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Chemotherapy Viruses > Chemotherapy IV > Flashcards

Chemotherapy IV Flashcards

1
Q

General MOA of Anti-metabolites

A

Structural analogs of naturally occurring metabolites
Substitute for the naturally occurring metabolites in biochemical pathways and cause cessation of synthesis- usually of nucleic acids
Cell cycle specific (S-phase)

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2
Q

Class of methotrexate

A

Antimetabolite

Anti-folate (structural analogue of folate)

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3
Q

Cycle specificity of methotrexate

A

CCS (S pase)

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4
Q

Macromolecular target of methotrexate

A

Dihydrofolate reductase

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5
Q

MOA of methotrexate

A

Enters the cell via a specific folate carrier proteins and binds reversibly to DHFR (dihydrofolate reductase)
Folate —DHFR—-> tetrahydrofolate

MTX (and folate) are polyglutamated by folylpolygutamate synthetase - polyglutamated forms are retained in cancer cells -> inhibitory effects on enzymes involved in purine synthesis and thymidylate synthesis

Dihydrofolate accumulates and tetrahydrofolate (carbon donor for purine synthesis) declines

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6
Q

MOA of leucovorin, citrovorum factor

A

Tetrahydrofolate analogue can rescue the cell from the cytotoxicity of MTX
Selectivity depends on the extent of polyglutamation of MTX in normal and malignant cells (bone marrow cells and intestinal epithelial cells do not form appreciable levels of MTX-polyglutamate = rescued)

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7
Q

Color of Methotrexate

A

Yellow in solution

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8
Q

Excretion of Methotrexate

A

Excreted in the urine as the salt of a weak acid (aspirin and penicillins are also excreted this way and these drugs will interfere with excretion; probenecid blocks the organic acid transport system and will also interfere with excretion)

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9
Q

Protein binding of Methotrexate

A

Highly protein bound: co-administration drugs which displace MTX from albumin binding sites may potentiate toxicity

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10
Q

Volume of distribution of Methotrexate

A

TBW: Gains access to third space accumulations of fluid and will slowly leak out and cause a prolonged tail of excretion (i.e. in ascites and pleural effusion)

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11
Q

Contraindications of Methotrexate

A

Ascites and pleural effusions (due to volume of distribution)
Caution in patients with impaired renal function- reduce dose (excretion in urine)

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12
Q

In what situation is Methotrexate solubility increased

A

Alkalinize excretion promotes excretion (esp. important at high doses)

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13
Q

SEs of Methotrexate (standard dose without rescue)

A

Mild nausea and vomiting, stomatitis, myelosuppression is dose limiting

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14
Q

Uses of Methotrexate

A

Intrathecal administration used to treat carcinomatous or lymphomatous meningitis
Breast CA, leukemia, lymphoma, brain tumors, RA, and psoriasis
Choriocarcinoma (first time that a cancer was cured using chemotherapy)

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15
Q

Administration cycle of High Dose Methotrexate with leucovorin rescue

A
  • IV hydration with sodium bicarbonate to alkalinize urine
  • Check urine pH each void - pH> 7 and give bicarb
  • IV MTX
  • Variable time period later begin IV or oral leucovorin administration
  • Monitor MTX levels and stop rescue when MTX level is
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16
Q

Toxicity of high dose Methotrexate therapy

A

No myelosuppression or Stomatitis with rescue

Enteritis, conjunctivitis, renal failure and rarely hepatic failure

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17
Q

Class of Pemetrexed

A

Anti-folate

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18
Q

MOA of Pemetrexed

A

Disrupts folate dependent metabolic processes

Drug is transported into the cell via a folate carrier and is polyglutamated

Inhibits thymidylate synthesis

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19
Q

Uses of Pemetrexed

A

Lung CA and mesothelioma

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20
Q

SEs of Pemetrexed

A

Myelosuppression is dose limiting
Rash, stomatitis, and diarrhea
Hand-foot syndrome

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21
Q

Dose limiting SE of Pemetrexed

A

Myelosuppression

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22
Q

Pretreatment to reduce Pemetrexed induced myelosuppression

A

Parenteral vitamin B12 and oral folic acid

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23
Q

Class of Cytarabine (Cytosine arabinoside)

A

Antimetabolite

Pyrimidine antagonist

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24
Q

Cycle specificity of Cytarabine

A

CSS (S phase)

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25
Q

Macromolecular target of Cytarabine

A

DNA

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26
Q

Bioactivation of Cytarabine

A

Successive phosphorylation via kinases to the triphosphate

27
Q

MOA of Cytarabine

A

Taken up in the cell via a carrier mediated nucleoside transport mechanism and converted to the triphosphate via kinases

ARA-CTP triphosphate is the main cytotoxic metabolite - inhibits DNA polymerase by incorporating into DNA and inhibiting template function and chain elongation

28
Q

What is the cytotoxicity of Cytarabine related to

A

Cytotoxicity is related to the duration of exposure of the cell to Ara-CTP

The retention of Ara-CTP at 4 hours is predictive of cancer cell kill

SCHEDULE DEPENDENT

29
Q

Half-life of Cytarabine

A 
7-20 minutes (initial)
2 hours (terminal)
30
Q

SEs of Cytarabine

A

SEs of Cytarabine Nausea and vomiting, hair loss, hepatic toxicity, stomatitis and myelosuppression (dose limiting)

