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SBL > Cancer Pharm: Antimetabolites > Flashcards

Cancer Pharm: Antimetabolites Flashcards

1
Q

What is the MOA of Methotrexate?

A
  • Inhibits synthesis of THF
  • Interferes w/ formation of DNA, RNA, and key cellular proteins
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2
Q

Which enzyme is responsible for activating and increasing the selectivity of the antifolates: methotrexate, pemetrexed, and pralatrexate?

A

Folyl polyglutamate synthase (FPGS) catalyzes formation of intracellular metabolites which are selectively retained in cancer cells

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3
Q

What are 4 mechanisms by which resistance to Methotrexate may develop?↓

A
  • ↓ drug transport via the reduced folate carrier or folate receptor protein
  • ↓ formation of cytotoxic methotrexate polyglutamines
  • ↑ levels of the target enzyme DHFR thru gene amplification, etc.
  • Altered DHFR protein with reduced affinity for methotrexate
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4
Q

What are 4 drug-drug interactions that you must be aware of when giving Methotrexate?

A

Aspirin, NSAIDs, penicillin, and cephalosporinsallinhibititsrenal excretion—> ↑toxicity

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5
Q

Which drug is sometimes used in combo with high-dose methotrexate therapy to rescue normal cells from undue toxicity?

A

Reduced folate leucovorin; reverses action of methotrexate

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6
Q

Which antifolate drug has activity during the S-phase?

A

Pemetrexed

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7
Q

What is the MOA of the antifolate, Pemetrexed?

A
  • Inhibition of thymidylate synthase (TS)
  • Targets and inhibits DHFR and enzymes involved in de novo purine nucleotide biosynthesis
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8
Q

What are some AE’s associated with the antifolate, Pemetrexed; which is unique to this drug?

A
  • Hand-foot syndrome* = painful erythema and swelling of hands and feet
  • Myelosuppression
  • Skin rash + Mucositis
  • Diarrhea + Fatigue
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9
Q

Vitamin supplementation with what can significantly reduce toxicities associated with Pemetrexed and Pralatrexate?

A

Folic acid and Vitamin B12

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10
Q

What are the 3 MOA’s of the antifolate, Pralatrexate?

A
  • Inhibits DHFR
  • Inhibits enzymes involved in de novo purine nucleotide biosynthesis
  • Inhibits thymidylate synthase (TS)
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11
Q

The antifolate, Pralatrexate has been approved for the tx of what?

A

Relapsed or refractory peripheral T-cell lymphoma

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12
Q

What are the 3 active metabolites of 5-FU and what is the MOA of each?

A
  • FdUMP —> inhibition of DNA synthesis thru “thymineless death”
  • FUTP –> incorporated in RNA; interferes w/ RNA processing and mRNA translation
  • FdUTP –> incorporated into DNA resulting in inhibition of DNA synthesis
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13
Q

What are 4 AE’s of the antimetabolite, 5-FU; which is unique?

A
  • GI toxicity (diarrhea/mucositis) = unique
  • Myelosuppression
  • Skin toxicity (hand-foot syndrome) = unique
  • Neurotoxicity
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14
Q

5-FU is the most widely used drug in the tx of which cancer?

A

Colorectal cancer

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15
Q

What is special about the antimetaboite, Capecitabine?

A

A prodrug that is metabolized to 5-FU by thymidine phosphorylase (which has higher expression in some solid tumors - breast and colorectal)

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16
Q

2 main AE’s of the antimetabolite, Capecitabine?

A

Main = diarrhea, hand-foot syndrome

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17
Q

Capecitabine used in conjunction with what drug is the first-line tx for metastatic colorectal cancer?

A

Capecitabine + oxaliplatin = XELOX regimen

18
Q

What are the 2 components of the antimetabolite, TAS-102 and how does each work?

A
  • Trifluridine = metabolized to monophosphate form (inhibits TS) or metabolized to triphosphate form (inhibits DNA synthesis and function)
  • Tipiracil = a TP inhibitor, the key enzyme that degrades trifluridine
19
Q

TAS-102 is useful in which type of colorectal cancer?

A
  • Wild-type and mutant RAS colorectal cancer
  • Used in progressive, refractory colorectal cancer
20
Q

Which phase of the cell cycle is Cytarabine specific for?

A

S phase

21
Q

The antimetabolite, Cytarabine is converted into what; describe the 3 MOA of this metabolite.

A
  • Converted to ara-CMP —> ara-CTP
  • Inhibits DNA polymerase-α and β (blocks DNA synthesis and repair)
  • Incorporated into DNA –> interferes w/ chain elongation and causes defective ligation of new DNA fragments
  • Incorporated into RNA
22
Q

What are 4 AE’s of Cytarabine?

