitrogen becomes less nucleophilic, which decreases the speed of the ion formation which can help with tissue/cell specificity and leads to decreased side effects and toxicity
How do intercalating agents work?
They are drugs with planar aromatic rings which can insert themselves in between successive DNA base pairs. This leads to slight unwinding of the DNA helix, initiating local structural changes, which leads to the inhibition of transcription and translation.
What is the function of topoisomerase enzymes?
They are enzymes which have key functions in DNA replication, transcription, chromosome separation, and DNA repair. TI 1 = single strand, TI 2 = double strand
What is mitoxantrone and how does it work?
It is an intercalating topoisomerase 2 inhibitor. It impairs topoisomerase 2 repair. Metabolites are blue/green so can cause blue skin
Give an example of an anthracycline
Doxorubicin
Give examples of non intercalating topoisomerase inhibitors
Etoposide, teniposide, irinotecan
How do non intercalating topoisomerase inhibitors work?
They stabilise the covalent intermediate between DNA and topoisomerase. DNA strands cannot be rejoined and therefore this leads to cell destruction
What are groove binding drugs?
Drugs that can bind into the major/minor groove of DNA, preventing DNA from unwinding and preventing replication
Which drug can bind into the minor groove of DNA?
Dacinomycin
Which drug binds into the major groove of DNA?
Bleomycin
Why is there reisistance to Bleomycin?
Because there is bleomycin hydrase in all tissues except the skin and the lung. Bleomycin hydrase converts bleomycin to an inactive metabolite, so there is rapid drug destruction
What toxicity is associated with bleomycin?
Pulmonary
Give examples of 06 methylators
Procarbazine, dacarbazine, temozolomide
How does 06 methylation lead to cell destruction?
06 methylguanine preferentially pairs with thymine when guanine usually pairs with cytosine. This leads to a mispair which leads to a point mutation and cell destruction
How does procarbazine cause cell destruction?
Benzylic oxidation produces methyldrazine which is a methyl radical, which reacts with DNA nucleophiles
What can procarbazine inhibit?
Monoamine oxidase, enzymes involved in ethanol metabolism
How can temzolomide resistance occur?
Enzyme binds to DNA, which flips out methylated base, and transfers cytosine back into the active site of the enzyme
How is temozolomide different to other o6 methylators?
it is administered orally
Which drug class is busulfan?
Alkylating agent
How do organoplatinum agents work?
They have an electron deficient metal atom which is bifunctional and can accept 2 bases from electron rich nucleophilic DNA bases, commonly 2 guanines. Before this can occur, the electron donating leaving groups are displaced by cellular water. Nucleophilic DNA bases attack and bond, forming cross-linked DNA. This damage cannot be undone and cancer cells cannot proliferate.
How are platinum agents excreted?
Via the kidneys, so renal function must be assessed and patients are usually aggressively hydrated/given diuretics
What are antimetabolites and how do they work?
False substrates for critical nucleotide biosynthesis enzymes, which entice enzymes to choose them over the endogenous substrate and bind. This means that DNA building block nucleotides cannot be synthesised, and tumour growth is arrested
Give some examples of antimetabolites
pyrimidine, purine and folate antagonists
How do pyrimidine antagonists work? Give examples
They inhibit thymidylate synthase. Thymidylate synthase converts dUMP to dTMP. Inhibtiion of this prevents the synthesis of thymidine, which is a major building block of DNA, leading to apoptosis. EXAMPLES: 5FU, capecitabine
How do purine antagonists work? Give examples
Inhibit the synthesis of AMP to GMP. They are thioanalogues of endogenous bases and inhibit elongation of DNA strands which leads to apoptosis. EXAMPLES: mercatopurine, thiopurine, which are prodrugs converted to ribonucleotides.
How do folate antagonists work? Give an example
They compete with dihydrofolic acid for the DHFR enzyme. DHFR is irreversibly bound, which prevents the synthesis of thymine, and cells die due to lack of thymine. EXAMPLE: methotrexate
How do DNA polymerase and elongation inhibitors work? Give an example
They stop the action of DNA polymerase. EXAMPLE: gemcitatbine, which binds to DNA polymerase and is incorporated into the growing chain
What are microtubules?
