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PT 2 > Block 10 - L3, L5 > Flashcards

Block 10 - L3, L5 Flashcards

1
Q

What is the role of topoisomerase I?

A

Introduces transient protein-bridged DNA breaks in one single strand of DNA, relaxes the strand and re-anneals the strand

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2
Q

What is the role of topoisomerase II?

A

Introduces transient protein-bridged DNA breaks in BOTH strands of DNA, relaxes the strand and re-anneals the strand

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3
Q

List the types of topoisomerase inhibiting drugs.

A
  1. Topoisomerase I inhibitors (topotecan, irinotecan)
  2. Topoisomerase II inhibitors - intercalators (daunomycin, doxorubicin, mitoxantrone, dactinomycin)
  3. Topoisomerase II inhibitors - non-intercalators (etoposide)
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4
Q

Which of these drugs are cross resistant and why?

A

Both types of topoisomerase II inhibitors and the tubulin inhibitors (vinc…)

Multidrug resistance due to a membrane bound efflux pump (P glycoprotein)

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5
Q

How can resistance of these drugs be reversed?

A
  1. Giving some of these drugs as continuous infusions

2. Giving quinine, verapamil, and cyclosporine to block the efflux pump

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6
Q

What is the cell cycle specificity and MOA of doxorubicin?

A

CCNS

MOA - intercalates into DNA and inhibits topoisomerase II, producing double-stranded DNA breaks

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7
Q

When is doxorubicin dose-reduced?

A

In the presence of jaundice (Excreted as a thiol adduct into the bile)

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8
Q

What are the AE and DL of doxorubicin?

A

N/V, hair loss, stomatitis, myelosuppression

DL - myelosuppression

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9
Q

What is the cumulative toxicity of doxorubicin and how is it monitored?

A

Cardiomyopathy; obtain EF prior to therapy

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10
Q

What is the maximum lifetime dose of doxorubicin?

A

400 mg/M^2

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11
Q

Discuss the schedule dependency of the cardiac toxicity and anti-tumor effect of doxorubicin.

A

Cardiac toxicity - schedule dependent

Anti-tumor effect - schedule independent

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12
Q

How can the cardiac toxicity of doxorubicin be addressed?

A

Longer infusion times are less cardiotoxic; pretreatment with dexrazoxane (iron chelator) may also be helpful

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13
Q

What is the cell cycle specificity and MOA of irinotecan?

A

CCNS

Prodrug, upon activation to SN-38, it inhibits topoisomerase I, leading to single strand DNA breaks

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14
Q

When is irinotecan dose-reduced?

A

Jaundice (hepatic metabolism)

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15
Q

What are the AE and DL of irinotecan?

A

AE - N/V, myelosuppression, stomatitis, hair loss, early cholinergic diarrhea, late secretory diarrhea

DL - myelosuppression

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16
Q

What is irinotecan indicated for?

A

Colon cancer

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17
Q

What is topotecan indicated for?

A

Ovarian cancer (resistant to other chemo)

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18
Q

What genetic mutation affects treatment with irinotecan?

A

Patients with UGT1A1*28 = Gilbert’s syndrome - (decreases glucuronidation, increases myelosuppression and diarrhea)

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19
Q

How is irinotecan-induced early diarrhea treated?

A

Atropine

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20
Q

How is irinotecan-induced late diarrhea treated?

A

Imodium, hydration

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21
Q

What is the cell cycle specificity and MOA of bleomycin?

A

CCS - G2-M

Free radical damage to DNA

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22
Q

When is dose reduction needed for bleomycin?

A

Renal insufficiency

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23
Q

What are the AE and DL of bleomycin? What is the cause of the unique AE?

A

AE - skin hyperpigmentation, pulmonary toxicity, stomatitis, hair loss, fever, chills, anaphylaxis

DL - pulmonary toxicity

Lungs and skin cannot inactivate the drug

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24
Q

How is bleomycin cumulative toxicity monitored/protected against?

A
  1. Monitor with pulmonary function tests; obtain baseline
  2. Avoid administering high oxygen concentrations
  3. Test dose to prevent anaphylaxis
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25
Q

What is the indication of bleomycin?

