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IHO Week 3 - WLB > Antimetabolites (Antineoplastics II) - Fitz > Flashcards

Antimetabolites (Antineoplastics II) - Fitz Flashcards

1
Q

What are the four antineoplastics that are natural products and consequently increase P-glycoprotein expression?

A
  1. Vincristine
  2. Paclitaxel
  3. Doxorubicin
  4. Etoposide
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2
Q

Long term use of what drug causes CHF?

A

Doxorubicin

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3
Q

What antineoplastic causes hemorrhagic cystitis?

A

Cyclophosphamide

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4
Q

What drug reverses hemorrhagic cystitis caused by an antineoplastic drug?

A

MESNA

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5
Q

What drug causes BOTH renal toxicity and ototoxicity?

A

Cisplatin

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6
Q

What two antineoplastics cause neurotoxicity?

A

Vincristine & Paclitaxel

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7
Q

What antineoplastic drug prevents DNA synthesis category, but is not actually an antimetabolite?

A

Hydroxyurea

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8
Q

Why is it important to monitor serum Methotrexate levels during the initial course of drug treatment?

A

High Methotrexate levels in the blood require additional Leucovorin rescue.

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9
Q

When a patient does not respond to antineoplastic drug therapy, what things should you be concerned about?

A
  1. Resistance
  2. Decreased activation
  3. Inherited deficiency of the metabolic enzyme (how drug is eliminated, increased toxicity if drug not eliminated)
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10
Q

What drug that we need to know causes Tumor Lysis Syndrome?

A

6-mercaptopurine

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11
Q

What are you going to do if a patient being treated with 6-mercaptopurine develops Tumor Lysis Syndrome?

A

Give Allopurinol! (excess uric acid)

Decrease dose of 6-MP (by 25%)

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12
Q

What are the two groups/mechanisms of drugs that prevent DNA synthesis?

A
  1. Nucleotide synthesis inhibitors
    1. blocking production of nucleotides
  2. Inhibitors of DNA synthesizing enzymes
    1. inhibit DNA polymerase
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13
Q

What are the three folic acid analogues that are nucleotide synthesis inhibitors?

A
  1. Methotrexate
  2. Pemetrexed
  3. Pralatrexate
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14
Q

What is the MOA of folic acid analogues? Differences in the three drugs?

A

competitive inhibitors of DHFR

  • MTX blocks DHFR more, and Thymidylate Synthase less
  • P drugs block DHFR less, and TS more
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15
Q

What are possible forms of resistance to folate analogues?

A
  • Change target enzyme
    • decrease DHFR affinity for MTX
  • increase DHFR expression
  • decrease polyglutamination
  • decrease accumulation of drug by decreasing transport
    • decrease expression of Reduced Folate Carrier
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16
Q

What is unique about the pharmacokinetics of folate analogues?

A
  • Have to use transport systems that are used by a cell to bring folate in
    • increased sensitivity in cells/tissues where folate receptor is increased
    • increased resistance where Reduced Folate Carrier expression is reduced
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17
Q

How are folate analogues administered?

A
  • MTX can be given orally for non-antineoplastic Tx
  • Antineoplastic Tx: given IV or intrathecally to cross BBB
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18
Q

How much of folate analogue drug is excreted unchanged in urine? How does this affect patients with altered kidney function?

A
  • Excreted 90% unchanged in urine
    • decreased kidney function → severe bone marrow suppression
    • administer with bicarbonate to maintain concentrations appropriately
  • Drug interactions: NSAIDs, Cisplatin (nephrotoxic), weak acids (Aspirin)
    • alter renal excretion
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19
Q

What are the therapeutic uses of folate analogues?

A
  • MTX: extremely broad spectrum antineoplastic
  • P drugs: more selective action
    • mesothelioma, NSCLC
20
Q

What are the potential cytotoxic side effects of folate analogues?

A
  • primary toxic effects are on bone marrow
  • pneumonitis (cough, fever and interstitial infiltrate)
  • hepatic fibrosis
  • alopecia, dermatitis
  • MTX is abortifacaent
21
Q

What is the advantage of Leucovorin Rescue?

A
  • allows use of higher doses of MTX
  • decreases toxicity
  • shorten treatment term
  • decrease chance of resistance
22
Q

When is Leucovorin administration fatal?

A

When given intrathecally (CNS)

23
Q

What are the two pyrimidine analogues?

A
  1. 5-Fluoruracil
  2. Capecitabine
24
Q

What is MOA of pyrimidine analogues?

A
  • 5-FU: inhibits thymidylate synthase
  • Capecitabine: converted to 5-FU in cancer cells → inhibits thymidylate synthase
  • Cells unable to make dTMP
25
Q

Why is Leucovorin also used in antineoplastic treatment with pyrimidine analogue drugs?

A

increases binding of 5-FU to thymidylate synthase

(increases 5-FU efficacy)

26
Q

What are two potential forms of resistance to pyrimidine analogues?

A
  • changes in target enzymes
    • increased expression of thymidylate synthase
  • decreased activation of prodrugs
    • decreased pyrimidine monophosphate kinase activity
27
Q

What is event is important for 5-FU to function?