Structural proteins which determine cell shape and are involved in the intracellular movement of organelles. They form the mitotic spindle to facilitate chromosomal replication. They are dynamic structures that undergo assembly and disassembly, and have a GTP binding site.
Which drugs target the microtubules?
Vinka alkaloids, taxanes, colchicine
What are the 2 categories of drugs that act on structural proteins and give examples?
Microtubule destabilising: vinka alkaloids, colchicine, estramustine
microtubule stabilising: taxanes
Where do vinka alkaloids bind on b tubulin?
To the vinka domain adjacent to the exchangeable GTP binding site
Where do taxanes bind on b tubulin?
To the deep hydrophobic pocket
How to vinka alkaloids work?
They inhibit polymerisation, by binding at the interface of 2 heterodimers on b tubulin, which inhibits the uptake of GTP which is essential for tubulin elongation, the mitotic spindle cannot be formed/disintegrates and the cell cycle cannot perform mitosis
How do taxanes work?
Taxanes are microtubule stabilising agents. They promote tubule polymerisation, and stabilisie the microtubule, which means that the mitotic spindle does not disintegrate and the cells are arrested in mitosis
How does colchicine work?
It is a vascular disrupting agent, binds to colchicine binding site and promotes polymerisation leading to apoptosis
What are the side effects/cautions of colchicine?
It is cytotoxic not just to cancer cells, can have severe side effects. It is a known emetic and teratogen
How does estramustine work?
It binds to microtubule associated protein 4, which leads to dissociation from the microtubule, which leads to depolymerisation and disassembly of the mitotic spindle. It is specific for prostate cells, so is useful in metastatic prostate cancer
How do histone deacetylase inhibitors work?
They silence tumour suppressor genes. Acetylation regulates gene expression. Forms a histone acetylase transcription activation complex
Discuss matrix metalloproteinases and give an example
MMP play an active role in cancer metastases. They are zinc dependant enzymes. EXAMPLE: marimostat
How do DNA repair enzyme inhibitors work?
They prevent PARP 1,2 and MGMT DNA repair in cancer patients.
How can DNA repair inhibitors be used in cancer therapy?
There is high levels of DNA damage which can cause cell cycle arrest and cell death. DNA lesions in the S phase of the cell cycle can obstruct the replication fork progression, which leads to DNA double strand break. In normal cells, there is 2 dna repair pathways, elimination of one leads to genome instability, adding in a second inhibitor leads to cell death. You can target the 2nd pathway with drugs
How does DNA-dependent protein kinase work?
It is involved in the pathway of DNA double strand break repair. Inhibitors of this can sensitise cells to radiation
How do PARP inhibitors work?
PARP plays a major role in the DNA base excision repair pathway. If you inhibit this, repair cannot occur. Give PARP inhibitors alongside DNA damaging agents to prevent cancer cells repairing damage
What are protein kinases?
They are involved in many cell signalling processes, regulating key processes such as proliferation, angiogenesis and invasion. They catalyse the transfer of a terminal phosphate group from ATP to tyrosine serine or tyrosine kinases. This leads to a signal cascade leading to pathways
How can protein kinases be used in anti-cancer therapy?
Genes coding for protein kinases are often over expressed in cancer cells. Protein kinase inhibitors are competitive inhibitors of ATP in order to inhibit the phosphorylation processes, which stops the signalling cascade and prevents uncontrolled proliferation. Different protein kinases have different ATP binding domains which can be used to target specific pathways.
Give some examples of tyrosine kinase inhibitors and what they are indicated for
Imatinib: chronic myeloid leukaemia, erlotinib: NSCLC as they are EGFR inhibitor, lapatanib: advanced metastatic cancers overexpressing HER2 in combo with capecitabine, sunetanib: GI and renal cell cancer, pazopanib: renal cell cancer
How does imatinib work?
it is a tyrosine kinase inhibitor specific for the bcr-abl oncogene in chronic myeloid leukaemia. Over expression of bcr-abl leads to uncontrolled proliferation.
