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Cytotoxic drugs damage the reproductive potential of cells by acting on DNA [blank_start]synthesis[blank_end]. Selectivity depends on [blank_start]rate[blank_end] of synthesis/division:
• [blank_start]Rapidly[blank_end] dividing cells more likely to respond to Tx
• [blank_start]Resting[blank_end] cancer cells resistant
Cell-cycle phase[blank_start]-specific[blank_end] drugs: schedule dependent (time dependent)
Cell-cycle phase-[blank_start]nonspecific[blank_end] drugs: dose dependent
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synthesis
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rate
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Rapidly
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Resting
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-specific
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nonspecific
Frage 2
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Growth fraction is number of cells in [blank_start]cell cycle[blank_end] over the total number of cells. This is normally [blank_start]20[blank_end]%. It changes in cancers eg Burkitt’s lymphoma: 100% GF, Colon carcinoma: <5%.
Greater growth fraction means a [blank_start]better[blank_end] chance of cell death.
The [blank_start]proportional cell kill[blank_end] is the proportion of cells a cytotoxic dose kills. Note that drugs kill a proportion of cells, not a given number of cells. Intermittent therapy [blank_start]maximizes[blank_end] tumour cell killing and allows [blank_start]recovery[blank_end] of healthy cells.
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cell cycle
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20
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better
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proportional cell kill
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maximizes
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recovery
Frage 3
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Toxicity related to cytotoxic drugs:
The therapeutic index is a measurement of the relative [blank_start]safety[blank_end] of a drug, usually around 1(below one is less safe). It is a comparison of the amount of a therapeutic agent that causes the therapeutic [blank_start]effect[blank_end], to the amount that causes [blank_start]toxicity[blank_end].
In cancer a therapeutic dose is a [blank_start]toxic[blank_end] dose.
The drug action is [blank_start]proportional[blank_end] to the growth rate; meaning a greater effect in [blank_start]high[blank_end] growth fraction & vice versa.
The drug with affect [blank_start]rapidly[blank_end] dividing (cancerous AND non-malignant) tissue.
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safety
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effect
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toxicity
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toxic
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proportional
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high
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rapidly
Frage 4
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Match the tissues to their types of proliferation.
Continuous rapid proliferation - [blank_start]Bone[blank_end] marrow, [blank_start]Gastrointestinal[blank_end] mucosa, [blank_start]Hair[blank_end] follicles, [blank_start]Testicular[blank_end] germ cells
Continuous slow proliferation - [blank_start]Tracheobronchial[blank_end] epithelium, [blank_start]Vascular[blank_end] endothelium
Cyclical proliferation - Glandular female [blank_start]breast[blank_end] tissue, [blank_start]Endometrial[blank_end] lining of uterus
Capacity to proliferate after injury - [blank_start]Liver, Bone[blank_end]
Non proliferating - [blank_start]Skeletal muscle, Cardiac muscle,[blank_end] Cartilage
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Hematopoietic system toxicity:
Bone marrow suppression occurs when [blank_start]stem[blank_end] cell pool is damaged by chemotherapy. Clinically we see a [blank_start]fall[blank_end] in circulating cells. Platelets gone within [blank_start]1-2[blank_end] weeks. Granulocytes within 14 days. Fall in white cell count by [blank_start]3-7[blank_end] days. No change in RBCs for [blank_start]6-8[blank_end] weeks. Then, bone marrow [blank_start]recovery[blank_end] occurs.
(Erythrocyte life span: [blank_start]120[blank_end] days. Platelet: [blank_start]9-10[blank_end] days. WBCs: [blank_start]4-5[blank_end] days.)
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stem
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fall
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1-2
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3-7
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6-8
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recovery
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120
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9-10
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4-5
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Infection, bruising and anaemia are signs of hematopoietic system toxicity.
Frage 7
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Nearly all cytotoxics cause BM suppression at therapeutic doses but severity and duration [blank_start]varies[blank_end]. Why?
