Lecture 26- Chemotherapy Flashcards
where do chemotherapy agents come from
- mustard gas
- serendipity= chance
- chemical engineering
- screening of compounds
new approaches to chemotherapy
molecular targeting e.g. imatinib
imatinib
- a Bcr-Abl tyrosine kinase inhibitor
- Magic bullet
- Rationally designed targets and inhibitors
- Tumour selective
- More efficacious
- Fewer side effects
- Tumour selective
describe DNA
double helix of nucleotides
- purines - adenosine and guanine
- pyridimines- cytosine and thymine (uracil in RNA)
nucleotides are
sugar-phosphate-base
nucleoside
same as nucleotide without phosphate
DNA replication involves
transcription- DNA conversion to RNA
translation- RNA conversion to amino acids which code for protein
transcription summary
RNA polymerase
The main enzyme involved in transcription is RNA polymerase, which uses a single-stranded DNA template to synthesize a complementary strand of RNA. Specifically, RNA polymerase builds an RNA strand in the 5’ to 3’ direction, adding each new nucleotide to the 3’ end of the strand.
Stages of transcription
Transcription of a gene takes place in three stages: initiation, elongation, and termination.
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Initiation. RNA polymerase binds to a sequence of DNA called the promoter, found near the beginning of a gene. Each gene (or group of co-transcribed genes, in bacteria) has its own promoter. Once bound, RNA polymerase separates the DNA strands, providing the single-stranded template needed for transcription.
- The promoter region comes before (and slightly overlaps with) the transcribed region whose transcription it specifies. It contains recognition sites for RNA polymerase or its helper proteins to bind to. The DNA opens up in the promoter region so that RNA polymerase can begin transcription.
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Elongation. One strand of DNA, the template strand, acts as a template for RNA polymerase. As it “reads” this template one base at a time, the polymerase builds an RNA molecule out of complementary nucleotides, making a chain that grows from 5’ to 3’. The RNA transcript carries the same information as the non-template (coding) strand of DNA, but it contains the base uracil (U) instead of thymine (T).
- RNA polymerase synthesizes an RNA transcript complementary to the DNA template strand in the 5’ to 3’ direction. It moves forward along the template strand in the 3’ to 5’ direction, opening the DNA double helix as it goes. The synthesized RNA only remains bound to the template strand for a short while, then exits the polymerase as a dangling string, allowing the DNA to close back up and form a double helix.
-
Termination. Sequences called terminators signal that the RNA transcript is complete. Once they are transcribed, they cause the transcript to be released from the RNA polymerase. An example of a termination mechanism involving formation of a hairpin in the RNA is shown below.
- The terminator DNA encodes a region of RNA that forms a hairpin structure followed by a string of U nucleotides. The hairpin structure in the transcript causes the RNA polymerase to stall. The U nucleotides that come after the hairpin form weak bonds with the A nucleotides of the DNA template, allowing the transcript to separate from the template and ending transcription.
translation summary
Steps of translation
Your cells are making new proteins every second of the day. And each of those proteins must contain the right set of amino acids, linked together in just the right order. That may sound like a challenging task, but luckily, your cells (along with those of other animals, plants, and bacteria) are up to the job.
- Initiation
In initiation, the ribosome assembles around the mRNA to be read and the first tRNA (carrying the amino acid methionine, which matches the start codon, AUG). This setup, called the initiation complex, is needed in order for translation to get started.
2. Elongation
Elongation is the stage where the amino acid chain gets longer. In elongation, the mRNA is read one codon at a time, and the amino acid matching each codon is added to a growing protein chain.
Each time a new codon is exposed:
- A matching tRNA binds to the codon
- The existing amino acid chain (polypeptide) is linked onto the amino acid of the tRNA via a chemical reaction
- The mRNA is shifted one codon over in the ribosome, exposing a new codon for reading
Elongation has three stages:
1) The anticodon of an incoming tRNA pairs with the mRNA codon exposed in the A site.
2) A peptide bond is formed between the new amino acid (in the A site) and the previously-added amino acid (in the P site), transferring the polypeptide from the P site to the A site.
3) The ribosome moves one codon down on the mRNA. The tRNA in the A site (carrying the polypeptide) shifts to the P site. The tRNA in the P site shifts to the E site and exits the ribosome.
During elongation, tRNAs move through the A, P, and E sites of the ribosome, as shown above. This process repeats many times as new codons are read and new amino acids are added to the chain.
For more details on the steps of elongation, see the stages of translation article.
3. Termination
Termination is the stage in which the finished polypeptide chain is released. It begins when a stop codon (UAG, UAA, or UGA) enters the ribosome, triggering a series of events that separate the chain from its tRNA and allow it to drift out of the ribosome.
