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Pharma 2- Semmelweis > B-33. Cancer chemotherapy I (antimetabolites) > Flashcards

B-33. Cancer chemotherapy I (antimetabolites) Flashcards

1
Q

Antimetabolite drugs

A
  • Methotrexate
  • Premetrexed
  • 5-Fluorouracil
  • Capecitabine
  • 6-Mercaptopurine
  • 6-Thioguanine
  • Cytarabine
  • Gemcitabine
  • Bleomycin
  • Actinomycin D
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2
Q

How are healthy cells vs tumor cells effected by antimetabolites? Which part of the cell cycle is halted by antimetabolites?

A

Tumor cells are more rapidly-dividing and thus more sensitive to anti-metabolites than healthy cells. Antimetabolites are “cell-cycle specific”, stopping cells in S phase.

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3
Q

Resistance mechanism of tumor cells to antimetabolites

A
  1. Decreased cellular drug uptake
  2. Decreased activating enzyme activity
  3. Increased enzymatic degradation
  4. Increased repair mechanisms
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4
Q

Side effect of all antimetabolites

A

Side Effects: all antimetabolites result in some degree of myelosuppression and GI effects (mucositis + diarrhea)

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5
Q

Antifolate drugs include

A

Methotrexate and Pemetrexed

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6
Q

How do Antifolate drugs work

A

Inhibit the synthesis of thymidine (pyrimidine deoxynucleotide) catalyzed by thymidylate synthetase (methylation of dUMP → dTMP) using a methylated H4-folate (methylene-THF becomes DHF).

THF is re-formed from DHF by DHF reductase which is then re-methylated and used again.

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7
Q

Methotrexate MOA

A

Acts as a folate analog → uses membrane transporters to enter cell → form MTX-polyglutamates which irreversibly inhibit DHF reductase + thus folate/dTMP synthesis (→ DHF builds up in cell)

● MTX-polyGlu also inhibits thymidylate synthesis and AICAR transformylase (↓ chemotaxis) and synthesis of some purines / AAs

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8
Q

Kinetics of Methotrexate How is it given? Drugs that inhibit it’s renal elimination?

A
  • Methotrexate Kinetics: oral or parenteral; given IV if high conc. desired systemically; intrathecally for CNS effects
    • NSAIDs, penicillins + cephalosporins inhibit MTX renal elimination
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9
Q

Methotrexate Indications

A
  • Indications of Methotrexate:
    • Solid tumors - breast cc. (combo with CP + 5-FU); head + neck, lung cc.
    • Lymphoma - NHL (including w/ CNS involvement)
    • Autoimmune conditions - RA, psoriasis, IBD, SLE (lower doses)
    • Childhood Tumors - Wilms’, choriocarcinoma (as monotherapy), etc.
    • (Abortion / Early Ectopic Pregnancy - in combo with misoprostol; inhibits trophoblast division)
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10
Q

Side effects of Methotrexate

A
  • Side Effects:
    • Folate Deficiency - in normal cells as well, leading to megaloblastic anemia + pancytopenia
      • “Leucovorin rescue” - leucovorin = folinic acid; treats folate deficit in normal cells, but some tumor cells can’t take it up → MTX still effective
      • ↑ LFTs common; fibrosis/cirrhosis more rare)
    • Pulmonary Fibrosis - restrictive lung disease
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11
Q

Pemedtrexed indication

A

Pemetrexed - similar to MTX; indicated in NSCLC, mesothelioma, solid tumors (combo w/ cisplatin)

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12
Q

Pyrimidine antagonist

A
  • Pyrimidine Antagonists:
    1. 5-Fluorouracil
    2. Capecitabine
    3. Cytarabine
    4. Gemcitabine
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13
Q

5-Fluorouracil (5-FU) MOA

A
  • 5-Fluorouracil (5-FU) MOA: a pyrimidine analog that complexes with THF and inhibits thymidylate synthase; forms false nucleotides (5-F-dUMP) that incorporate into DNA/RNA and alter their function
    • Because thymidylate synthase is more directly inhibited by 5-FU than MTX, leucovorin rescue therapy is not effective with 5-FU!
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14
Q

