2 - Cytotoxic Agents

Question 1

Cytotoxic agents can be categorised into anti metabolites and alkylating agents

Answer 1

True

Question 2

The general risks associated with cytotoxic agents are carcinogenesis, teratogenesis, and myelosuppression and an increased potential for infection

Answer 2

True

Question 3

Cytotoxic agents modulate the behaviour of cells through inhibition of growth and development

Answer 3

True

Question 4

Anti metabolites are cell cycle specific and mimic the DNA nucleotides, and are most active during the S phase when DNA is being synthesised

Answer 4

True (S “synthesis” phase)
G1 = preparing the cell for DNA reproduction
S = DNA synthesis
G2 = interphase for preparation for division
M = “mitosis” cell division
G0 (some cells) = resting phase awaiting to re-enter cell cycle

Question 5

The anti metabolites are methotrexate, azathioprine, mycophenolate, topical 5-fluorouracil, thioguanine and hydroxyurea

Answer 5

True

Question 6

Cyclophosamide, chlorambucil and melphalan are alkylating agents

Answer 6

True

Question 7

Alkylating agents are independant of the cell cycle

Answer 7

True (exert effect by direct damage to DNA through physiochemical interactions I.e. Alkylation, cross-linking, carbamylation which are cell cycle independent)

Question 8

Patients using cytotoxic agents should be given general instructions on bleeding risks

Answer 8

True (thrombocytopenia from myelosuppression)

Question 9

Thioguanine is an antimetabolite from the thioguanine family with a mechanism of action similar to Azathioprine

Answer 9

True

Question 10

Thioguanine is a not a first line agent in psoriasis

Answer 10

True (third line agent in psoriasis)

Question 11

Thioguanine is metabolised by the liver and converted to 6-thioguanilyic acid, which is then further converted to di- and triphosphates

Answer 11

True

Question 12

Thioguanine and hydroxyurea are both renally excreted

Answer 12

True (similar to methotrexate)

Question 13

Thioguanine has an unpredictable absorption pattern

Answer 13

True

Question 14

Thioguanine is metabolised by thiopurine methyltransferase (TPMT) and not by xanthine oxidase

Answer 14

True (contrary to Azathioprine which is degraded by both enzyme pathways, Thioguanine is metabolised by TPMT only and so TPMT is more important in its detoxification)

Question 15

Thioguanine may be administered concurrently with allopurinol (xanthine oxidase inhibitor) without the need for dose reduction

Answer 15

True (xanthine oxidase is not involved in the metabolism of Thioguanine)

Question 16

Aminosalicylates use should be minimised or avoided in patients on Thioguanine

Answer 16

True (aminosalicylates may inhibit TPMT activity which is involved in metabolism of Thioguanine)

Question 17

Thioguanine is a prodrug that yields nucleoside analogs which is then converted to nucleotides and incorporated into cellular DNA during the S phase of the cell cycle

Answer 17

True (This produces cytotoxic effects via apoptosis of activated T lymphocytes and decreased T lymphocyte counts in skin lesions)

Question 18

Myelosuppression and GI side effects are the most common adverse effects in Thioguanine use

Answer 18

True

Question 19

Thrombocytopenia is an early indicator of myelosuppression in patients using Thioguanine

Answer 19

True

Question 20

Thioguanine does not usually need to be discontinued due to GI side effects

Answer 20

True (GI adverse effects are usually tolerated without drug discontinuance)

Question 21

Thioguanine is less hepatotoxic than methotrexate (another antimetabolite agent)

Answer 21

True (Unlike Methotrexate, Thioguanine is not considered particularly hepatotoxic though there have been rare cases of hepatic veno-occlusive disease)

Question 22

TPMT levels should be considered before starting Thioguanine

Answer 22

True (TPMT levels may guide selection of an adequate starting dose and improves Thioguanine dosing)

Question 23

Hydroxyurea is a third line agent for psoriasis

Answer 23

True

Question 24

Hydroxyurea is well absorbed though the metabolism is incompletely understood

Answer 24

True

Question 25

Patient with renal impairment are more susceptible to hydroxyurea toxicity

Answer 25

True (80% of the drug is excreted through the kidneys)

Question 26

Hydroxyurea impairs DNA synthesis through inhibition of ribonucleotide diphosphate reductase which reduces nucleotides to deoxynucleotides and limits the supply of DNA bases available for synthesis, resulting in strand breakage and cell death

Answer 26

True

Question 27

Hydroxyurea prevents cells from repairing damage due to UV or ionising radiation

Answer 27

True

Question 28

Hydroxyurea is most effective in cells with a high proliferative index, preferentially concentrated within leukocytes

