13.2 Cancer Chemotherapy Flashcards
What are the different methods used in discovering new chemotherapy drugs?
Screening of compounds
Chemical engineering
Serendipity
Molecular engineering - most used now
What is imatinib used to treat?
Chronic myeloid leukaemia
How does imatinib work?
Designed as a small molecule inhibitor for a particular target
The Philadelphia chromosome is a pathognomonic signature of chronic myeloid leukaemia.
The Philadelphia chromosome is responsible for forming the BRC-Abl fusion protein. This protein provides the energy for the CML cells to proliferate.
Imatinib sits in the catalytic pocket of the BRC-Abl fusion protein receptor to inhibit the ATP generation and stopping the proliferation of CML cells.
What are the advantages of molecular targeting approaches?
More tumour selective
More efficacious
Fewer side effects
What is the structure of DNA?
Nucleotides form bases that are held together in the correct order by the sugar-phosphate backbone of DNA. The structure is a double helix
What are the different types of nucleotide bases?
Purines = Adenine & Guanine Pyridimines = Cytosine & Thymine (Uracil in RNA)
Describe the process of DNA replication
- one of the DNA strands are transcribing, and one is non-transcribing
- DNA helix unwinds
- messenger RNA is formed during transcription from the DNA molecule
- translation is RNA conversion to amino acids which code for protein
What is the length of the cell cycle in cancer cells?
Cell Proliferation variation in cycle 9-43hrs between cancer cells
What are the different stages in the cell cycle?
Mitosis
G1
S
G2
What occurs in the G1 stage of the cell cycle?
cell grows in size and synthesises mRNA and proteins
What occurs in the S phase of the cell replication cycle?
DNA synthesis
What occurs in the G2 phase of the cell replication cycle?
rapid cell growth and protein synthesis DNA checking
What is G0 in the cell replication cycle?
Dormant phase where there is no cell proliferation
What does the rate of tumour growth depend on?
The growth fraction (number of cells dividing at any one time)
Duration of the cell cycle
Rate of cell loss
How does growth fraction indicate the cancers sensitivity to chemotherapy?
The higher the growth factor the more sensitive the tumour is likely to be to chemotherapy
Why are repeated cycles of chemotherapy necessary?
As Tumours are heterogeneous with respect to cell division. Some cells are proliferating, others dying or lying dormant. Therefore repeated cycles are required to eradicate remaining and re-growing cells.
What is the fractional cell kill hypothesis?
- A given dose kills a constant PROPORTION of a tumour cell population (rather than a constant NUMBER of cells). First order kinetics
- Repeated doses are required
- Frequency and duration of treatment limited by toxicities to patient
What cancers often have high Growth fractions?
90% in certain leukaemias and lymphomas
How is the growth fraction of a tumour dependent on size?
In the early stages when tumour volume is low growthfraction is high. Adjuvant chemotherapy is given on this
basis.
The bigger the tumour, the smaller the growth fraction. A smaller growth fraction means less actively dividing cells to be targeted by the chemotherapy.
What tumours are highly sensitive to chemotherapy?
Lymphomas
Germ cell tumours
Small cell lung Neuroblastoma
Wilm’s tumour
What tumours are modestly sensitive to chemotherapy?
Breast Colorectal Bladder Ovary Cervix
What tumours have low sensitivity to chemotherapy?
Prostate
Renal cell
Brain tumours
Endometrial
How do antimetabolites work?
By targetting DNA synthesis
How do alkylating agents work?
By stopping DNA replication
How do intercalated agents work?
By stopping DNA transcription and DNA duplication
How to spindle poisons work?
Work by targetting mitosis
Give an example of an alkylating agent
Carmustine
Describe the mechanism of action of carmustine
Alkyl groups on the drug react with electron rich atoms to form covalent bonds
Reactive intermediate is the carbonium ion
Carmustine has 2 alkylating groups so that it can form cross links with both strands of DNA leading to defective DNA replication
Cell dies as DNA replication doesn’t happen
How does cisplatin work?
Forms covalent bonds via platinated inter and intrastrand adduct.
