Pharmacology of cancer agents Flashcards
mechanism of action of alkylating agents:
Alkylates DNA, major cytotoxic effect results from formation of positively charged carbonium ion which binds to electron-rich nucleophilic sites on biological molecules
MoA of cyclophosphamide (nitrogen mustard)
Activated in liver to active metabolites
Stop cell division by alkylating DNA
Formation of positively charged carbonium ion which binds to electron-rich nucleophilic sites on biological molecules
Also binds to reactive molecules on DNA
inhibits DNA replication and transcription
Mispairing of DNA
Strand breakage
Tissues most susceptible to cancer treatment:
tissues with fast renewal cell populations (bone marrow, GI mucosal cells, skin and hair)
examples of delayed toxicities in cancer treatment:
anthracycline-induced cardiac toxicities
methotrexate-induced pneumonitis
what is cyclophosphamide metabolised by:
CYP450
Dose-limiting toxicity for alkylating agents:
myelosuppression
- usually neutropenia with nadir at 6-10 days and recovery in 14-21 days
- demonstrates delayed nadir and recovery for nitrosoureas
Common toxicities for alkylating agents:
- mucocitis, chemo-induced N/V or CI NA, neurotoxicity alopecia, stomatitis
important counselling points when cyclophosphamide is given:
patients need to drink more water
active metabolites of cyclophosphamide:
4-hydroxycyclophosphamide, aldophosphamide, phosphramide mustard, acrolein
Inactive metabolites of cyclophosphamide:
4-keto-cyclophosphamide, carboxyphospamide, nornitrogen mustard
MoA of alkylators:
analogue of cyclophosphamide activated in liver by CYP 3A4
Cytotoxic action primarily through DNA crosslinks caused by alkylation of isophosphoramide mustard at guanine N-7 positions
Formation of inter and intra strand cross links in DNA –> cell death
what is ifosfamide (IV) used for:
Testicular cancer, diffuse B-cell lymphoma
What is usually given with ifosfamide:
MESNA, to prevent dose-limiting hemorrhagic cystitis as it acts as a scavenger to remove excess cytotoxic material
examples of platinum analogues:
cisplatin, carboplatin, oxaliplatin
Important counselling point for cisplatin:
drink more water – nephrotoxic
How to prevent nephrotoxicity in cisplatin users:
Avoid use in renal dysfunction
hydration with ≥1-2 L 0.9% NaCL IV pre and concurrent with cisplatin, with K+ and Mg2+ supplementation
maintain urine output > 100mL/h
provide mannitol or furosemide to protect patient
prolong infusion time but may reduce efficacy of the drug
things that need to be done if cisplatin is used
Replenish K+ and Mg2+ in patients
Why is ototoxicity and peripheral neuropathy less of a concern compared to nephropathy in Cisplatin use?
they may be reversible and is related to high peak doses (ototoxicity) and cumulative doses (peripheral neuropathy)
what is usually done in peripheral neuropathy in Cisplatin use?
- limit cumulative doses
- Decrease dose/discontinue treatment
- Substitute with carboplatin
- Use of medications to reduce neuropathic pain
General MoA of platinum analogues:
form reactive electrophile that covalently binds to DNA
what is oxaliplatin commonly used for:
colorectal cancer
important adverse event to take note of in the use of oxaliplatin:
cumulative peripheral neuropathy
- acute: usually within the first 2 days, reversible and primarily peripheral symptoms after exacerbated by cold air
- Persistent: often interferes with daily activities
- symptoms may improve upon treatment discontinuation
MoA of enzyme inhibitors (topoisomerase inhibitors):
prevention of religation of DNA, causing strand break during replication and replication cannot proceed.
Examples of topoisomerase I inhibitors:
irinotecan (CPT-11)
Example of topoisomerase II inhibitors:
etoposide
Active metabolite of irinotecan:
SN-38
metabolism of irinotecan:
primarily hepatic, rapidly converted to SN-38 by hepatic carboxylesterase enzymes
what is irinotecan usually used for?
metastatic colorectal cancer
Symptoms of toxicity in irinotecan used:
dose-limiting diarrhea
Cholinergic syndrome: salivation, sweating, lacrimation, urination, diarrhea
How to prevent cholinergic syndrome in patients on irinotecan?