1. Different effects on [blank_start]precursor[blank_end] stem cells (pluripotent vs unipotent)
2. Kinetics of cell types in peripheral blood ([blank_start]life span and turnover[blank_end] of cells)
3. Cycle nonspecific drugs: greater [blank_start]duration of BMS[blank_end] than phase specific
Low BMS with [blank_start]bleomycin[blank_end].
Cancer cells have [blank_start]low[blank_end] [hydrolase], BM cells have [blank_start]high[blank_end] [hydrolase].
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varies
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precursor
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life span and turnover
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duration of BMS
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bleomycin
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low
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high
Frage 8
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Nausea and vomiting as a SE has a complex mechanism, only partly due to [blank_start]direct[blank_end] action of drugs on GIT. It can affect the [blank_start]vagus[blank_end] nerve which affects the [blank_start]emetic[blank_end] centre. Anticipatory nausea is common and the pathway uses [blank_start]catecholamines/DA[blank_end].
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direct
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vagus
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emetic
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catecholamines/DA
Frage 9
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GI Tract toxicity:
Observed as oesophagitis, diffuse ileitis, colitis, oral [blank_start]mucositis[blank_end].
• Mucosal cells have [blank_start]high[blank_end] turnover (4-7 days)
• [blank_start]3-4 days[blank_end] after cytotoxic administration: Pain, tingling, dryness, loss of taste - - - [blank_start]ulceration[blank_end]
• Consider the combo of [blank_start]local[blank_end] trauma/low [blank_start]WBC[blank_end] count/pathogen [blank_start]rich[blank_end] environment
• Severity: dose related, schedule of administration
• Worse in [blank_start]younger[blank_end] people.
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mucositis
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high
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3-4 days
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ulceration
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local
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WBC
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rich
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younger
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Dermatological toxicity:
1. Alopecia
• [blank_start]60-90%[blank_end] hair follicles actively dividing, 24h doubling time
• [blank_start]Reversible[blank_end]
2. Specific skin toxicity (uncommon)
• [blank_start]Capecitabine[blank_end]: Palmar-plantar syndrome (redness, swelling, and [blank_start]pain[blank_end] on palms and soles). Affects growth of skin cells, capillaries
3. Extravasation
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60-90%
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Reversible
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Capecitabine
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pain
Frage 11
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Match the cytotoxics to the cell phase they act in.
G1 - [blank_start]Steroids, asparaginase[blank_end]
S phase - [blank_start]Antimetabolites[blank_end]
G2 - [blank_start]Bleomycin[blank_end]
Mitosis - [blank_start]Vinca alkaloids, taxanes[blank_end]
Phase non-specific - [blank_start]Alkylating[blank_end] agents, Cytotoxic [blank_start]antibiotics[blank_end], [blank_start]Platinum[blank_end]-based drugs
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Steroids, asparaginase
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Antimetabolites
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Bleomycin
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Vinca alkaloids, taxanes
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Alkylating
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antibiotics
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Platinum
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Alkylating agents:
[blank_start]Covalent[blank_end] binding to 1) DNA - blocks DNA/RNA [blank_start]synthesis[blank_end] and 2) proteins - blocks DNA [blank_start]repair[blank_end].
Cell-cycle [blank_start]nonspecific[blank_end].
Causes [blank_start]BM[blank_end] suppression, hair loss, GI disturbances.
PK depends on structure.
e.g. [blank_start]Cyclophosphamide[blank_end] for breast and bronchi cancer. Hydroxylation in liver makes the active [blank_start]metabolites[blank_end]. Risks: Haemorrhagic cystitis (stay [blank_start]hydrated[blank_end]), [blank_start]Cardiac[blank_end] damage (with high dose).
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Covalent
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synthesis
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repair
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nonspecific
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BM
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Cyclophosphamide
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metabolites
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hydrated
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Cardiac
Frage 13
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Cytotoxic antibiotics:
Anthracyclines (Streptomyces): e.g. Daunorubicin, [blank_start]doxorubicin[blank_end], epirubicin
In general - cell cycle [blank_start]non[blank_end] specific.