Why is oxaliplatin more effective in treating tumours than cisplatin?
As oxaliplatin has a bulky side chain group, making it hard for the repair processes to ligate this group out. As cisplatin does not have this bulky side group chain, it can be more easily removed by DNA repair mechanisms
Give some examples of antimetabolite chemotherapy agents?
Methotrexate
5-fluorouracil
Describe the mechanism of action of 5-fluorouracil
5-FU acts as a thymidylate synthase inhibitor. Thymidylate synthase methylates the deoxyuridine monophosphate to form thymidine monophosphate.
Causes a deficiency in thymidine monophosphate and therefore stops the formation of DNA
What is the mechanism of action of methotrexate?
Competitively inhibits dihydrofolate reductase, a critical enzyme within the folate cycle. Inhibition of dihydrofolate reductase inhibits the formation of purines and therefore DNA synthesis
What is the role of spindle fibres during mitosis?
Once chromosomes are aligned at metaphase plate, spindle microtubules depolymerize, moving sister chromatids toward opposite poles during anaphase.
What occurs during telophase?
Nuclear membrane reforms and cytoplasm divides
What are the 2 different groups of spindle poisons?
Vinca alkaloids
Taxanes
How do spindle poisons broadly work?
By causing the polymerisation of the microtubules.
Vinca alkaloids - prevent spindle formation
Taxanes - promote the assembly and prevent the disassembly
What are the 3 different mechanisms of resistance of tumour cells?
- Decreased entry or increased exit of agent (different pumps on the cell membrane)
- Inactivating the agent in the cell.
- Enhances repair of DNA lesions produced by alkylation and intercalated gene agents
Why is there so many side effects to chemotherapy?
Impact of the drugs affecting rapidly dividing cells in the body
What are some of the common side effects of chemotherapy?
Mucositis (inflammation of the GI tract) Alopecia Pulmonary fibrosis Nausea and vomiting Cardiotoxicity Local reaction Renal failure Myelosuppression Phlebitis Neuropathy Myalgia Sterility Cystitis Diarrhoea
Why is vomiting a common side effect of chemotherapy?
Multifactorial but includes direct action of chemotherapy drugs on the central chemoreceptor trigger zone
What are the different patterns of emesis seen in chemotherapy patients?
– acute phase 4 - 12 hours (during the chemotherapy)
– delayed onset, 2 - 5 days later
– chronic phase, may persist up to 14 days
How does alopecia present in chemotherapy patients?
2-3 weeks following treatment
May be total loss over body
May regrow during therapy
Loss is dependant on the type of chemotherapy used.
Marked with doxorubicin, vinca alkaloids, cyclophosphamide
Minimal with platinums
What can we do to help reduce the chance of alopecia as a side effect of chemotherapy?
Scalp cooling
What skin toxicity is seen as a side effect of chemotherapy?
Local – Irritation and thrombophlebitis of veins – extravasation General – bleomycin • hyperkeratosis • hyperpigmentation • ulcerated pressure sores – busulphan, doxorubicin, cyclophosphamide, actinomycin D • Hyperpigmentation
What is extravasation?
When the flow of blood is forced out of a vessel and into the surrounding tissue.
In chemotherapy this is an oncological emergency as agent stays in local tissue, burns deeper tissue. Plastic surgery with a skin graft will be required.
How does mucositis present in chemotherapy?
• Gastrointestinal tract epithelial damage • May be profound and involve whole tract • Most commonly worst in oropharynx • Presents as – sore mouth/throat – diarrhoea (may be bloody) - dehydration and AKI - secondary infection (oral thrush) – G.I. bleed
What are the presentations of cardio-toxicity of chemotherapy agents?
• Cardio-myopathy
– doxorubicin ++ (> 550 mg/m2)
– high dose cyclophosphamide
– mortality approx. 50%
• Arrhythmias
– cyclophosphamide
– etoposide
Coronary artery spasm causing angina and MI
- 5FU
What is belong in most commonly used for?
To treat testicular tumours
What are the effects of lung toxicity seen due to chemotherapy?
