Week 4 - Chemotherapy Drugs Flashcards
Name the stages in the cell cycle
M - mitosis G1 - gap one (G0 - cells no longer dividing) S phase - (DNA synthesis) G2 - gap two
What enzyme catalyses mitosis?
DNA polymerase
Which cells are fitted with a safety mechanism that if they end up in the wrong tissue they lose their survival signals and die?
Muscle cells
What are the different options for cancer treatment?
Surgery
Irradiation (radiotherapy)
Drug therapy (chemo)
Combination of above
What type of cells are most susceptible to cytotoxic drugs?
Dividing cells
What is the aim of chemotherapy?
To kill all malignant cells in the body
Why can’t you rely on the immune system to kill malignant cells?
Unable to recognise tumour cells as foreign because essentially they are normal cells
What cancer has a cell doubling time of 24 hours?
Burkitt’s lymphoma
Why are the effects of chemotherapy so toxic?
all rapidly dividing normal tissues are affected
What are the toxic effects of chemotherapy?
Bone marrow suppression Impaired wound healing Loss of hair Damage to GI epithelium (inc. mouth) Growth stunted (children) Reproductive system - sterility Teratogenicity - cause harm to foetus Bleeding/bruising due to lack of platelets/clotting factors N+V Kidney damage
What are the possible targets for anti-cancer drugs?
- hormonal regulation of tumour growth
- defective cell cycle controls
What are the classes of anti-cancer drugs?
- Cytotoxic (block DNA synthesis/ prevent cell division)
- Hormones -and their antagonists (suppress hormone secretion or inhibit their actions)
- Monoclonal antibodies (target specific cancer cells)
- Protein kinase inhibitors (block cell signalling pathways in rapidly dividing cells)
What causes cancer?
DNA mutation
What are the classes of alkylating agents?
Nitrogen mustards, nitrosoureas, busulphan, platinum compounds
How do alkylating agents work?
- target cells in S phase (DNA synth phase)
- form covalent bonds with DNA (cross linking) - prevent uncoiling –> inhibits replication
What are the side effects for prolonged use of alkylating agents?
- sterility (esp. men)
- higher risk of non-lymphocytic leukaemia (AML)
Name some nitrogen mustards
Cyclophosphamide, melphalan, chlorambucil, bendamustine, estramustine
What is estramustine and what is it often used in the treatment of?
A nitrogen mustard
-analogue of oestrogen so stops cell division and has a hormonal effect
-prostate cancer
How are nitrogen mustards administered?
IV only
-very reactive, often infused with large volumes of fluid
What is cyclophosphamide and how does it work?
- nitrogen mustard
- prodrug (can be administered orally -activated in liver to phosphoramide mustard and acrolein)
What is a well known side effect that can occur from cyclophosphamide?
Acrolein –> haemorrhagic cystitis (sudden onset of haematuria combined with bladder pain and irritative bladder symptoms)
What is a prodrug?
A biologically inactive compound which can be metabolised in the body to produce a drug
What are nitrosoureas? Name some examples
Alkylating agents
-lomustine (CCNU), carmustine (BCNU)
How do nitrosoureas work?
-highly lipophillic - cross b.b.b. -> CNS tumours
What is carmustine (BCNU), how is it administered and what does it treat?
- nitrosourea - alkylating agent
- given IV
- multiple myeloma, non-Hodgkin’s lymphomas, brain tumours e.g. glioblastomas
What is lomustine (CCNU), how is it administered and what does it treat?
- nitrosoureas - alkylating agent
- given orally
- Hodgkin’s disease resistant to conventional therapy, malignant melanoma and certain solid tumours
What is busulphan and what does it treat?
- alkylating agent
- selective for bone barrow - leukaemia treatment
What does procarbazine treat and what are its side effects?
-alkylating agent
- used to treat Hodgkin’s disease
- can cause hypersensitivity rash and inhibits MOA (monoamine oxidase)
What does trabectedin treat and what is a side effect?