• DNA intercalation
• Inhibits [blank_start]topoisomerase II[blank_end]
• Blocks [blank_start]transcription[blank_end], disrupt normal replication = cell death
Poor gut absorbtion so given [blank_start]IV[blank_end].
Toxicitity:
[blank_start]Cardiotoxicity[blank_end] – dose dependent and cumulative
Maximum [blank_start]cumulative[blank_end] dose recommended to prevent heart failure.
Special case: Bleomycin. Non-anthracycline cytotoxic AB for [blank_start]germ cell[blank_end] tumours, Hodgkin’s [blank_start]Lymphoma[blank_end].
Mode: DNA intercalation, free radical-induced [blank_start]strand breaks[blank_end] (cell cycle [blank_start]specific[blank_end]).
Pulmonary and dermatological toxicity, low BM suppression: pulmonary [blank_start]fibrosis[blank_end] (partially reversible), [blank_start]erythema, hyperkeratosis, pigmentation[blank_end](50% of patients).
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Platinum compounds e.g. cisplatin, carboplatin, oxaliplatin. AKA ‘Non-classical alkylating agents’.
MoA: [blank_start]Clions[blank_end] interact with [blank_start]N-7 of guanine[blank_end] - INTRA strand [blank_start]X[blank_end]-linking.
[blank_start]IV[blank_end] infusion, excreted by [blank_start]kidney[blank_end]. Long t1/2: [blank_start]24-60[blank_end]h, due to protein binding.
◦ BM suppression and GI toxiciity - requires [blank_start]anti-emetic[blank_end] support
◦ Renal toxicity ([blank_start]reversible[blank_end])
◦ [blank_start]Ototoxicity[blank_end], tinnitus, hearing loss
◦ Peripheral neuropathy
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Clions
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N-7 of guanine
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cross
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IV
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kidney
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24-60
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anti-emetic
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reversible
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Ototoxicity
Frage 15
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Antimetabolites:
• Structural similarity to [blank_start]intermediates[blank_end] of normal metabolism
• Incorporation into nucleic acids e.g. [blank_start]5-FU, capecitabine[blank_end] (prodrug)
• Enzyme substrates that inhibit RNA and DNA [blank_start]synthesis[blank_end]
• Good [blank_start]gut[blank_end] absorption, also IV, intrathecal
• [blank_start]Renal[blank_end] excretion
e.g. Methotrexate (MTX) for leukaemias (breast, head, lung and neck).
• [blank_start]Folate[blank_end] analogue, stops [blank_start]purine[blank_end] synthesis
Toxicity: BM (leukocytes) – infection, GI (mucosa)
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intermediates
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5-FU, capecitabine
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synthesis
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gut
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Renal
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Folate
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purine
Frage 16
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Mitotic inhibitors which are [blank_start]plant[blank_end] derivatives are cell cycle-specific.
1. Vinca alkaloids
e.g. Vincristine, vinblastine, vindesine, vinorelbine
Bind to [blank_start]tubulin[blank_end], inhibits polymerisation (mitosis). Eliminated via metabolism. Given [blank_start]IV[blank_end] usually. Toxicity: constipation, BMS usually dose limiting (absent for [blank_start]vincristine[blank_end]), dose-limiting [blank_start]neurotoxicity[blank_end] for vincristine, neuropathy (mixed motor/sensory), paraesthesia, loss of deep reflexes (axonal transport).
2. Taxanes
e.g. Docetaxel, paclitaxel
Stabilise [blank_start]microtubule[blank_end] structure, prevent cell division. Poor [blank_start]oral[blank_end] absorbtion. Hepatic metabolism. Toxicity: Dose-limiting [blank_start]neutropaenia[blank_end], arthralgia/myalgia syndrome (mechanism unknown)
Paclitaxel: [blank_start]sensory[blank_end] neuropathy (motor at higher dose)
Docetaxel: leg [blank_start]oedema[blank_end] (fluid retention – peripheral effect)
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plant
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tubulin
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IV
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vincristine
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neurotoxicity
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microtubule
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oral
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neutropaenia
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sensory
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oedema