Session 10 - Lecture 1 - Chemotherapy Flashcards
1 - Professor Anne Thomas
Professor of Cancer Therapeutics and Consultant in Medical Oncology
Cancer Chemotherapy
Professor Anne Thomas
Professor of Cancer Therapeutics and Consultant in Medical Oncology
“I’m director of Leicester Cancer Research Centre here. 50 mins to tell you about chemotherapy which is quite unrealistic – so will pick out key concepts - but don’t lose these notes! So when they ask how much do you know about chemo later on - everything is in the lecture – so this is your basis, and you’ve also got standard textbooks such as Kumar and Clark often have a v good section on chemotherapy as well.”
2 - Learning Objectives
Learning Objectives
After this session you should be able to:
• Describe relevance of DNA structure and cell cycle to chemotherapy
• Understand how different classes of chemotherapy affect cancer cells
• Describe some common side effects of chemotherapy
• Apply pharmacokinetic principles to chemotherapy
• Understand clinical monitoring required
• Appreciate how clinical trials are used in getting new drugs from the laboratory to the clinic
3 - Lecture overview
Lecture overview • Background • Mechanism of action • Pharmacokinetics and pharmacodynamics* • Clinical indications : first principles • Side effects of chemotherapy • Drug interactions • Drug monitoring • Importance of Clinical Trials
4 - How did we find out about chemotherapy?
Mustard Gas
In 1940s investigators used nitrogen mustard to treat lymphoma
Serendipity
Cisplatin
Microbiological experiments passing electric currents through E coli
Platinum electrodes stopped E coli growth
Platinum complex found to be responsible
Screening of compounds
As part of that program extract from the sea squirt Ecteinascidia turbinata
Chemical engineering
Paclitaxel discovered in 1967
Tubulin poison
Pacific Yew stem bark
“So, how did we find out about chemotherapy? – Well a bit like the antibiotics, some of it was purely by chance, experiments were done using platinum electrodes, actually these were looking at experimetns, understanding, how can you kill E. coli? And the E. coli died, and they realised it was due to the platinum within the electrodes. So Sometimes it’s pure luck, just like penicillin.
SOmetimes there’s an agent that you know causes toxic harm – and so it was noticed in WW2 that mustard gas that was used actually caused profound drop in WBCs – mustine is a chemotherapy drug developed from that observation.
We’ve actually screened compounds: NCRI (national cancer institute in US) – actually had a big programme back in the 1960s where they looked at all the most venomous things they can find virtually – they found a particularly noxious creature – reliably told by Google this is a sea squirt – identified that it produced a really unpleasant poison – caused a significant neuropathy, and that’s why the actual sea squirt could paralyse its prey. When they worked on this they found out what was the active moiety, and believe it or not, that is now used in chemotherapy agent called Trabectedin used to treat pts with sarcoma in the clinic? Sounds bizarre but sometimes screening compounds will be accurate.
More laterally, moved onto chemical engineering – good example is Paclitaxel back in 1960s, only found in bark of Pacific Yew, only found in certain parts of the world – horrendously expensive to use – started the term post code lottery, i.e. people’s access to drugs on the NHS – luckily now, they’ve actually managed to chemically engineer the drug so we can mass produce it and it’s much cheaper.”
5 - Imatinib
Molecular targeting approaches: Imatinib (STI571, Glivec) a Bcr-Abl tyrosine kinase inhibitor
• Magic bullet
• Rationally designed targets and inhibitors
• Tumour selective
• More efficacious
• Fewer side effects
“But of course, we’re now Much much more rational in our new drug development – in this day and age we’re moving v much to targeted agents rather than chemotherapy. So a clinic this morning, I’ve been Treating pts with a rare form of gastric cancer – called a gastrointestinal stromal tumour. Now 15 yrs ago, I only could use chemotherapy and the outcomes were terrible - would only work in ~5% of people originally. Now, some really clever scientists in the US, decided that If you took a particular disease that had a signature that was absolutely pathognomic (pronounced pathomnemonic) i.e. just seen in that disease – could you target that and get a better/more effective response. And so the First drug developed from this sort of approach was developing imatinib. Now it was Developed for chronic myeloid leukaemia. So CML is a condition where you have one particular abnormal genetic pathway which produces a particular protein – and if you look at the receptor you can actually use an agent to actually block the catalytic part of the receptor: so you’re not actually able to transmit the signals down to fuel the CML cells. And in fact we know that this particular receptor is also actually quite important in GI stromal pts. So I was seeing pts this morning who have been treated with imatinib, and One pt in particular first started treating in 2003, and here he was, right as rain, coming into my clinic – so we’ve made fantastic advances with targeted chemotherapy. But I have to talk about just standard chemotherapy now.”
6 - STRUCTURE OF DNA
STRUCTURE OF DNA Nucleotide = sugar-phosphate-base DNA = double helix of nucleotides Purines = Adenine & Guanine Pyridimines = Cytosine & Thymine (Uracil in RNA)
AT TA CG TA etc. - sugar-phosphate backbone
“We all know that DNA, you have this double helix, and what’s really important in DNA replication – you have DNA the double helix, it will unwind and get daughter identical DNA helixes forming at the replication fork – so go back and just remind yourself at tx and translation etc. bc it’s going to be key to understanding how chemo works.”
7 - TUMOUR GROWTH
TUMOUR GROWTH
- growth fraction
- duration of cell cycle
- rate of cell loss
y-axis: 10^9 10^12 number of cancer cells
x-axis: time
undetectable cancer -limit of clinical detection detectable cancer -host death Exponential tumour growth diagnostic threshold (1cm)
“We also know that when you’re looking at your cancer cells in the body they are actually growing at exponential rate – what’s scary is limit of clinical detection, is when you have 10^9 cancer cells in the body – equivalent to 1 cm3 volume. You Only needto go up to 1012 cancer cells and that is no longer compatible with life. So we’ve actually got quite a short window of opportunity to get in there with cancer treatments, so this is why at the moment when you look at the media and medical media there is a lot about early diagnosis – because if we can actually find a cancer with cells at this level, you stand a far better chance of actually curing it.”
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