A

Testicular cancer

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26
Q

What are two hormone dependent cancers?

A

Breast and prostate cancer

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27
Q

What are the indications of prednisone in cancer treatment?

A

Myelo- and lymphoproliferative disorders

Multiple myeloma
Hodgkin’ disease
Non-Hodgkin’s lymphoma
Some leukemia

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28
Q

What are the AE of prednisone?

A

Weight gain, HTN, edema, carbohydrate intolerance, suppression of pituitary-adrenal axis, weakness, euphoria, increased appetite

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29
Q

How is dexamethasone used in treating cancer?

A
  1. Treatment of cerebral edema in patients with brain metastases
  2. Adjunct with 5-HT3 inhibitors to prevent/ameliorate chemo-related N/V
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30
Q

What is the MOA and indication of tamoxifen?

A

Oral SERM that antagonizes the E2 receptor on cancer cells; breast cancer treatment AND prevention

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31
Q

What are the AE of tamoxifen?

A

Hot flashes, thrombosis, endometrial cancer, decreased rates ob one loss in post-menopausal women

32
Q

What is the MOA of anastrozole/letrozole/exemestane?

A

Rapid reduction of estrogen levels via inhibition of aromatase

33
Q

What is the indication of aromatase inhibitors?

A

Breast cancer

34
Q

What are the AE of aromatase inhibitors?

A

Arthralgias, bone pain, bone loss, osteoporosis, hot flashes

35
Q

What is the goal of treatment of prostate cancer?

A

Decrease testosterone production via androgen deprivation therapy

36
Q

What is the MOA of fluatmide/bicalutamide and what is it used for?

A

Inhibit cancer cell uptake of testosterone; prostate cancer

37
Q

What is the MOA of leuprolide acetate/goserelin?

A

Decreases levels of testosterone by decreasing FSH and LH (GnRH agonist)

38
Q

What are the AE of leuprolide acetate?

A

Weakness, decreased libido, ED, loss of muscle mass, gynecomastia, change in body fat distribution

39
Q

What is the general MOA of anti-metabolites?

A

These are structural analogs of naturally occurring metabolites; they can substitute for the naturally occurring metabolites and cause cessation of synthesis (usually of nucleic acids)

40
Q

What is the cycle specificity of methotrexate?

A

S phase

41
Q

What is the MOA of methotrexate?

A

Binds to dihydrofolate reductase (DHFR), decreasing tetrahydrofolate and impairing purine synthesis

42
Q

How does polyglutamation affect the MOA of methotrexate?

A

Polyglutamation retards cellular egress of methotrexate, increasing the inhibition of enzymes involved in purine and thymine synthesis

43
Q

What rescues a cell treated with methotrexate?

A

Administration of tetrahydrofolate (leucovorin)

44
Q

What are the AE and DL of methotrexate?

A

N/V, stomatitis, myelosuppression

DL - myelosuppression

45
Q

When is methotrexate dose-reduced?

A

Renal insuficiency

46
Q

What are the indications of methotrexate?

A 
Lymphoma
Leukemia
Brain tumors
Breast cancer
RA
Psoriasis
*Meningitis - can be given intrathecally
47
Q

Discuss the clinical impact of protein binding on administration of methotrexate.

A

Highly protein bound; when co-administered with drugs (aspirin, sulfonamides, penicillins) that displace methotrexate from albumin, toxicity may increase

48
Q

Discuss the clinical impact of volume distribution on administration of methotrexate.

A

Methotrexate can access third space accumulations of fluid and will slowly leak out, causing prolonged excretion (contraindicated in ascites and pleural effusions)

49
Q

When should methotrexate be dose-reduced?

A

Patients with impaired renal function (filtered, secreted, and reabsorbed by the kidney)

50
Q

What is the clinical important of methotrexate being excreted by the kidney?

A

Aspirin and penicillins are also excreted this way, and can interfere with urinary excretion of methotrexate; probeneecid blocks the organic acid transport system and will also interfere

51
Q

What happens to methotrexate in alkaline pH?

