topic 19 - Cancer 1 Flashcards
what is cancer?
Populations of cells which lose regulatory control on growth and multiplication.
Any type of tissue can become cancerous. The cells often lose their differentiating features.
Cells will grow and multiply out of control
Some cancers are localised and cause little direct harm – they are benign
If this results in interfering with key organs, blocking oxygen/nutrient supplies and building up waste, it can lead to serious illness and death – a malignant cancer
Cancer cells may invade other parts of the body and start new tumours – metastasis.
what is cancer pt 2?
A huge array of different things can go wrong in a cell to result in a cancer
Cancer is not just one disease but many.
In general cancers are caused by mutations which alter protein activity
Mutations can occur through:
Chemical damage (smoking, pollution, diet, medicinal side effects…)
Viruses (Hepatitis causes liver cancer, HPV causes cervical cancer…)
Genetics (BRCA gene raises risk of breast cancer…)
Random mistakes in biochemistry
Cancers are commonly classified by tissue – used for developing treatment regimes (administration and pharmacokinetics) and statistics
Classification by mutation may be just as important – target right biochemistry.
how do you treat cancer?
Cancer cells cannot be returned to a normal state – all the strategies involve eliminating them.
Three main strategies, often used together:
Surgery – some cancers can be cut out – limited to those which are localised and accessible (e.g. some skin cancers)
Radiotherapy – kills the cells using radiation, often after surgery
Chemotherapy – using medicines (i.e. chemicals) to kill the cancer cells.
Anticancer medicines are generally cytotoxic
Drug design will aim to make compounds more toxic to cancer cells
Not easy – the cells come from the same source as normal cells
Risk of death lowers barrier to side effects and intravenous administration.
nucleic acids - alkylation
All cells need their genome to be properly ordered and accessible to survive.
Alkylating agents form strong bonds with DNA. Drugs with two active groups form crosslinks.
Alone, they are unselective for cancer cells – and DNA in general
By mimicking nutrients, cells can be tricked into active uptake. Will most affect cells which are most metabolically active = cancers.
Nucleic acid - metallation
Cisplatin is used intravenously for various cancers, often in combination. Side effects include nausea/vomiting.
Carboplatin has reduced side effects (reasons unclear)
Cancer cells can develop resistance because they multiply and mutate rapidly.
Resistance to cisplatin/carboplatin can be overcome using oxaliplatin which alters the part recognised in resistance mechanisms.
what is topoisomerase inhibition?
Cancer cells divide more rapidly, so targeting DNA replication machinery can be selective.
Intercalation into DNA can stop the TopoII Tyr residue accessing the strand to cut it.
what is topoisomerase pt 2?
Many planar aromatic compounds are intercalators, but not medicinally useful.
Note basic amines and polycyclic rings
Doxorubicin is one of the most effective anticancer drugs – used to treat broad spectrum of cancers
Not orally active (6 HB donors, 9 HB acceptors, Mw = 543, LogP = 0.31) – intravenous administration
Liposome formulation keeps the drug in the bloodstream longer – reduces elimination.
what are DNA related anti-metabolites?
Antimetabolites can stop cells making what they need for DNA synthesis
Cancer cells divide more frequently – affect them most.
Methotrexate is a competitive inhibitor of dihydrofolate reductase.
Orally available despite too many HB donors/acceptors by Lipinski’s rules.
what are hormone receptors?
Some cancers (prostate, breast) are hormone-dependent treat with hormones with have the opposing effect, or with antagonists.
Estrogen receptors (ER) are intracellular receptors – they operate in the cytosol – but like membrane receptors dimerise on binding, and migrate to the nucleus where they act as transcription factors leading to cell proliferation
ERs are overexpressed in 70% of breast cancers – “ER positive”
what is the process hormone recepetors take?
Binding site –> estrogen receptor –> dimerization anf exposure of AF-2 regions –> nuclear transcription factor –> transcription –> DNA
hormone receptors - androgen receptors and enzalutamide
Prostate cancers can be driven by testosterone-triggered pathways. The androgen receptor (AR) works in a similar way to estrogen receptors.
Enzalutamide is an antagonist for AR, developed from a lead compound agonist. Modern target-based discovery: orally 85% bioavailable. Steady state concentrations achieved within 28 days. 97% bound by serum albumins. Metabolised in the liver by CYP2C8 firstly by demethylation. Elimination half life of 5.8 days.
what are some examples of structural proteins?
Microtubes are needed for cell division Cancer cells divide more frequently.
Vincristine comes from the Madagascan periwinkle plant used traditionally against tumours – stops microtubule polymerisation. Intravenous administration for some acute cancers. Many side effects – peripheral neuropathy
Liposomal formulation (Mariqbo) withdrawn for lack of clinical benefit.
Paclitaxel (Taxol) inhibits tubulin depolymerisation
Isolated from Pacific yew from screening programme
Outstanding activity against breast and ovarian cancers
Intravenous administration. Resistance develops in tubulin mutations and efflux Solubility is poor but can be improved as albumin-bound formulation.
summary of cancer pt 1
Cancer is a serious illness in which cells uncontrollably grow and divide
Because of the severe need, drugs are used despite side-effects and intravenous administration
The general strategy is to use cytotoxic compounds – side effects are unavoidable
These may be more effective against cancer cells if they target mechanisms related to growth and division
DNA and related processes are good targets because DNA replication is needed for cell division – modify DNA so it can’t be processed, or stop its synthesis
Some cancers are driven by hormones – use agonists or antagonist
Cell division requires microtubules – arrest their activity
