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Hematology/Oncology > Cancer treatment - Traditional Chemotherapy - Antimetabolites (1) > Flashcards

Cancer treatment - Traditional Chemotherapy - Antimetabolites (1) Flashcards

1
Q

Are antimetabolite chemotherapeutics cell cycle specific or non specific?

A

They are cell cycle specific - s phase specific

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2
Q

Which drugs are antimetabolites for cancer treatment?

A
  1. Methotrexate
  2. Pemetrexed
  3. Fludarabine
  4. Cytarabine
  5. Gemcitabine
  6. 5-Fluorouracil
  7. Capecitabine
  8. 6-mercaptopurine
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3
Q

How do antimetabolites work? (in general)

A

They inhibit DNA synthesis
(therefore they are s phase specific - this is the phase during which DNA replication occurs)

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4
Q

What is the difference in using antimetabolites for autoimmmune disease vs cancer?

A

They are used at much lower doses for auto-immune diseases

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5
Q

Methotrexate MOA (2)

A

MTX is a folic acid analog - looks like folic acid with 2 slight differences

Dehydrofolate reductase (DHFR)

MTX binds to and inhibits DHFR, inhibiting the formation of THF (thus inhibiting DNA synthesis)

Polyglutamate derivatives of MTX also have cytotoxic action

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6
Q

How does the structure of MTX effect resistance?

A

MTX is highly water soluble - it needs carrier receptors to get inside of cells
Cancer cells downregulate these carrier receptors (RFC, folate receptor) and increase p-gp (which increases efflux from cell) - thus establishing resistance

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7
Q

Since MTX is not ____________ it can not be used to treat _________________

A

MTX is not lipophilic, so it can not be used to treat brain tumors (doesn’t cross BBB)

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8
Q

MTX route of administration for chemo?

A

IV
(not used PO or subq for chemo)

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9
Q

What is the dose limiting toxicity of methotrexate? What should be done because of this?

A

Myelosuppression

Because of severe myelosuppression - leucovorin rescue therapy should be given with high dose methotrexate chemo - should be given 24 hours after the end of the MTX infusion

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10
Q

MTX acute ADRs (5)

A

Dose limiting - myelosuppression

Nephrotoxicity
Hepatoxicity
Mucositis
Neurotoxicity

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11
Q

MTX chronic ADRs (2)

A

Hepatic fibrosis
Pneumonitis

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12
Q

MTX DDIs (7)

A

There are a lot of drug interactions with MTX, the following drugs should be held for at least 48 hours before starting the MTX infusion and for 5 days following infusion - otherwise they interfere with MTX clearance and can cause nephrotoxicity ….

  1. Penicillin
  2. Sulfonamides
  3. Tetracyclines
  4. Ciprofloxacin
  5. NSAIDs
  6. Salicylates
  7. PPIs
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13
Q

Prevention of toxicity with high dose MTX (5)

A
  1. Check renal function before starting
    -renal dose adjustments required
  2. Discontinue interacting mediations
    -for 48 hours before administration of MTX and for 5 days after (interacting medications delay clearance and can cause nephrotoxicity)
  3. Urine alkalization and IV hydration
    -helps clear MTX better (to avoid nephrotoxicity)
    -give sodium bicarb infusion until urine pH is at least 7 (sometimes patients take sodium bicarb tablets at home beforehand to save time)
  4. Monitor MTX levels periodically
    -12 and 24 hours after infusion
  5. Leucovorin rescue therapy
    -should be started 24 hours after the end of the infusion (this is a folate analog - helps with myelosuppression)
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14
Q

What can be used if MTX toxicity occurs?

A

Glucarpidase
-If MTX level is > 1 micromole/L with delayed clearance and renal impairment

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15
Q

Pemetrexed MOA

A

Inhibits thymidylate synthetase
-which inhibits dihydrofolate synthesis, and therefore DNA synthesis

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16
Q

Pemetrexed pre-treatment (3)

A
  1. Folic acid
    -(instead of leucovorin rescue therapy like with MTX)
    -folic acid PO starting 7 days prior to infusion and for 21 days after
    -to help with myelosuppression
  2. Vitamin B12
    -given IM once, 7 days prior to infusion and every 3 cycles thereafter
    -to prevent anemia
  3. Dexamethasone
    -PO BID x 3 days, starting 1 day before infusion
    -to prevent skin pealing (desquamation) and rash
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17
Q

Pemetrexed DDI (1)

A

NSAIDs
-these delay clearance of pemetrexed
-discontinue for 2-5 days before infusion and for 2 days after
(but doesn’t interact with all those other agents like MTX)

18
Q

What is the dose limiting ADR of pemetrexed?

A

Myelosuppression
-particularly thrombocytopenia

19
Q

Pemetrexed ADRs (4)

A

Myelosuppresion (dose limiting)
Skin peeling/rash (desquamation)
Mucositis
Diarrhea (not too severe)

20
Q

Fludarabine MOA

A

Purine analog (antagonist)
Inhibits DNA polymerase
Causing DNA strand breaks and apoptosis (inhibits DNA replication = antimetabolite)

21
Q

What is the dose limiting toxicity of fludarabine?