Pre-medicate with IV or SC atropine
Genetic considerations in the use of irinotecan:
UGT1A1 deficiency: decrease starting dose by at least one dose level for homozgosity for UGT 1A1*28 allele
- because these patients cannot inactivate SN-38
Available forms of etoposide:
IV (100mg injection)
oral(50mg caplet)
instructions for the administration of etoposide:
- IV infusion should be infused ≥1hr to avoid hypotension
- IV solution diluted to concentration of <0.4mg/mL
- use non-PVC tubing
- PO dose is x2 of IV for same effect
Symptoms of toxicity in etoposide use:
- Dose-limiting myelosuppression and hypotension (if infuse too quickly)
symptoms of toxicity in cisplatin use:
Dose-limiting acute and delayed CINV, nephrotoxicity, ototoxicity, peripheral neuropathy, irritation to veins
symptoms of toxicity in carboplatin use:
- dose limiting myelosuppression (esp thrombocytopenia)
- nephrotoxicity, ototoxicity, delayed N/v
- Hypersensitivity –> after 6-7 doses
why is carboplatin preferred over cisplatin use:
much lower incidence of nephrotoxicity, ototoxicity and delayed N/V
wha can be used to treat dose-limiting diarrhea in irinotecan use:
loperamide (4mg at earliest sign, followed by 2mg PO q2h until diarrhea free for 12 hours)
Examples of anthracyclines:
Doxorubicin, Daunorubicin, epirubicin, idarubicin, Liposomal doxorubicin, mitoxantrone
MoA of anthracyclines:
- induce formation of covalent topoisomerase II DNA complexes – prevent religation of DNA during DNA replication – DNA strand breaks
- Intercalations beween base pairs in DNA formed, causing DNA breaks
- Metabolised in liver to form oxygen free radicals – add to cytotoxicity
Symptoms of toxicity in anthracycline use:
- Dose-limiting myelosuppression (neutropenia)
- Cardiotoxicity
- Alopecia
- Acute N/V
- vesicant
- Red discolouration of urine
what procedure should be performed before the use of anthracyclines:
baseline MUGA/ECHO (check left ventricular ejection fraction)
Methods to prevent anthracycline-induced cardiotoxicity:
- limit cumulative dose
- Administration schedule
- Less cardiotoxic anthracycline analogues (mitoxantrone, liposomal doxorubicin)
- Use dexrazoxane (cardioprotectant)
why is dexrazoxane seldom used:
- Expensive
- N/V and myelosuppression
- not easy to administer
- same outcome as if you change therapy entirely
Risk factors for anthracycline-induced cardiotoxicity:
- high cumulative doses
- high peaks due to administration schedule
- Age
- Mediastinal radiation
- Known cardiac disease
MoA of antimetabolites:
- structurally related to naturally occuring components found in the body
- Exert damage on DNA by competing for binding sites on enzymes or incorporation directly into DNA or RNA
MoA of methotrexate:
- Irreversibly binds to and inhibits dihydrofolate reductase –> conversion of folic acid to tetrahydrofolate is inhibited
- purine and thymidylates cannot be produced – lack of the two compounds
- decrease in DNA synthesis, repair and cellular replication
Symptoms of toxicity in methotrexate use:
- Dose-limiting myelosuppression, nephrotoxicity, mucositis, diarrhea, hepatitis, pulmonary pneumonitis, CNS toxicities
Drugs to avoid administering with methotrexate:
- NSAIDs
- penicillin
- ascorbic acid
- Probenecid, sulfonamides
- salicylates
- omeprazole
Drugs excreted via renal route (need to remind patients to drink more water and pee)
- cyclophosphamide (but metabolised le)
- ifosfamide
- cisplatin (NEED DIURETIC)
- carboplatin
- oxaliplatin
- irinotecan (but drink water cos of diarrhea)
- methotrexate
Examples of pyrimidine analogues:
5-FU
capicitabine
MoA of 5-FU
analogue of pyrimidine uracil – acts as pyrimidine antagonist
Symptoms of toxicity of 5-FU
Dose limiting:
- leukopenia
- thrombocytopenia
- anemia
- hand-foot syndrome
- diarrhea
Skin discolouration, nail changes, photosensitivity, neurologic toxicity, vasospastic anemia
MoA of capecitabine. Account for its selectivity towards tumour cells
Prodrug of FU to be selectively activated by tumor cells – 3 step conversion to fluorouracil
- selectivity due to TPs higher in tumor cells (thymidine phosphorylase is in charge of phosphorylation in the third step) – rest of the metabolism is in the liver
Symptoms of toxicity in capecitabine:
Dose-limiting:
- hand-foot syndrome (more prominent in capecitabine)
- Mucositis
- diarrhea
Others:
- CINV
- vomiting
- fatigue
- rash
MoA of vinca alkaloids:
- Binds to tubulin (protein consisting of alpha and beta subunits)
- Inhibits polymerisation
- mitotic spindle cannot form during metaphase
SEs that are common in all Vinca Alkaloids (i.e. vinca-induced toxicities)
Generally low emetogenic potential
- vesicants
- alopecia
symptoms of toxicity of vincristine:
- peripheral neuropathy (max dose 2mg/wk)
- Ileus, constipation
- Rare: bone marrow suppression
Symptoms of toxicity for vinblastine and vinorelbine:
dose-limiting: neutropenia, thrombocytopenia – need to ensure that patient blood profile is good
Neurologic toxicity, constipation
MoA of taxanes:
similar to vinca, but bind preferentially to microtubles shifting microtubules towards polymerisation