A
  • activation of drug
    • drug must enter pyrimidine synthesis pathway (3 steps)
      • pyrimidine monophosphate kinase (form of resistance)
28
Q

How are folate analogue antineoplastics eliminated?

A
  • broken down by dihydropyrimidine dehydrogenase
  • significant metabolic degradation occurs (~80% of the drug is eliminated by hepatic metabolism and 20% by renal excretion)
  • many other tissues also degrade 5-FU (GI tract, so cannot give drug orally)
  • inherited deficiency of dihydropyrimidine dehydrogenase leads to greatly increased drug sensitivity (~8% of US population)
29
Q

What are the therapeutic uses of pyrimidine analogues?

A
  • tends not to be particularly effective when given alone - synergistic with METHOTREXATE
  • colorectal cancer (most widely used drug for this purpose)
  • ovarian and breast cancer (part of CMF and FAC regimens)
30
Q

What are the possible toxic side effects of pyrimidine analogues?

A
  • 5-FU has a low therapeutic index (even for an antineoplastic drug)
  • primary toxic effects are on bone marrow
    • myelosuppression reaches maximum in 9-14 days
  • acute cerebellar syndrome (somnolence, ataxia of trunk or extremities, unsteady gait, slurred speech, nystagmus)
    • occurs within weeks/months of initiating treatment in 5% of patients
    • complete recovery following cessation of treatment
  • alopecia, dermatitis
  • hand-foot syndrome (palmar-plantar erythrodysesthesia)
31
Q

What two drugs are purine analogues?

A
  1. 6-Mercaptopurine
  2. 6-Thioguanine
32
Q

How do 6-MP and 6-TG become activated?

A

HGRPT in the Salvage Pathway of purine synthesis

33
Q

What enzyme do purine analogues block?

A

Guanylyl kinase and cause “pseudofeedback inhibition”

(GMP builds up)

34
Q

What does the inhibition of guanylyl kinase and “pseudofeedback inhibition” result in?

A
  1. interference with DNA and RNA synthesis
  2. inhibition of purine nucleotide interconversion
  3. a decrease in intracellular levels of guanine nucleotides (inhibition of glycoprotein synthesis)
  4. incorporation of purinethiols into both DNA and RNA, leading to DNA damage
35
Q

What are potential forms of resistance to purine analogues?

A
  • changes in target enzymes
    • decreased ability to inhibit PNP and HGPRT
  • decreased activation of prodrugs
    • decreased expression of activation enzymes (esp. HGPRT)
  • increased inactivation
    • increased rates of degradation of the drugs or their “activated” analogues
36
Q

What are possible toxic side effects of purine analogues?

A
  • primary toxic effects are on bone marrow
  • anorexia, nausea and vomiting occur in 25% of adults; less often in children
  • as with any drugs used to treat leukemias, can cause TUMOUR LYSIS SYNDROME
37
Q

How are purine analogues administered?

A

orally

38
Q

What are the two metabolic pathways of 6-MP in the liver? What are “issues” of these systems?

A
  • xanthine oxidase oxidizes 6-MP to 5-thiouric acid, which is inactive
    • DOSE MUST BE ADJUSTED IF GIVEN WITH ALLOPURINOL (due to TUMOUR LYSIS SYNDROME)
    • if you are treating the gout with Allopurinol, you must decrease 6-MP dose
  • methylation and subsequent oxidation
    • the enzyme responsible (thiopurine methyltransferase) has no known natural function, and polymorphic inheritance; 15% of the UK population has little or no enzyme activity, which causes increased toxicity
39
Q

T/F Unlike 6-MP, 6-TG can be administered concurrently with ALLOPURINOL.

A

True

(different metabolism)

40
Q

What are the therapeutic uses of purine analogues?

A
  • acute leukemias
  • 6-TG is synergistic with CYTARABINE
41
Q

What are the four antineoplastic drugs that inhibit DNA synthesizing enzymes?

A
  • PYRIMIDINES: CYTARABINE (Ara-C), GEMCITABINE (converted into compounds that compete with/mimic CDP and CTP)
  • PURINE: CLADRIBINE, FLUDARABINE (converted into compounds that compete with/mimic ADP and ATP)
42
Q

What is the MOA of DNA synthesizing enzyme inhibitors?

A
  • incorporated into DNA where they block DNA polymerases (α = DNA synthesis and β = DNA repair)
    • also inhibit ribonucleotide reductase
43
Q

What DNA synthesizing enzyme inhibitor is not considered an Antimetabolite?

A

Hydroxyurea

44
Q

What are three effects of Cytarabine (Ara-C)?

A
  1. blocks DNA elongation
  2. can cause repititions → mutagenic
  3. forces differentiation of cells
45
Q

What cause cell apoptosis when treating with Gemcitabine?

A

DNA strand termination

46
Q

What diseases/conditions is Hydroxyurea used to treat?

A
  • CML
  • sickle cell anemia
    • increases production of fetal hemoglobin γ, interfering with the polymerization of HbS, and therefore decreasing painful crises in patients with severe sickle cell disease
47
Q

What is unique about Hydroxyurea?

A

synchronizes cells in a radiation-sensitive phase of the cell cycle (G1)

IHO Week 3 - WLB (10 decks)

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