A
  • Myelosuppression
  • Mucositis
  • N/V
  • Neurotoxicity (at high doses)
23
Q

2 clinical uses for Cytarabine?

A

AML and NHL’s; only has activity against hematologic malignancies

24
Q

The anti-metabolite Gemcitabine is phosphorylated to a diphosphate and triphosphate form, what is the MOA of each form?

A
  • Diphosphate = inhibits ribonucleotide reductase; ↓ level of deoxyribonucleotide triphosphates needed for DNA synthesis
  • Triphosphate = inhibits DNA polymerase-α and β (blocks DNA synthesis and repair)
25
Q

What is the dose limiting toxicity of Gemcitabine and which AE is most common?

A
  • Dose limiting = myelosuppression in form of neutropenia
  • Nausea and vomiting (70% of patients) + flu-like syndrome
26
Q

Although both deoxycytidine analogs, how does the clinical use of Cytarabine differ from Gemcitabine?

A
  • Cytarabine only effective against hematologic malignancies
  • Gemcitabine can be used for both solid and hematologic malignancies
27
Q

Gemcitabine was initally approved for use in what type of cancer?

A

Advanced pancreatic cancer

28
Q

Which enzyme is responsible for metabolizing the 6-thiopurines; which toxic effects may be seen with loss of this enzyem?

A
  • Metabolized by thiopurine methyltransferase (TPMT)
  • Loss of this enzyme can lead to: myelosuppression and GI toxicity (mucositis and diarrhea)
29
Q

6-mercaptopurine (6-MP) is inactive in parent form and becomes active when metabolized to what?

A

Metabolized by HGPRT –> monophosphate nucleotide 6-thioinosinic acid

30
Q

What is the MOA of the active metabolite of 6-MP, mono- and triphosphate nucleotide 6-thioinosinic acid?

A
  • Monophosphate acts to inhibit several enzymes of de novo purine nucleotide synthesis
  • Triphosphate form incorporated into both DNA and RNA
31
Q

How is the active form of 6-mercaptopurine (6-MP) inactivated and what clinical implication does this have?

A
  • Converted to inactive metabolite by xanthine oxidase
  • Allopurinol (xanthine oxidase inhibitor) is commonly used in tx of acute leukemia for prevention of hyperuricemia
  • If allopurinol is used w/ 6-MP, would result in ↑ levels of 6-MP and excessive toxicity
32
Q

6-mercaptopurine is used in the tx of what?

A

Childhood acute leukemia

33
Q

List the 5 MOA of 6-thioguanine?

A
  • Inhibits several enzymes in de novo purine nucleotide synthesis
  • Inhibition of purine nucleotide interconversion
  • ↓ IC levels of guanine nucleotides –> inhibits glycoprotein synthesis
  • Interferes w/ formation of DNA and RNA
  • Incorporation of thiopurine nucleotides in DNA and RNA
34
Q

6-thioguanine synergizes with what drug in the tx of adult acute leukemia?

A

Cytarabine

35
Q

What is the MOA of the triphosphate and diphosphate form of Fludarabine (purine antagonist)?

A
  • Triphosphate: inhibits DNA polymerase-α and β (interferes w/ DNA synthesis and repair)
  • Diphosphate: inhibits ribonucleotide reductase leading to inhibition of production of deoxyribonucleotide triphosphates
  • Also induces apoptosis in susceptible cells
36
Q

What is an AE you must consider when using the purine antagonist, Fludarabine; how can this AE be managed?

A
  • ↑ risk for opportunistic infections i.e., P. jiroveci pneumonia (PCP)
  • PCP prophylaxis w/ TMP-SMX at least 3x/week during tx and for one week after
37
Q

2 clinical uses for the purine antagonist, Fludarabine?

A
  • Low-grade NHL’s
  • Chronic lymphocytic leukemia
38
Q

The purine antagonist, Cladribine, has a high specificity for what cells?

A

Lymphoid cells

39
Q

What is the MOA of the purine antagonist, Cladribine, when in active triphosphate form?

A
  • Incorporated into DNA, causing inhibition of synthesis and function
  • Inhibition of DNA polymerase-α and β (interferes w/ synthesis and repair)
40
Q

What AE must you keep in mind when using the purine antagonist, Cladribine?

A
  • Main effect = myelosuppression
  • ↓ in CD4 and CD8 T cells can last 1+ year
41
Q

2 main clinical applications of the purine antagonist, Cladribine?

A
  • Hairy cell leukemia
  • Low-grade lymphoid malignancies: CLL and low-grade NHL’s

SBL (44 decks)

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