-alkylating agent
- soft tissue (skin, adipose tissue, muscle) sarcoma and advanced ovarian cancer
- hepatotoxic
What class of drugs are platinum compounds? Name some examples
- alkylating agents
- cisplatin, carboplatin, oxaliplatin
What is cisplatin, how does it work, how is it administered and what is it used to treat?
-potent alkylator, platinum compound
- binds to RNA>DNA>protein
- binds to purine bases (e.g. G, A, U)
- resistance may develop -> DNA repair by DNA polymerase
- testicular/ovarian cancer - low levels of repair enzymes so more sensitive to drug, lung, cervical, bladder, head and neck
- given by slow IV injection/infusion
What are the side effects of cisplatin?
- very nephrotoxic - requires hydration/infusion
- causes severe N+V
- risk of tinnitus, peripheral neuropathy, hyperuricaemia (gout) and anaphylaxis
- numbness/tingling in hands and feet
- changes in taste
What is carboplatin, what does it treat and what are its side effects?
- platinum compound - alkylating agent
- derivative of cisplatin
- less side effects (can be given as out patient) but more myelotoxic (bone marrow suppression)
- advanced ovarian cancer and lung cancer
What is oxaliplatin and what is it used to treat?
- platinum compound -alkylating agent
- colorectal cancer (with fluorouracil and folinic acid)
What are the classes of antimetabolites?
Folate antagonists, pyrimidine analogues, purine analogues
What is folate essential for in the body?
DNA synthesis/cell division
Name a folate antagonist
Methotrexate
What is methotrexate and what is its mechanism of action?
- folate antagonist - antimetabolite
- inhibits dihydrofolate reductase
How can methotrexate be given?
Orally
IM
IV
Intrathecally - between bones of vertebrae
What is methotrexate used to treat?
Childhood acute lymphoblastic leukaemia
Choriocarcinoma
Non-Hodgkin’s lymphoma
A number of solid tumours
Explain about the complications of methotrexate
- low lipid solubility - doesn’t readily cross b.b.b.
- mostly excreted unchanged in urine - lower doses in patients with renal impairment
- NSAIDS can reduce excretion - increases toxicity
- tumour cells may develop resistance
What is methotrexate administered with in high doses and what effect does it have?
- given with folinic acid (folate derivative) at high doses
- given to rescue normal cells
What other disease apart from cancer is methotrexate used in?
Rheumatoid arthritis
-used to suppress immune system
Name some pyrimidine analogues and what group of drugs they come from
Antimetabolite
Fluorouracil
Capecitabine, cytarabine, gemcitabine
How do pyrimidine analogues work?
Compete with C and T bases which make up RNA and DNA - inhibits DNA synthesis
How are pyrimidine analogues given?
Parenterally - IV
-less well absorbed (orally) than methotrexate
When is fluorouracil commonly used?
- pyrimidine analogue -antimetabolite
- commonly used with folinic acid in advanced colorectal cancer
- may also be used topically for certain malignant and pre malignant skin lesions
Name some purine analogues and the group of drugs they are in
Antimetabolites
- fludarabine
- mercaptopurine, tioguanine, pentostatin
How do purine analogues work?
-compete with A and G - inhibit purine metabolism
What is tioguanine mainly used in the treatment of?
Leukaemia
Name some cytotoxic antibiotics
Doxorubicin, bleomycin
Dactinomycin, mitomycin
What is doxorubicin and what is its mechanism of action?
-cytotoxic antibiotic
- binds to DNA and inhibits DNA/RNA synthesis
- inhibits topoisomerase II (helps to swivel DNA when separating - so when inhibited DNA can’t replicate properly)
How are cytotoxic antibiotics administered and what precautions should be taken?
- IV infusion
- must be careful to avoid extravasation at injection site - causes local necrosis (make sure it goes in vein)
What are the side effects of doxorubicin?
-cardiac dysrhythmias, heart failure in high doses
What is bleomycin and what is its mechanism of action?