After termination, the polypeptide may still need to fold into the right 3D shape, undergo processing (such as the removal of amino acids), get shipped to the right place in the cell, or combine with other polypeptides before it can do its job as a functional protein.
cell cycle
growth fraction =
- “proportion of cells dividing at any given time.”
- Useful indicator of sensitivity to chemotherapeutic agents.
- The larger the growth fraction, the more responsive the tumours are
- Tumours are heterogeneous with respect to cell division some cells proliferating, others dying or lying dormant therefore repeated cycles are required to eradicate remaining and re-growing cells
different tumours can be classified according to
chemosensitivity
The larger the growth fraction, the
more responsive the tumours are to chemotherapy
In the early stages when tumour volume is low growth fraction is
high
- Adjuvant chemotherapy is given on this basis- to eradicate micrometastasis.
The bigger the tumour, the
smaller the growth fraction.
A smaller growth fraction means less actively dividing cells to be targeted by the chemotherapy.
The fractional kill hypothesis states
that a defined chemotherapy concentration, applied for a defined time period, will kill a constant fraction of the cells in a population, independent of the absolute number of cells
Site of action of cytotoxic agents
- Antimetabolites
- alkylating egents
- interclating agents
- spindle poisons
antimetabolites target
DNA synthesis
alkylating agents target
DNA
Intercalating agents target
DNA transcription and duplication
spindle poisons target
microtubules
name three alkylating agent
Carmustine (BCNU)
Alkylating compounds under the class Platinum compounds:
- Cisplatin
- Oxaliplatin
name two Spindle poisons e.g. Microtubule-binding agents
Vinca alkaloids
Taxanes
name 2 antimetabolites
- methotrexate
- 5-flourouracil
carmustine (BCNU) is an
alkylating agent
carmustine uses
chemotherapy e.g. lymphoma
MOA of carmustine
- Alkyl groups on the drug can form covalent bonds with the cell constituents
- Reactive intermediate is the carbonium ion (A carbon atom with only 6 electrons in its outer shell)
- Many have 2 alkylating groups so can form cross links leading to defective DNA replication
- Not phase specific
carmustine emchanism of resistance
- decreased entry or increased exit of agent
- inactivation of agent in cell
- enhanced repair of DNA lesions produced by alkylation
cisplatin and oxaliplatin are
platinum compounds (still alkylating agents)
uses of cisplatin and oxaliplatin
cancer e.g. ovarian cancer, testicular cancer, and bladder carcinoma
MOA of cisplatin and oxalplatin
- Formation of platinated inter- and intrastrand adducts, leading to inhibition of DNA synthesis
- DACH platinum adducts are bulky and thought to be more effective in inhibiting DNA synthesis than platinum adducts – Oxaliplatin
methotrexate and 5-flourouracil are both
antimetabolites and target DNA synthesis
MOA of 5-fluorouracil
- 5-FU is converted to fluorodeoxyuridine monophosphate (FdUMP)
- FdUMP forms a stable complex with thymidylate synthase (TS), and thus inhibits deoxythymidine mono-phosphate (dTMP) production.
- dTMP is essential for DNA replication and repair and its depletion therefore causes cytotoxicity
methotrexate MOA
- methotrexate competitively inhibits dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis.
- The affinity of methotrexate for DHFR is about 1000-fold that of folate. DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate.
- Folic acid is needed for the de novo synthesis of the nucleoside thymidine, required for DNA synthesis.
- Also, folate is essential for purine and pyrimidine base biosynthesis, so synthesis will be inhibited.
- Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins
methotrexate used to treat both
Cancer and rheumatoid arthritis
vinca alkaloids and taxanes are
Spindle poisons e.g. Microtubule-binding agents (disrupt microtubule dynamics)
Spindle poisons e.g. Microtubule-binding agents (disrupt microtubule dynamics) MOA
- inhibits polymerisation
- stimulate polymerisation and prevent depolymerisation
Side effects of chemotherapy
Down to the chemo targeting rapidly dividing cells
Vomiting
- Multifactorial but includes direct action of chemotherapy drugs on the central chemoreceptor trigger zone
- Patterns of emesis
- acute phase 4 - 12 hours
- delayed onset, 2 - 5 days later
- chronic phase, may persist up to 14 days
Alopecia
- Hair thins at 2 - 3 weeks
- May be total
- May re-grow during therapy
- Marked with doxorubicin, vinca alkaloids, cyclophosphamide
- Minimal with platinums
- Help sometimes with scalp cooling
Skin Toxicity
-
Local
- Irritation and thrombophlebitis of veins
- Extravasation
-
General
- Bleomycin
- Hyperkeratosis
- Hyperpigmentation
- ulcerated pressure sores
- Busulphan, doxorubicin, cyclophosphamide, actinomycin D
- Hyperpigmentation
- Bleomycin
Mucositis
- Gastrointestinal tract epithelial damage
- May be profound and involve whole tract
- Most commonly worst in oropharynx
- Presents as
- sore mouth/throat
- diarrhoea
- G.I. bleed
Cardio-Toxicity
Cardio-myopathy
- doxorubicin ++ (> 550 mg/m2)
- high dose cyclophosphamide – mortality approx. 50%
Arrhythmias
- cyclophosphamide
- etoposide
Lung Toxicity
- Bleomycin
- pulmonary fibrosis
- beware concurrent radiotherapy
- Mitomycin C, cyclophosphamide, melphalan, chlorambucil
- pulmonary fibrosis
Haematological Toxicity of Cancer Therapy
*
- Most frequent dose limiting toxicity
- Most frequent cause of death from toxicity
- Different agents cause variable effects on degree and lineages
- Neutrophils
- Platelet
- Erythrocytes
chemotherapys increase risk for infections
- chemotherapy kills fastest growing cells e.g. WBC
- neutropenia makes your body more vulnerable to infection
specific toxicities
Clinical indications of chemotherapy
- May seem obvious…. Cancer
- but aim is very different in different malignancies
- predicted response is also different within the same cancer based on:
- performance score
- clinical stage
- prognostic factors or score (often involving biological factors)
- Molecular or cytogenetic markers
- Side effects vs anticipated or best outcome
Chemotherapy – route of administration
- For many types of cancer, chemotherapy regimen will consist of a number of different drugs - combination chemotherapy – usually an acronym eg CHOP, FOLFOX
- Routes of administration:
- IV is the most common – bolus, infusional bag, continuous pump infusion
- PO convenient, dependent on oral bioavailability
- SC convenient in community setting
- Into a body cavity – bladder, pleural effusion
- Intralesional - directly into a cancerous area – consider pH
- Intrathecal - into the CSF – by lumbar puncture
- Topical -medication will be applied onto the skin
- IM rarely
Chemotherapy adverse effects – those due to effect of treatment on the tumour
- Acute renal failure - often multifactorial – hyperuricaemia caused by rapid tumour lysis leads to precipitation of urate crystals in renal tubules
- GI perforation at site of tumour – reported in lymphoma
- Disseminated intravascular coagulopathy eg onset within a few hours of starting treatment for acute myeloid leukaemia
Pharmacokinetics and chemotherapy
What causes variability?
- Abnormalities in absorption
- N+V, compliance, gut problems
- Abnormalities in distribution
- Weight loss, reduced body fat, ascites etc
- Abnormalities in elimination
- Liver and renal dysfunction, other meds
- Abnormalities in protein binding
- Low alb, other drugs
Chemotherapy - important drug interactions
- Other drugs may increase plasma levels of the chemotherapy drug (and therefore side effects)
- Vincristine and itraconazole (a commonly used antifungal) leads to more neuropathy
- Capecitabine (oral 5FU) and warfarin
- Methotrexate – caution with prescribing penicillin, NSAIDs
- Capecitabine and St Johns Wort, grapefruit juice
Monitoring during treatment
*
- Response of the cancer
- Radiological imaging
- Tumour marker blood tests
- Bone marrow/cytogenetics
- Drug levels
- Eg Methotrexate drug assays taken on serial days to ensure clearance from the blood after folinic acid rescue
- Checks for organ damage
- Creatinine clearance
- Echocardiogram
Chemotherapy is the treatment
of cancer with drug therapy – traditionally this applies to cytotoxic drugs
- Over the years more classes of drugs have been introduced to treat cancer..
- Hormones
- Now… targeted drug therapy
targeted drug therapy e.g.
Chemotherapy: cytotoxic drugs
Considered ‘dangerous’ drugs, need specialists to prescribe because:
- Narrow therapeutic indices
- Significant side effect profile
- Dose needs to be altered for the individual patient based on :
- their surface area and/or body mass index
- drug handling ability (eg liver function, renal function… dependent on the metabolism and excretion routes)
- general wellbeing (performance status and comorbidity)
-
Treatment phasing needs to take into account the balance between:
- growth fraction
- the ‘cell kill’ of each cycle of the chemotherapy regimen
- marrow and GI tract recovery before next cycle
- how tolerable is the regimen – both short term organ toxicity and physical side effects and long term damage causing late effects
- Hence…weigh up the role and dose of chemotherapy for every cancer patient individually and always remember the aim of the treatment