5-Fluorouracil (5-FU) kinetics

A

Given IV; short DOA → multiple hours infusion

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15
Q

5-Fluorouracil (5-FU) side effects

A
  • 5-Fluorouracil (5-FU) Side Effects:
    • Cardiotoxic and neurotoxic
    • Skin reactions - photosensitivity, hyperpigmentation and rashes
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16
Q

5-Fluorouracil (5-FU) indications

A
  • 5-fluorouracil indications:
    • Solid tumors - breast cc. (combo with CP / MTX); colorectal and gastric cc.; BCC; head + neck, liver and pancreas cc.
17
Q

Capecitabine MOA? Kinetics? Indication?

A
  • MOA: prodrug of 5-FU; activation requires thymidine phosphorylase which is most active in tumor cells
  • Kinetics: good oral availability
  • Indications: same as 5-FU
  • Side Effects: mostly milder than 5-FU, less GI / marrow sfx
    • Skin reactions - +/- ulceration, exfoliation
      • neuropathy than 5-FU
18
Q

Deoxycytidine Analogs: inhibit DNA polymerases (drugs)

A

Cytarabine and Gemcitabine

19
Q
  • Cytarabine
    • MOA?
    • Kinetics?
    • Indication?
    • Side effects?
A

Cytarabine

  • MOA: pyrimidine analog; triphosphate metabolites inhibit DNA polymerases α / β
  • Kinetics: given IV for 5-7 day infusion (fast degradation)
  • Indication: leukemias + lymphomas - NHL and AML especially
  • Side Effects: neurotoxicity - hand/foot neuropathy, CNS effects; rarely used due to this
20
Q
  • Gemcitabine
    • MOA?
    • Indication?
    • Side effects?
A

Gemcitabine

  • MOA: similar to cytarabine; metabolites can cause chain termination + inhibit ribonucleotide reductase
  • Indication:
    • Solid tumors - pancreatic, NSCLC, ovarian + bladder cc.
    • Some lymphomas + leukemias
  • Side Effects:
      • severe, life-threatening
    • Flu-like syndrome
      • hand/foot paresthesia
21
Q

Purine antagonist (drugs)

A
  • Purine Antagonists:
    1. 6-Mercaptopurine
    2. 6-Thioguanine
    3. Cladribine and fludarabine
22
Q
  • 6-Mercaptopurine (6-MP)
    • MOA?
    • Kinetics?
    • Side effects?
    • Indication in chemotherapy?
A

6-Mercaptopurine (6-MP)

  • MOA: is a prodrug converted by HGPRT to active metabolites that inhibit PRPP → IMP (inosine monophosphate) and IMP → AMP/GMP conversion + thus de novo purine nucleotide synth
  • Kinetics: good oral availability; metabolized by xanthine oxidase
    • allopurinol inhibits XO → must ↓ 6-MP dose ifusing allopurinol for tumor lysis syndrome
  • Side Effects:
    • Hepatoxicity
  • Indication:
    • ALL - acute lymphocytic leukemia
23
Q
  • 6-Thioguanine (6-TG)
    • MOA?
    • Kinetics?
    • Indications?
A
  • 6-Thioguanine (6-TG)
    • MOA: same as 6-MP
    • Kinetics: no interaction with allopurinol!
    • Indications: AML - acute myeloid leukemia
24
Q
  • Fludarabine and cladribine
    • MOA?
    • Kinetics?
    • Side Effects?
    • Indications?
A
  • Fludarabine and cladribine
    • MOA: are purine analogs that inhibit DNA polymerase α/β + incorporate into DNA → breakage
      • is resistant to adenosine deaminase (a purine disposal enzyme) → reaches high IC concentrations
    • Kinetics: given parenterally with short DOA → multiple days of admin
    • Side Effects:
      • Immunosuppression- very strong; infection reactivation, esp. P. jiroveci (give w/ 1 yr TMP-SMX)
      • CNS toxicity - at high doses
    • Indications:
      • Leukemias and lymphomas - CLL; NHL; cladribine is DOC for hairy cell leukemia
25
Q
A

Pharma 2- Semmelweis (43 decks)

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