• Bleomycin – pulmonary fibrosis – beware concurrent radiotherapy • Mitomycin C, cyclophosphamide, melphalan, chlorambucil – pulmonary fibrosis
What are the effects seen due to 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. This causes neutropenia sepsis, and cant fight off infections
– Platelets. Thrombocytopenia causing bleeding and bruising
– Erythrocytes. Causes anaemia
What are the main toxicities of cisplatin and carbonplatin?
Ototoxicity
Nephrotoxicity
What is the main toxicity of viscristine?
Peripheral neuropathy
What is the main toxicity of bleomycin and busulfan?
Pulmonary fibrosis
What are the main problems caused by the toxicity of trastuzumab and doxorubicin?
Cardiotoxicity
What is the main problems caused by the toxicity of cyclophosphamide?
Haemorrhagic cystitis
What are the main problems caused by the toxicity of methotrexate, 5FU and 6-MP?
Myelosuppression
What factors do we use to base the predicted response of a tumour on?
Type of malignancy
Performance score - level of activity a patient can manage
Clinical stage
Prognostic factors or score (often involving biological factors)
Molecular or cytogenic markers
Why do we tend to use a combination of therapies/ drugs during chemotherapy?
As it increases the activity as it uses a variety of different mechanisms of action, meaning cancer cells will have to have a combination of different mechanisms of resistance to overcome the variety of drugs
What are some of the disadvantages of combination therapy of chemotherapy?
Must ensure drugs have compatible side effects e.g. cant both cause myelosuppression.
Need to have non-overlapping side effects
What is the most common route of administration of chemotherapy agents?
IV - is the most common. CN be given as a bolus, infusional bag, continuous pump infusion
Give an example of IV pumps used in chemotherapy?
PICC line (peripherally inserted central catheter) Hickman line
Other than IV, what other routes of administration of chemo therapies can we use?
– 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
What causes variability of doses?
- Abnormalities in absorption (N+V, compliance, gut problems such as reaction to toxicity)
- Abnormalities in distribution (weight loss, reduced body fat, ascites, excess fluid needs draining)
- Abnormalities in elimination ( liver and renal dysfunction, other meds)
- Abnormalities in protein binding ( low albumin, other drugs)
What are the common drug drug interactions of chemotherapy?
– 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
What are some of the adverse effects that can be experiences due to the 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 as lymphoma can be giving the integrity of the gut wall.
• Disseminated intravascular coagulopathy eg onset within
a few hours of starting treatment for acute myeloid leukaemia
How do we monitor the response of the cancer to chemotherapy?
Radiological imaging
Tumour marker blood tests
Bone marrow / cytogenetics
Why is it necessary to measure chemotherapy drug levels?
To ensure they are being cleared
– Eg Methotrexate drug assays taken on serial days to ensure
clearance from the blood after folinic acid rescue
Why is it important to monitor creatinine clearance and do ECGs during chemotherapy treatment?
To monitor for organ damage ( kidneys and heart especially as commonly affected by chemotherapy drug toxicity)
Other than chemotherapy, what other drugs are used to treat cancer?
Hormones targeted drug therapy eg • Monoclonal antibodies • Drugs inhibiting angiogenesis • Drugs targeting gene expression • Signal Transduction inhibitors • Drugs interfering with the apoptotic pathways • Drugs interfering with cell cycle control • Cytokines • Immunotherapy
Why are specialists needed to prescribe chemotherapeutic drugs?
Due to narrow therapeutic index and 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)
What is neoadjuvant chemotherapy?
given before surgery or radiotherapy for the primary cancer
What is adjuvant chemotherapy?
Given after surgery to excise the primary cancer, aiming to reduce relapse risk e.g. breast cancer
What is palliative chemotherapy?
Chemotherapy used to treat current or anticipated symptoms without curative intent
What is primary chemotherapy?
1st line treatment of cancer.. In many
haematological cancers this will be with curative intent,
initially aiming for remission
What is salvage chemotherapy?
Chemotherapy used for relapsed disease