Answer 28

True

Question 29

Hydroxyurea is relatively contraindicated in patients with bone marrow suppression I.e. Leukopenia, thrombocytopenia, severe anaemia

Answer 29

True (relatively contraindicated in haematologic disorders)

Question 30

Myelosuppression is the most common adverse effect with hydroxyurea use (anaemia > leukopenia > thrombocytopenia)

Answer 30

True

Question 31

Mild megaloblastic changes on FBC are common among patients receiving hydroxyurea but is not a reason for discontinuance of the drug

Answer 31

True | N.B. Megaloblastic changes may also be seen with folate supplementation

Question 32

Dyspepsia may occur with hydroxyurea

Answer 32

True (hydroxyurea can be taken with food, milk or antacids if this occurs)

Question 33

Hydroxyurea is the most common cause of a drug-induced dermatomyositis-like eruption

Answer 33

True

Question 34

Hydroxyurea may cause a lichenoid drug eruption and drug-induced lupus

Answer 34

True

Question 35

Hydroxyurea may cause leg ulcers

Answer 35

True

Question 36

Hydroxyurea may cause hyperpigmentation of the skin and nails

Answer 36

True

Question 37

Hydroxyurea may cause limited and reversible alopecia

Answer 37

True

Question 38

Hydroxyurea may cause photosensitivity and radiation recall

Answer 38

True

Question 39

Hydroxyurea and its link to non-melanoma skin cancers is unclear

Answer 39

True (reported as an association but confounding factors exist and the degree of risk is unclear although close surveillance for non-melanoma skin cancers is indicated)

Question 40

Hydroxyurea should not be administered with other myelosuppression agents

Answer 40

True (added bone marrow toxicity with concurrent use of other myelosuppressive agents)

Question 41

Cyclophosphamide and chlorambucil are derivatives of nitrogen mustard which act independently of the cell cycle

Answer 41

True

Question 42

In dermatology, Cyclophosphamide is primarily used in the treatment of immunobullous disorders and vasculitis

Answer 42

True

Question 43

Cyclophosphamide is metabolised by the CYP 450 system in the liver

Answer 43

True

Question 44

Chronic liver disease such as cirrhosis may prolong the plasma half life of cyclophosphamide due to decreased CYP 450 activity

Answer 44

True

Question 45

Cyclophosphamide is a prodrug that is first converted in the liver to 4-hydroxycyclophosamide (an inactive metabolite) that exists in equilibrium with Aldophosamide which diffuses directly into cells but is not directly cytotoxic; Aldophosamide is then converted to the directly cytotoxic active metabolite phosphoramide mustard and acrolein

Answer 45

True

Question 46

Acrolein, a by-product from the cleavage of Aldosphosphamide (yielding the toxic active metabolite phosphoramide mustard and acrolein) is highly reactive and enhances cellular damage by depleting glutathione stores

Answer 46

True

Question 47

Aldophosamide (a molecule that exists in equilibrium with 4-hydroxycyclophosphamide, the first inactive metabolite of cyclophosphamide) may be converted by aldehyde dehydrogenase to a second inactive metabolite (carboxyphosphamide)

Answer 47

True

Question 48

Cyclophosphamide has a greater effect on B lymphocytes than T lymphocytes

Answer 48

True (Unlike other immunosuppressive agents with mainly affect T lymphocytes)

Question 49

Cyclophosphamide has a greater effect on suppressor T cells than helper T cells

Answer 49

True (unlike other immunosuppressive agents which inhibit cytokines produced by T helper cells)

Question 50

Resistance to cyclophosphamide may occur due to decreased cellular penetration, increased competition from other nucleophilic substances, improved DNA repair or increased drug metabolism

Answer 50

True

Question 51

Cyclophosphamide is FDA approved for treatment of mycosis fungoides

Answer 51

True

Question 52

Cyclophosphamide can be used in the treatment of vasculitis

Answer 52

True

Question 53

Cyclophosphamide is a useful agent in treating mucous membrane pemphigoid (cicatricial pemphigoid) particularly when there is involvement of the ocular mucosa

Answer 53

True

Question 54

Cyclophosphamide is uncommonly used in the treatment of pemphigus

Answer 54

True (widespread availability of other less toxic medications I.e. Azathioprine and mycophenolate tempers the use of cyclophosphamide in immunobullous disease)

Question 55

Cyclophosphamide is contraindicated in patients with a history of bladder cancer

Answer 55

True (genitourinary toxicity with haemorrhaging cystitis and bladder carcinoma is the single most widely recognised consequence of cyclophosphamide use)

Question 56

Cyclophosphamide should be used with caution in patients with a history of lymphoproliferative disease

