Overview of Cancer Chemotherapy Flashcards
What is cancer?
Neoplasia - “New growth”
Uncontrolled proliferation of abnormal forms of the body’s own cells
What characteristics are seen in cancer cells that are not seen in normal cells?
1) Uncontrolled proliferation
2) Invasiveness
3) Metastases
What are the causes of cancer?
1) Mutations in DNA resulting in production of altered cells which have changes in proliferating mechanisms
2) Changes in the DNA caused by covalent modification
• Spontaneous or genetic predisposition
• Ionising radiation or UV radiation
• Chemical carcinogens
What are the three main ways to dealing with established cancers?
- 1) Surgical excision
- 2) Radiotherapy
- 3) Chemotherapy
What are the four types of traditional agent to deal with cancer?
- Alkylating agents
- Antimetabolites
- Cytotoxic antibiotics
- Plant derivatives
What are alkylating agents?
• Most commonly employed anti cancer drugs
• These are compounds which have the property of forming covalent bonds
with suitable nucleophillic substances in the cell under physiological conditions.
• Intrastrand crosslinking of DNA
How do alkylating agents work?
- Normally guanine residues in DNA exist predominantly in the keto tautomer
- This allows them to readily make Watson-Crick base pairs by hydrogen bonding with cytosine
- When the 7 nitrogen of guanine is alkylated it becomes more acidic and the enol tautomer is formed. (i.e. keto to enol)
- This modified guanine can mispair with thymine residues during DNA synthesis. i.e. G-T not G-C, creating a mutation.
- Also, alkylation of the 7 nitrogen destabilises the imidazole ring
- Opening of the imidazole ring (ring-cleavage)
- Depurination-excision of guanine residues and repair of DNA – opportunity for mutation
- The resulting damage to DNA by alkylating agents triggers cell death by apoptosis.
What are the major groups of alkylating agents?
1) Nitrogen mustards – e.g. cyclophosphamide
2) Ethylenimines - e.g. Thiotepa
3) Alkylsulphonates - e.g. Busulphan
4) Hydrazines and Triazines – e.g. Temozolomide
5) Nitrosoureas – e.g. lomustine, carmustine
6) Platinum based compounds – e.g. cisplatin
How does the nitrogen mustard cyclophosphamide work?
- Cyclophosphamide activated in liver by P450 mixed function oxidases
- Aldophosphamide transported to other tissues where it forms phosphoramide (cytotoxic)
- Mesna counteracts effects of acrolein (haemorrhagic cystitis)
How does the alkylsuphonate busulphan work?
• Busulphan has a selective effect on the bone marrow, depressing the formation of granulocytes and platelets in low dosage and red cells in higher dosage. It has little or no effect on lymphoid tissue or the gastrointestinal tract. It is used in chronic granulocytic leukaemia.
How do the notrosoureas lomustine and carmustine work?
• Nitrosoureas; Lomustine and Carmustine because they are lipid soluble and can, therefore, cross the blood-brain barrier, may be used against tumours of the brain and meninges
How do the platinum based components like cisplatin work?
- Cisplatin is a water-soluble planar coordination complex containing a central platinum atom surrounded by two chlorine atoms and two ammonia groups.
- Its action is analogous to that of the alkylating agents. When it enters the cell, Cl- dissociates leaving a reactive complex that reacts with water and then interacts with DNA.
- It causes intrastrand cross-linking- probably between N7 and O6 of adjacent guanine molecules-which results in local denaturation of the DNA chain.
What are the major groups of antimetabolites?
1) Antifolates – e.g. methotrexate
2) Antipyrimidines – e.g. 5-FU, gemcitabine
3) Antipurines – e.g. mercaptopurine, thioguanine
Discuss methotrexate
Antifolate
• Folate analogue
• Usually given orally but can also be given
intramuscularly, IV or intrathecally.
• Low lipid solubility so does not cross the blood brain barrier easily.
• Polyglutamated which means it can be retained within cells for weeks.
Discuss antipyrimidines
- Fluorouracil (5-FU) interferes with thymidylate synthesis (DTMP).
- It is converted into a fraudulent nucleotide FDUMP. Cannot be converted into DTMP.