Cytotoxic antibiotic
- degrades pre-formed DNA
- active against non-dividing cells (G0 - useful feature)
What are the side effects of bleomycin?
- causes little myelosuppression but causes pulmonary fibrosis in 10% pts
- 50% pts develop mucocutaneous reactions (mouth sores, hair loss, fungal infections etc)
- hyperpyrexia
Name some plant derivatives
Vinca alkaloids: vincristine, vinblastine, vindesine
Taxanes: paclitaxel, docetaxel
Etoposide
What are vinca alkaloids and what is their mechanism of action and side effects?
Plant derivatives
- derived from Madagascar periwinkle
- prevent polymerisation of tubulin –> microtubules –> prevents spindle formation
- effects only occur during mitosis
-relatively non-toxic
(Except vincristine - neuromuscular effects)
What are taxanes and what is their mechanism of action and side effects?
Plant derivatives
- derived from bark of yew tree
- similar mechanism to vinca alkaloids (prevent polymerisation of tubulin–>microtubules–>prevents spindle formation
- treats adv. breast cancer
- paclitaxel/carboplatin - ovarian cancer
What is Etoposide, what is its mechanism of action and side effects?
Plant derivative
- derived from mandrake root
- treats testicular cancer/lymphomas
- must avoid skin contact
- can cause rapid fall in BP during IV infusion
When are hormones used in the treatment of cancer?
- used in treatment of cancers in hormone-sensitive tissues (e.g. breast, prostate, ovaries)
- tumour growth inhibited by R antagonists, hormones with opposing actions, or drugs which block synthesis of endogenous hormones
- rarely cure disease but reduce symptoms
Name some types of hormones used in cancer treatment
Glucocorticoids Oestrogens Progestogens Gonadotropin-releasing hormone analogues Antioestrogens Antiandrogens
Name some glucocorticoids
Prednisolone
Dexamethasone
What else are glucocorticoids used for?
Asthma, arthritis
How do prednisolone and dexamethasone work in treating cancer
- glucocorticoids
- inhibit lymphocyte proliferation - treatment of lymphomas/leukaemias
Counter some side effects of other anti-cancer drugs (e.g. N&V)
-used as supportive therapy/in palliative care
Name some oestrogens
Diethylstilbestrol
Ethinyloestradiol
How does Diethylstilbestrol and Ethinyloestradiol work?
Oestrogens
- antagonists of androgen dependant prostate cancer (used in palliative treatment)
- Diethylstilbestrol sometimes used to treat prostate cancer (not usually 1st line therapy due to side effects)
What are the side effects of oestrogens (Diethylstilbestrol and Ethinyloestradiol)?
- nausea
- fluid retention
- thrombosis
- impotence and gynaecomastia
- stimulate resting mammary cancer cells to proliferate - proliferating cells are more susceptible to drugs (easier to destroy)
Name some progestogens and what they are used to treat
Megestrol, medroxyprogesterone, norethisterone
-used to treat endometrial cancer
Name some gonadotropin-releasing hormone analogues and what they do
Goserelin, buserelin, leuprorelin, triptorelin
- inhibit GnRH release - so lowers LH/FSH - so decreases testosterone
- used to treat prostate cancer/advanced breast cancer (in pre menopausal women)
Name some antioestrogens and what they do
Tamoxifen (+ fulvestrant)
-competitive antagonist at oestrogen Rs - inhibits transcription of oestrogen-responsive genes - breast cancer treatment
Tamoxifen - treats oestrogen R-positive breast cancer, also approved for prevention of of cancer in women at high risk of breast cancer in the US
What are the side effects of antioestrogens?
