Test
ON4 Pharmacology of Anti-Cancer Drugs
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Preguntas del test (16)
1Cytotoxic 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- Asynthesis
- Brate
- CRapidly
- DResting
- E-specific
- Fnonspecific
2Growth 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.- Acell cycle
- B20
- Cbetter
- Dproportional cell kill
- Emaximizes
- Frecovery
3Toxicity 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.- Asafety
- Beffect
- Ctoxicity
- Dtoxic
- Eproportional
- Fhigh
- Grapidly
4Match 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- ABone
- BGastrointestinal
- CHair
- DTesticular
- ETracheobronchial
- FVascular
- Gbreast
- HEndometrial
- ILiver, Bone
- JSkeletal muscle, Cardiac muscle,
5Hematopoietic 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.)- Astem
- Bfall
- C1-2
- D3-7
- E6-8
- Frecovery
- G120
- H9-10
- I4-5
6Infection, bruising and anaemia are signs of hematopoietic system toxicity.
- AVerdadero
- BFalso
7Nearly 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].- Avaries
- Bprecursor
- Clife span and turnover
- Dduration of BMS
- Ebleomycin
- Flow
- Ghigh
8Nausea 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].
- Adirect
- Bvagus
- Cemetic
- Dcatecholamines/DA
9GI 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.- Amucositis
- Bhigh
- C3-4 days
- Dulceration
- Elocal
- FWBC
- Grich
- Hyounger
10Dermatological 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- A60-90%
- BReversible
- CCapecitabine
- Dpain
11Match 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- ASteroids, asparaginase
- BAntimetabolites
- CBleomycin
- DVinca alkaloids, taxanes
- EAlkylating
- Fantibiotics
- GPlatinum
12Alkylating 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).- ACovalent
- Bsynthesis
- Crepair
- Dnonspecific
- EBM
- FCyclophosphamide
- Gmetabolites
- Hhydrated
- ICardiac
13Cytotoxic 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).- Adoxorubicin
- Bnon
- Ctopoisomerase II
- Dtranscription
- EIV
- FCardiotoxicity
- Gcumulative
- Hgerm cell
- ILymphoma
- Jstrand breaks
- Kspecific
- Lfibrosis
- Merythema, hyperkeratosis, pigmentation
14Platinum 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- AClions
- BN-7 of guanine
- Ccross
- DIV
- Ekidney
- F24-60
- Ganti-emetic
- Hreversible
- IOtotoxicity
15 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)- Aintermediates
- B5-FU, capecitabine
- Csynthesis
- Dgut
- ERenal
- FFolate
- Gpurine
16Mitotic 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)- Aplant
- Btubulin
- CIV
- Dvincristine
- Eneurotoxicity
- Fmicrotubule
- Goral
- Hneutropaenia
- Isensory
- Joedema
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