- Cytarabine is an analogue of cytosine but has arabinose and not ribose attached.
- Undergoes phosphorylation to give cytosine arabinoside triphosphate.
- This inhibits DNA polymerase.
- Gemcitabine is an analogue of cytarabine.
Discuss antipurines
- Mercaptopurine, thioguanine, fludarabine
- Mercaptopurine is converted to 6- mercaptopurine-ribose phosphate, called “Lethal Synthesis”.
- 6 mercaptopurine-ribose-phosphate inhibits a number of enzymes in the de novo synthesis of purines. Fraudulant nucleotide
- Fludarabine in its triphosphate form inhibits DNA polymerase.
What metabolite is fludarabine related to?
Adenosine
What metabolite is 5-FU related to?
Uracil
What metabolite is gemcitabine related to?
Deoxycytidine - component of DNA
What metabolite is 6-mercaptopurine related to?
Purine
What is the difference between fludarabine and its metabolite?
F replaces H of adenosine and arabinose replaces
ribose
What is the difference between 5-FU and its metabolite?
F replaces H of
uracil
What is the difference between gemcitabine and its metabolite?
F replaces H
and OH on ribose ring
What is the difference between 6-mercaptopurine and its metabolite?
S substitute
In purine
What are cytotoxic antibiotics?
• Antitumour antibiotics produce their effects
mainly by direct action on DNA.
- Anthracyclines - e.g. doxorubicin.
- Dactinomycin
- Bleomycin
- Mitomycin
Discuss anthracyclines
- The main anticancer anthracycline antibiotic is doxorubicin. Others are daunorubicin, idarubicin, epirubicin, aclarubicin, and mitoxantrone (mitozantrone).
- It binds to DNA and inhibits both DNA and RNA synthesis
- Its main cytotoxic action appears to be mediated through an effect on topoisomerase II the activity of which is markedly increased in proliferating cells.
How does doxorubicin work?
- During replication of the DNA helix, reversible swivelling needs to take place around the replication fork in order to prevent the daughter DNA molecule becoming inextricably entangled during mitotic segregation.
- The swivel is produced by topoisomerase II, which nicks both DNA strands and subsequently reseals the breaks.
- Doxorubicin intercalates in the DNA and its effect is to stabilise the DNA-topoisomerase II complex after the strands have been nicked, thus causing the process to seize up at this point.
How does dactinomycin work?
- Dactinomycin intercalates in the minor groove of DNA between adjacent guanosine- cytosine pairs, interfering with the movement of RNA polymerase along the gene and thus preventing transcription.
- There is also evidence that it has a similar action to the anthracyclines on topoisomerase II.
How do bleomycins work
- The bleomycins are a group of metal-chelating glycopeptide antibiotics that degrade preformed DNA, causing chain fragmentation and release of free bases.
- Their action on DNA is thought to involve chelation of ferrous iron and interaction with oxygen, resulting in the oxidation of the iron and generation of superoxide and/or hydroxyl radicals.
- Bleomycin is most effective in the G2 phase of the cell cycle and mitosis, but it is also active against non-dividing cells
How does mitomycin work?
- Mitomycin, after enzymic activation in the cells, functions as a bifunctional alkylating agent, alkylating preferentially at O6 of guanine.
- It cross-links DNA and may also degrade DNA through the generation of free radicals.
What are some plant derivatives used to treat cancer?
- Spindle poisons – affect microtubule function and prevent mitotic spindle formation
- Vinca alkaloids, e.g.Vincristine, vinblastine
- Taxanes - Paclitaxcel (taxol), docetaxel
- Camptothecins e.g. irinotecan
- Etoposide
How do vinca alkaloids, e.g.Vincristine, vinblastine work?
Bind tubulin and prevent polymerisation into microtubules
How do taxanes - paclitaxel (taxol), docetaxel work?
They stabilise (freeze) microtubules
How do camptothecins, e.g. irinotecan work?
They bind to and inhibit topoisomerase I
How does etoposide work?
Inhibits mitochondrial function, nucleoside transport and topoisomerase II
Name some ‘other’ types of anticancer drugs
- Hormones (hormone inhibitors)
- Monoclonal antibodies
- Protein kinase inhibitors
- Miscellaneous agents
What are the main drawbacks of chemotherapy of cancer
?