How does imatinib work?
it is a tyrosine kinase inhibitor specific for the bcr-abl oncogene in chronic myeloid leukaemia. Over expression of bcr-abl leads to uncontrolled proliferation. Imatinib competitively inhibits the bcr-abl protein kinase, preventing phosphorylation, preventing the signalling cascade, preventing uncontrolled proliferation
What are they key points to remember about imatinib?
It is taken with food to minimise GI effects
has excellent bioavailability
Increase dose by 50% in the presence of cyp3a4 inducers
can cause diarrhea, nausea, rash
can be given as a salt to improve solubility
How do EGFR inhibitors work? Give examples
They bind irreversibly to the ATP binding site of EGFR and prevent the signalling cascade. EXAMPLES: erlotinib, gefitinib
What is erlotinib indicated for?
Stabilised NSCLC after 4 rounds of chemotherapy. Given in combination with gemcitabine in advanced metastatic cancer
What are the side effects/cautions for erlotinib?
They require a dose reduction with CYP3A4 inducers
Can cause hepatotoxicity and rash which is worse in sunlight
When is gefitinib indicated?
As a single agent in platinum/docetaxel refractory NSCLC
What are the side effects/cautions for gefitinib?
It can cause severe side effects such as pulmonary fibrosis, eyelash growth
dose is limited by toxicity
CYP1A4 causes smokers to produce reactive quinolone metabolite
How does lapatinib work?
It inhibits tyrosine kinase activity of oncogenes EGFR and HER2 in breast cancer. It inhibits the receptor signalling process by binding to the ATP binding pocket.
When is lapatinib indicated?
With capecitabine as second line therapy post anthracycline, taxane, trastuzamab in HER2 positive breast cancer. Taken on an empty stomach
How does pazopanib work?
It is a multi-targeted tyrosine kinase inhibitor, which blocks tumour growth by inhibiting VEGFR (involved in angiogenesis)
What is steroidogenesis?
When aromatase converts androstendione to oestrogen and testosterone to estradiol, which produces oestrogen to fuel the growth of hormone-receptor positive breast cancer
What are selective oestrogen receptor modulators?
Chemically diverse compounds which lack steroid structure of oestrogens but possess a tertiary structure and can bind to the oestrogen receptor, eg tamoxifen, raloxifen
What is the mechanism of action of tamoxifen?
Tamoxifen competitively binds to the oestrogen receptor leading to a reduction of transcription of oestrogen regulated genes. The dimethylaminoethoxy side chain and trans configuration are crucial for the antiestrogenic activity of tamoxifen. It blocks the G1 phase of the cell cycle and slows cell proliferation
How is tamoxifen metabolised?
By CYP450 3A4 enzyme and is excreted in the faeces.
How do aromatase inhibitors work?
they cause selective oestrogen deprivation without impairment of adrenal androgen synthesis
How is symptomatic metastatic prostate cancer treated?
Hormonal therapy and removal of androgens as prostate cells rely on androgens for survival and growth
Which methods are used for the removal of androgens in prostate cancer?
- castration
- oral drug to block testosterone production
- anti androgens
- 5a reductase inhibitor
- combination
What is enzalutamide and how does it work?
- targets androgen receptor
- inhibits binding of androgens to the androgen receptor
- inhibits nuclear translocation of the androgen receptor
- inhibits association of androgen receptor to DNA
How does hormone-refractory prostate cancer occur?
Prostate cells can grow in the absence of androgens
How do MMPis work?
Inhibition of metalloproteinase
Zinc ion interacts with susceptible carbonyl oxygen
Activates the peptide bond for hydrolysis
NH of the susceptible peptide forms a hydrogen bond to alanine
Bridging water molecule present between zinc cofactor and glutamate residue
Bridging water acts as a nucleophile for hydrolysis