A

Myelosuppression

22
Q

Fludarabine nadir considerations

A

Thrombocytopenia nadir is slightly more prolonged than neutropenia nadir…
Neutropenia nadir = ~13 days
Thrombocytopenia nadir = ~16 days

23
Q

Fludarabine ADRs/considerations (3)

A

Myelosuppression - dose limiting

Neurotoxicity (delayed symptoms- 3-4 weeks after infusion)

Increased risk of infections
-prophylax for PCP (with Bactrim)

24
Q

Cytarabine and gemcitabine MOA

A

Pyrimidine antagonists
Modified sugar moieties, integrate into DNA - inhibit DNA polymerase, and therefore DNA synthesis (= antimetabolites)

25
Q

Gemcitabine is one of the most important drugs for treating what type of cancer?

A

Pancreatic cancer

26
Q

Cytarabine standard vs high dose toxicities

A

Standard
-dose limiting toxicity is myelosuppression
-rash

High dose
-dose limiting toxicity is cerebellar syndrome (ataxia, difficulty walking and speaking)
-conjunctivitis (dexamethasone eye drops should be given during and after infusion)
-hand foot syndrome (numbing/tingling/swelling)

27
Q

Gemcitabine ADRs

A

Dose limiting toxicity - myelosuppression (specifically thrombocytopenia)

Others:
-skin rash
-peripheral edema
-hepatotoxicity
-flu like symptoms
-drug fever

28
Q

5-Fluorouracil MOA (2) - and how this relates to administration of the drug

A

Prodrug, similar in structure to uracil but with a fluoride

It is metabolized to a nucleotide which is the active drug - cells will think that this is a pyrimidine, binds to an inhibits thymidylate synthetase - resulting in no thymine production - inhibiting DNA synthesis - resulting in cell death

Also… uracil is part of RNA- so it will also incorporate into RNA and inhibit RNA synthesis and protein translation

The DNA synthesis inhibition occurs with continuous administration of the drug (over time)
The RNA inhibition occurs right away
So we give a bolus dose, followed by a continuous infusion

29
Q

What drug is given to enhance the function of 5-FU, how does this work?

A

Leucovorin is given with 5-FU
-5-FU binds to thymidylate synthetase (inhibiting formation of thymine) - leucovorin enhances the affinity between 5-FU metabolites and the thymidylate synthetase - thus enhancing the anticancer effect

30
Q

5-FU is often used in combination with ___________ for treatment of _____________

A

Oxaliplatin for treatment of colorectal cancer

31
Q

5-FU Metabolism consideration

A

5-FU is metabolized by DPD (Dihydropyrimidine dehydrogenase) into an inactive metabolite
-some people may have DPD deficiencies - so they will have increased toxicities (hematologic and diarrhea)
-so we test people for enzyme expression before giving

32
Q

5-FU DDI

A

Warfarin
-causes increased INR - so dose of warfarin should be decreased (or switch to another agent)

33
Q

What is the dose limiting toxicity of 5-FU bolus vs continuous infusion

A

bolus = myelosuppression
continuous infusion = GI toxicity (diarrhea - very severe)

34
Q

5-FU ADRs

A

General ADRs -
photosensitivity (counsel patients to use sunscreen, avoid exposure)
rash
hand foot syndrome

Bolus dose limiting ADR - myelosuppression

Continuous infusion dose limiting ADR - diarrhea
Other continuous infusion adrs:
-mucositis
-coronary vasospasm

35
Q

5-FU administration

A

IV only (due to short half life)

36
Q

Capecitabine MOA/administration considerations

A

Oral prodrug for 5-FU

Error prone dosing- taken BID for 2 weeks, and then not taken for 1 week

37
Q

Capecitabine DDI

A

Warfarin (increases INR, decrease warfarin dose or change drug)

38
Q

Capecitabine dose limiting toxicity

A

Myelosuppression

39
Q

Capecitabine ADRs

A

Dose limiting - myelosuppression
❖Hand-foot syndrome
❖Mucositis
❖Diarrhea
❖Bilirubin elevation
❖Cardiotoxicity

40
Q

Capecitabine contraindication

A

CrCl < 30 mL/min

41
Q

Mercaptopurine (6-MP) and Thioguanine (6-TG) MOA

A

Similar to purines - function as fake purines, get into the cell, inhibit DNA synthesis as a result

42
Q

What should patients be screened for before taking mercaptopurine?

A

TPMT enzyme
-TPMT metabolized 6-MP into an inactive metabolite, if patient has deficiency in TPMT, it will go down the other pathway more - resulting in more active toxic metabolite … which can result in more bone marrow suppression
-dose reduction may be needed if they have less TPMT expression

Hematology/Oncology (17 decks)

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