- Target cell proliferation not the more lethal properties of invasiveness and metastasis
- Non-specific cell killers rather than being aimed at the particular changes which make a cell malignant
- The development of resistance (particularly multidrug resistance) to anticancer drugs
- Leaves some remaining cells
- Healthy cells which have a high rate of growth and multiplication include cells of the bone marrow, hair, GI mucosa and skin therefore side-effects often relate to these body systems
- Severity of side effects varies between drugs – the summary of product characteristics (SPC) can be referred to on the eMC website for details on specific side-effects of each drug. https://www.medicines.org.uk/emc
- May be drug specific e.g. anthracyclines and cardiotoxicity; vinca alkaloids and neuropathy; high dose cisplatin and ototoxicity
- Side effects often occur 7-14 days post treatment. These can be cumulative over many cycles
• Patient compliance due to side-effects Not completing the therapy regimen
What is tumour lysis syndrome?
- An acute side-effect and a metabolic emergency
- Occurs due to rapid cell lysis (death) & large amounts of cell metabolites in blood.
- It is characterized by hyperuricaemia, hyperphosphataemia, hyperkalaemia and hypocalcaemia
- If untreated can lead to acute renal failure, cardiac arrest and death.
- Risk assess patient prior to chemotherapy
- Monitor and respond to deranged urea and electrolytes / fluid balance: dialysis may be required
What are some specific side effects of anticancer drugs related to the bone marrow?
- Myelosuppression – reduced production of cells which provide immunity, oxygen transport and clotting common with many chemotherapy agents (except Vincristine and Bleomycin)
- Only actively dividing cells in the bone marrow are affected (i.e. stem cells)
- Monitor full blood count prior to then daily during treatment cycles
- Occasional use of recombinant human granulocyte-colony stimulating factors (e.g. Filgrastim) recommended to reduce incidence/duration of myelosupression
- Cells with shorter life span are more affected
What are some specific side effects of anticancer drugs related to the GI tract?
- Nausea & Vomiting
- Loss of appetite
- Constipation
- Diarrhoea
- Ulceration, dry mouth, pain, taste alterations
Discuss Nausea and vomiting as a side effect of anticancer drugs in the GI tract
• Chemotherapy agents vary in their emetogenic potential:
Highly emetogenic – cisplatin
Moderately emetogenic – doxorubicin
Mildly emetogenic – etoposide
• Treatment choices vary between pretreatment with low dose benzodiazepine (e.g. lorazepam), use of steroids (e.g. dexamethasone) and use of anti-emetics such as the 5HT3-receptor antagonists (e.g. ondansetron or metoclopramide).
Discuss constipation as a side effect of anticancer drugs in the GI tract
- Due to reduction in gastric motility, reduced fluid intake and activity, side-effects of concurrent anti-emetics e.g. granisetron.
- Management – add laxatives
Discuss diarrhoea as a side effect of anticancer drugs in the GI tract
- can cause severe dehydration and electrolyte disturbances
- Manage by stopping oral chemo
- May need to give IV fluid support
- Consider adding anti-diarrhoeal e.g. loperamide
Discuss ulceration, dry mouth, pain, taste alterations as a side effect of anticancer drugs in the GI tract
This specific side effect is known as Mucositis
- Prevention and management:
- Assess the oral cavity regularly
- Encourage good oral hygiene and regular dental visits
- Anti-bacterials and anti-virals
What is Ulceration, dry mouth, pain, taste alterations as a side effect of anticancer medication known as?
Mucositis
What are some non GI Bone marrow or tumour lysis related side effects of anticancer drugs?
- Fatigue: Often multi-factorial, treat cause if known, involve physio/occupational therapists in care
- Body image side-effects – hair loss, weight loss/gain, appearance of intervention wounds
- Peripheral neuropathy – counsel patient about need for care if injured, consider analgesia for nerve pain
- Altered renal function – care with drug choices, doses and frequency
- Delayed effects: infertility, secondary malignancy
Name a novel drug from the ProGEM1 study
Acelarin (Gemcitabine analogue)