- allows for stabilisation against depolymerisation – cells cannot divide
Issue with methotrexate in terms of distribution
Escape into 3rd spaces –> patients with ascites/pleural effusions in high risk for toxicity
concurrent medication needed with methotrexate:
Folinic acid
Premedications needed for paclitaxel:
H1 or H2 blocker, or corticosteroids – due to hypersensitivity
Premedication needed for docetaxel:
Dexamethasone 8mg PO BD (one day before chemo) to prevent accumulation in the lungs – continue for 2 additional days
Symptoms of toxicity in paclitaxel:
myelosuppression (WBC nadir @8-11 days with recover by 15-21 days), peripheral neuropathy, myalgias, hypersensitivity reactions, mucositis (more with prolonged infusions for 3-4 days)
symptoms of toxicity in docetaxel:
Dose limiting neutropenia
Compared to paclitaxel: less peripharal neuropathy, hypersensitivity reactions and asthenia
Example of antiestrogens:
tamoxifen
MoA of tamoxifen:
inhibit nuclear binding of estrogen receptor, blocks estrogen stimulation of breast cancer cells – for the treatment of estrogen-receptor positive breast cancer (also for advanced endometrial cancer)
- antagonism in breast epithelial cells
- agonism in bone, lipids, endometrium – increased risk of endometrial cancer 7x especially when taken long term
MoA of aromatase inhibitors:
block steps most important in synthesising estradiol (androstenedione –> estrone and testosterone –> estradione)
examples of aromatase inhibitors:
anastrozole
letrozole
exemestane
side effects for aromatase inhibitors:
fatigue, hot flushes, myalgia/athralgia, bone loss (supplement with Ca2+ and vit D)
when is targeted therapy considered:
with reference to diagnostic test – need to be performed before patient can receive drug
Pertinent issues with targeted therapies:
- Patient education issues (Adherence due to SE)
- Unknown long-term toxicities
- Toxicities and response issues
- Financial burden
- DDI
Types of targeted therapies:
small molecule drugs
monoclonal antibodies
MoA of small molecule drugs:
Inhibit cell proliferation by blocking intracellular signals that stimulate gene expression – intracellular portion of protein tyrosine kinase
Symptoms of toxicity for epidermal growth factor tyrosine kinase inhibitors
- dermatological toxicities
- GI side effects
requirements before epidermal growth factor tyrosine kinase inhibitors can be used:
EGFR testing for EGFR positive lung cancer
Examples of epidermal growth factor tyrosine kinase inhibitors:
Gefitinib, erlotinib, afatinib
targeted therapy induced toxicities:
dermatological toxicity GI toxicity Pulmonary toxicity Hepatotoxicity Cardiotoxicity Neurotoxicity Immunotoxicity
Management principles of small molecule drugs:
- Treatments should not interfere with anti tumor effects of EGFR inhibitors
- Management should be achieved with minimal side effects
- Ease of administration with rapid results mandatory to ensure patient compliance
- Therapies tailored to type of clinical presentation
side effects of rituximab:
infusion related reactions:
- fever, chills, rigors, bronchospasm, hypotension – first infusion has higher incidence – premedicate with paracetamol and diphenhydramine
N/V, infection and myelosuppression
Side effects of bevicizumab
hemorrhage, increased risk of thrombotic events, wound healing complications, GI perforations (abdominal pain, N/V, constipation, fever), proteinurea
C/I in bevicizumab use:
patients with:
- High risk for bleeds
- CNS metastasis
- Nephrotic syndrome
Toxicities in Trastuzumab (herceptin)
cardiotoxicity, hypersensitivity (can use paracetamol for premed)
Examples of passive immunotherapy:
antitumor mabs (tumor-directed mabs) adoptive (cell therapies)
examples of active immunotherapy:
- cytokines: interleukins, interferons
- therapeutic cancer vaccines: cell-based, single antigen/peptide based
- immuno-oncology therapies: immune effector cell modulators (checkpoint inhibitors, co-stimulatory agonists)
MoA of ipilimumab (Yervoy)
block cytotoxic T-cell lymphocyte associate antigen (CTLA-4) inhibitory signal to allow CTLs to destroy cancer cells
side effects of yervoy:
immunological related – rash, diarrhea, thyroid, fatigue, flulike symptoms
what is Anti-programmed cell death-1 (PD-1)
inhibitory signalling receptor expressed on activated T cells
Examples of PD-1 inhibitors:
pembrolizumab, nivolumab, cemipilimab
Examples of PD-L1 inhibitors:
Atezolizumab, Avelumab, Durvalumab
common adverse events of PD-1 inhibitors:
immune related adverse events:
hypophysitis, pneumonitis, thyroiditis, hepatitis, adrenal insufficiency, colitis, pancreatitis, dermatitis, arthritis, motor and sensory neuropathies
State the Vehicle that Oxaliplatin has to be administered in:
Dextrose 5% – only stable in there
Method to reduce nephrotoxic effects in methotrexate use:
- high dose (>1g/m2) require therapeutic drug monitoring and folinic acid rescue until levels are less than 0.1 mcgM
Important toxicities of 5-FU:
- Aplastic anemia
2. Dose-limiting hand-foot syndrome
Adverse effects of acrolein
bladder irritation, shedding of epithelial cells, local inflammation, can cause bleeding
Irritant to veins
cisplatin