Answer 56

True (to be used with caution due to association of cyclophosphamide with non-Hodgkins B cell lymphoma and leukaemia)

Question 57

Acrolein is the metabolite responsible for haemorrhagic cystitis, an adverse effect of cyclophosphamide

Answer 57

True (Mesna may be used as a scavenging thiol agent that binds acrolein in the bladder and reduce irritation)

Question 58

Mesna (sodium 2-mercaptoethane sulfonate) may be used orally or intravenously as a protective measure against haemorrhagic cystitis from cyclophosphamide use, especially in high doses

Answer 58

True (though Mesna has also been associated with fixed drug eruption when used for this indication)

Question 59

Bladder toxicity (haemorrhagic cystitis) is less frequent in patients on intravenous cyclophosphamide than oral form of the drug

Answer 59

True (perhaps due to the lower total dose used in the intravenous form as compared to oral form)

Question 60

Increased fluid intake may prevent bladder toxicity (haemorrhagic cystitis) caused by cyclophosphamide

Answer 60

True

Question 61

Mesna may be prescribed to patients on cyclophosphamide

Answer 61

True (co-administration of Mesna in dermatological doses of cyclophosphamide is not evidence based due to the lower doses prescribed in dermatological conditions, though Mesna can be considered for patients on prolonged courses of cyclophosphamide and/or high doses)

Question 62

Continued monitoring of the urinary tract is indicated in all patients who have used cyclophosphamide

Answer 62

True (bladder cancer may arise decades after discontinuation of cyclophosphamide)

Question 63

There is a potential association between cyclophosphamide and SCC

Answer 63

True (though much of this risk is found in transplant and oncology patients exposed to high doses for extended durations)

Question 64

GI adverse effects affect 70-90% of cyclophosphamide users

Answer 64

True (this can be managed with ondansetron and dexamethasone)

Question 65

Anaemia associated with cyclophosphamide and chlorambucil use is usually reversible

Answer 65

True (also less common)

Question 66

Leukopenia is a dose-limiting common adverse effect from cyclophosphamide and chlorambucil

Answer 66

True

Question 67

Thrombocytopenia usually occurs with higher doses of cyclophosphamide and chlorambucil

Answer 67

True

Question 68

Pigmented band on the teeth is an irreversible adverse event from cyclophosphamide

Answer 68

True

Question 69

Alopecia due to anagen effluvium is a reversible side effect of cyclophosphamide

Answer 69

True

Question 70

Cyclophosphamide may cause hyperpigmentation of the skin and nails

Answer 70

True (just as in minocycline, hydroxychloroquine and hydroxyurea)

Question 71

Amenorrhea may occur in 27-60% of women treated with cyclophosphamide

Answer 71

True (also in chlorambucil)

Question 72

Premature ovarian failure from cyclophosphamide and chlorambucil may be prevented with luprolide acetate

Answer 72

True

Question 73

Cyclophosphamide may cause azoospermia in men

Answer 73

True (testosterone may lessen this risk)

Question 74

Urinalysis and cytological examination is indicated when the cumulative cyclophosphamide dose is > 50g

Answer 74

True

Question 75

Evaluation for palpable lymphadenopathy and age appropriate cancer screening I.e. FOBT and Pap smear should be included in the follow up of patients on cyclophosphamide

Answer 75

True

Question 76

Unlike cyclophosphamide (a prodrug), Chlorambucil is also metabolised in the liver but does not require activation in the liver (active drug)

Answer 76

True

Question 77

Chlorambucil has a slower onset of action than cyclophosphamide

Answer 77

True (and also less toxic)

Question 78

Unlike cyclophosphamide, metabolism of chlorambucil does not yield acrolein

Answer 78

True (and so chlorambucil does not cause haemorrhagic cystitis)

Question 79

In dermatology, Chlorambucil is used most consistently in necrobiotic xanthogranuloma

Answer 79

True

Question 80

Epilepsy and mood alterations are specific to chlorambucil

Answer 80

True (differs to cyclophosphamide)

Question 81

There is a risk of carcinogenesis from chlorambucil use

Answer 81

True (as for cyclophosphamide, there is potential risk for leukaemia, non-Hodgkins lymphoma and SCC)

Question 82

Hepatotoxicity is an uncommon adverse effect of chlorambucil

Answer 82

True

Question 83

Drugs which may potentiate myelosuppressive, immunosuppressive and carcinogenic effects of cyclophosphamide and chlorambucil should be used with caution

Answer 83

True

Question 84

There is possible decreased immunologic response with all vaccines and disseminated infection with live vaccines if used in Cyclophosphamide and chlorambucil patients

Answer 84

True

Question 85

Cyclophosphamide and chlorambucil are teratogenic

Answer 85

True