A

Increased solubility (can alkalinize the urine to promote excretion)

52
Q

Methotrexate penetrate the ___ at high doses.

A

CNS

53
Q

Describe the process of giving high dose methotrexate with leucovorin rescue.

A
  1. IV hydration with sodium bicarbonate to alkalinize the urine
  2. Check the urine pH each void; do not administered MTX unless pH >/= 7
  3. Administer MTX IV
  4. Variable time period later, begin IV or oral leucovorin
  5. Monitor MTX levels
  6. Stop rescue when MTX level is <5E-7 M at 48 hours
54
Q

Which cells are rescued by leucovorin and why?

A

Bone marrow and GI epithelial cells - they do not form polyglutamates

55
Q

What is the MOA of pemetrexed?

A

Inhibition of thymidylate synthase

56
Q

What are the AE and DL of pemetrexed?

A

AE - rash, stomatitis, diarrhea, hand foot syndrome, myelosuppression

DL - myelosuppression

57
Q

How can the extent of myelosuppression be reduced in pemetrexed treatment?

A

Pre-treat with vitamin B12 and oral folic acid

58
Q

What are the indication of pemetrexed?

A

Lung cancer

Mesothelioma

59
Q

What is the cell cycle specificity and MOA of cytosine arabinoside?

A

CCS - S-phase

Undergoes sequential phosphorylation to the triphosphate and is incorporated into the DNA; inhibits DNA polymerase and chain elongation

60
Q

What are the AE and DL of cytosine arabinoside?

A

AE - myelosuppression, N/V, hair loss, stomatitis, hepatic toxicity
DL - myelosuppression

61
Q

What is the indication of cytosine arabinoside?

A

Leukemia

62
Q

What is the 3+7 regimen for treatment of AML with cytosine arabinoside?

A

3 days IV anthracycline

7 days continuous infusion of cytosine arabinoside

63
Q

What are the AE of high dose cytosine arabinoside therapy?

A

Myelosuppression, cerebellar toxicity, conjunctivitis

64
Q

What are the indications of gemcitabine?

A

Pancreatic and lung cancers

65
Q

What is the cell specificity and MOA of 5-flurouracil?

A

CCS - S phase

Production of FdUMP, which inhibits thymidylate synthase and decreases thymidine production

66
Q

What are the AE and DL of 5-flurouracil?

A

AE - N/V, stomatitis, rash, diarrhea, myelosuppression, hyperpigmentation of the palms, increased sensitivity to sunlight, coronary artery vasospasm (rare), cerebellar toxicity (rare), excess lacrimation, hand foot syndrome

67
Q

What enhances the cytotoxicity of 5-FU and why?

A

Leucovorin
5-FDUMP + leucovorin form a strong inhibitory complex with thymidylate synthetase, leading to thymineless death

(also enhances GI toxicity)

68
Q

Initial metabolism of 5-FU requires what enzyme?

A

Dihydropyrimidine dehydrogenase (DPD)

Patients who lack this enzyme (3-5% of population) can have severe toxicity

69
Q

What are the indications of 5-FU?

A

Breast cancer
Head and neck cancer
GI cancer

70
Q

5-FU is frequently given with ___.

A

Radiation therapy (as a radiation sensitizer)

71
Q

Why can capecitabine replace 5-FU?

A

Oral administration (5-FU is IV)

72
Q

What is the cell cycle specificity and MOA of 6-mercaptopurine?

A

CCS - S

Inhibits enzymes of de novo purine nucleotide synthesis

73
Q

Why must 6-mercaptopurine be dose-reduced in patients taking allopurinol? What is an alternate option?

A

It is inactivated by xanthine oxidase; allopurinol inhibits xanthine oxidase = toxicity

6-thioguanine - no adjustment needed

74
Q

What is the indication of 6-mercaptopurine?

A

Childhood acute leukemia

75
Q

What is the AE and DL of 6-mercaptopurine

A

AE - myelosuppression

DL - myelosuppression

PT 2 (15 decks)

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