31
Q

Dose limiting SE of Cytarabine

A

Myelosuppression

32
Q

Use of Cytarabine

A

Intrathecal use for treatment of carcinomatous or lymphomatous meningitis
Used almost EXCLUSIVELY in the treatment of acute leukemia (not in solid tumors)

33
Q

Why does Cytarabine show schedule dependent cytotoxicity

A

Short half life

CCS

34
Q

What is HIDAC (high dose ara-c) therapy

A

Cytarabine (2-3 gm/M2) IV every 12 hours for 6-12 doses

35
Q

Toxicity of HIDAC

A

Myelosuppression
Cerebellar toxicity (frequent neuro exams)
Conjunctivitis (excreted in tears- prevented by steroid eye drops)

36
Q

Regimen of Cytarabine for acute leukemia (3+7 induction regimen)

A

3+7 induction regimen

Anthracycline (doxyrubicin or donamycin) administered IV for 3 days and a continuous IV infusion of cytarabine for 7 days (Schedule dependent cytotoxicity)

37
Q

MOA of gemcitabine

A

Similar to cytosine arabinoside

38
Q

SE of gemcitabine

A

Myelosuppression (dose limiting)

39
Q

Use of gemcitabine

A

Palliative treatment of cancer of the pancreas and lung CA (solid tumors)

40
Q

Class of 5- flurouracil

A

Anti metabolite

Fluorinated pyrimidine

41
Q

Cycle specificity of 5- flurouracil

A

CCS (S-phase)

42
Q

Macromolecular target of 5- flurouracil

A

Thymidylate synthetase, RNA and DNA

43
Q

Bioactivation of 5- flurouracil

A

Successive phosphorylation to the triphosphate and metabolism to FdUMP

44
Q

MOA of 5- flurouracil

A

1) Production of FdUMP which inhibits thymidylate synthetase (dUMP -> dTMP inhibited)
Tetrahydrofolate + FdUMP binds tightly to thymidylate synthetase and decreases the production of thymine nucleotides (thyminless death***)

2) Sequential phosphorylation and incorporation into the RNA and DNA

45
Q

Metabolism of 5- flurouracil

A
  • Extensively metabolized by the liver (80%)
  • Initial metabolism required dihydropyrimidine dehydrogenase (DPD): 3-5% of population is deficient (autosomal recessive)= severe toxicity
46
Q

SEs of 5- flurouracil

A
  • Standard dose: rash, stomatitis, and diarrhea and mild myelosuppression
  • Hyperpigmentation of the skin occurs and there is an increased sensitivity to sunlight
  • Chest pain (due to coronary artery vasospasm) and cerebellar ataxia rarely occur
  • Excess lacrimation
  • Hand foot syndrome
47
Q

Administration of 5- flurouracil

A
  • Infusion may be more effective than bolus due to short half-life and cell-cycle specificity
  • 5-FU and leucovorin lead to better response rates but worse SEs (leucovorin potentiates 5-FU effects)
48
Q

Uses of 5- flurouracil

A
  • Frequently given with radiation therapy as a radiation sensitizer
  • Breast CA, head and neck cancer, **GI CA
49
Q

Class of Capecitabine

A

Prodrug of 5-FU

50
Q

Metabolism of Capecitabine

A

Metabolized in the liver by carboxylesterase to an intermediate, then converted by cytadine deaminase to 5’deoxy-5-fluorouradine
Hydrolyzed by thymidine phosphorylase to fluorouracil in the tumor

Tumor cells have higher concentrations then normal cells of thymidine phosphrylase

51
Q

Uses of Capecitabine

A

GI tract malignancies and breast CA

52
Q

SEs of Capecitabine

A

Rash
Hand foot syndrome* (red, thick, painful skin reaction)
Diarrhea*
Myelosuppression

53
Q

Administration of Capecitabine

A

Orally (given on the same days as radiation to sensitize)

Substitute for IV infusions of 5-FU

54
Q

Class of 6-mercaptopurine

A

Antimetabolite

Purine antagonist

55
Q

Cycle specificity of 6-mercaptopurine

A

CSS (S phase)

56
Q

Macromolecular target of 6-mercaptopurine

A

Enzyme inhibition and incorporation into RNA and DNA

57
Q

Bioactivation of 6-mercaptopurine

A

Metabolized by hypoxanthine-guanine phophoribosyl transferase to form 6-thioinosinic acid

58
Q

MOA of 6-mercaptopurine

A

6- thioinosinic acid inhibits enzymes of de novo purine nucleotide synthesis

59
Q

Metabolized by 6-mercaptopurine

A

Metabolized to inactive 6-thiouric acid by the enzyme xanthine oxidase (allopurinol inhibits xanthine oxidase)

60
Q

SEs of 6-mercaptopurine

A

Myelosuppression (dose limiting)

61
Q

In which case must 6-mercaptopurine dose be reduced

A

Reduce 50-75% when given with allopurinol (xanthine oxidase inhibitor)

62
Q

Uses of 6-mercaptopurine

A

Childhood acute leukemia (ALL)

63
Q

Metabolism of 6-thioguanine???

A

Undergoes a deamination during its metabolism

No interaction with xanthine oxidase

64
Q

In which case must 6- thioguanine dose be reduced

A

NONE

Do not need to reduce when combined with allopurinol

Chemotherapy Viruses (5 decks)

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