- similar to menopausal effects
- may cause endometrial cancer
- high risk of blood clots
Name some aromatase inhibitors, their mechanism of action and potential side effects
Letrozole, exemastine
- block conversion of androgens to oestrogens in peripheral tissues
- aromatase = enzyme involved in key stage of oestrogen synthesis
- don’t inhibit ovarian oestrogen synthesis
-shouldn’t be used in premenopausal women
Name some Antiandrogens and what they are used in the treatment of
Flutamide, cyproterone, bicalutamide
-androgen antagonists - prostate cancer treatment
Name some somatostatin analogues and what they do
Octreotide, lanreotide (also treats thyroid tumours)
-inhibit cell proliferation/hormone (CCK/gastrin) secretion - used to treat hormone secreting tumours of GI tract
- somatostatin secreted by hypothalamus and stomach/intestines - inhibits release of GH/TSH and gut hormones such as gastrin/CCK - red gut motility and gastric emptying and also pancreatitis secretions
- works because tumours reliant on hormone secretion in order to grow
How are monoclonal antibodies produced?
By cultured hybridoma cells (hybridoma cells formed by fusing antibody producing B lymphocytes with B cell cancer (myeloma))
How are monoclonal antibodies used to treat cancer and what are the +ves and -ves?
- react with specific target proteins expressed on cancer cells - activates immune system - lysis of cancer cells
- some mAbs activate GF-Rs on cancer cells - inhibit survival/promote apoptosis
+ves - targeted therapy - fewer side effects
-ves - expensive, must be given in combo with other drugs
Name some monoclonal antibodies
Rituximab, trastuzumab (herceptin), ofatumumab, bevacizumab
How does rituximab work, what does it treat and what are its side effects?
- binds to CD20 protein, expressed on certain lymphoma cells - lysis of B lymphocytes
- effective in 40-50% cases (when combined with trad. chemo)
- used to treat non-Hodgkin’s lymphoma (only useful if tumour cells express CD20 protein - requires biopsy and staining)
- hypotension, chills and fever
- long term - hypersensitivity - can be fatal
How does trastuzumab (herceptin) work, what does it treat and what are its side effects?
- binds to HER2 (a GF-R)
- induces immune response and cell cycle inhibitors
- HER2 over expressed in 25% of breast cancer patients - rapid proliferation (I.e. aggressive form)
- given with standard drugs - inc. survival rate
-tremor, flu-like symp, itchy eyes, BP changes, palpitations
What is ofatumumab used to treat?
Resistant chronic lymphocytic leukaemia
What does bevacizumab do and what does it treat?
- colorectal cancer
- neutralises VEGF, prevents angiogenesis
- given IV - usually with other drugs
Name some protein kinase inhibitors
Imatinib, dasatinib, nilotinib
How does imatinib work, what does it treat and what side effects does it cause?
- blocks tyrosine kinases involved in GF signalling pathways
- used to treat chronic myeloid leukaemia (CML) - prev. poor prognosis - 90% sufferers have a chromosome defect (Philadelphia chromosome) which encodes an active tyrosine kinase protein - leads to uncontrolled cell proliferation
-problems with drug resistance (may be primary - poor initial response or acquired - following s period of successful treatment) - if resistant - high dose of imatinib or dasatinib or nilotinib
What is the treatment regime of cytotoxic drugs?
Often given in combination
- inc. cytotoxicity without inc. general toxicity (drugs have diff. side effects)
- decreases chance of developing resistance to individual drugs
- often given in large doses ever 2-3 weeks (usually over 6 months)
- allows bone marrow to regenerate - which decreases chance of resistance
- more effective than several small doses
How is the side effect nausea and vomiting controlled?
- needs to be controlled because patient compliance decreases
- ondansetron, granisetron - 5HT3R antagonists -effective vs. cytotoxic drug induced vomiting
- metoclopramide - dopamine D2R antagonist
How is the side effect anxiety controlled?
Lorazepam - anti-anxiety drug (benzodiazepine)
How is the side effect myelosuppression controlled?
-stem cell transplant
(Autologous - stem cells harvested from patient and if used back after chemo)
(Allogenic - stem cells from matched donor - collected by blood dialysis or bone marrow)
-lenograstim (recombinant GM-CSF) - used to boost stem cell production - speeds recovery of immune system
