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Pharm Block 2 > Cancer Pharmacology (part I) > Flashcards

Cancer Pharmacology (part I) Flashcards

1
Q

What are alkylating agents?

A

Highly reactive organic molecules which “alkylate” DNA by
interacting with nucleophilic groups in the DNA molecule. This disrupts normal DNA causing induction of
apoptosis.

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2
Q

What part of the cell cycle do alkylating agents target?

A

Alkylating agents are phase non-specific. Cells must be cycling to be killed, but the drugs are active at any point in the cycle

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3
Q

What type of response curve do alkylating agents have?

A

Alkylating agents have a linear response curve

- higher dose => more cells killed

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4
Q

What are common side effects of alkylating agents?

A
  • Nausea
  • Marrow suppression
  • Mutagenesis
  • Secondary carcinogenesis
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5
Q

What is mechlorethamine (nitrogen mustard)?

A

Mechlorethamine was the first chemotherapeutic agent

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6
Q

How is nitrogen mustard administered?

A

Nitrogen mustard is usually given via IV infusion but also topical to treat T-cell neoplasms

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7
Q

Why does mechlorethamine not require dose adjustment in renal or hepatic failure?

A

Mechlorethamine is rapidly regraded by NON-ENZYMATIC hydrolysis and therefore does not require dose adjustment in renal or hepatic failure

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8
Q

What are the major side effects of mechlorethamine?

A
  • Nausea
  • Vomiting
  • Alopecia
  • Myelosuppression
  • Secondary cancers (especially leukemia, lymphoma, MDS)
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9
Q

What is Cyclophosphamide?

A
  • A chemical derivative of mechlorethamine

- The most widely used of the alkylating agents – used in a variety of hematologic and solid tumors.

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10
Q

How is cyclophosphamide administered?

A

May be given either IV (used for higher doses) or orally.

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11
Q

How is cyclophosphamide activated and eliminated?

A
  • Must be activated by the hepatic p450 system.

- Eliminated by hepatic metabolism (75%) of kidneys (25%).

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12
Q

What is a unique side effect of cyclophosphamide and how is it caused?

A
  • Hemorrhagic cystitis.
    • This is caused by the metabolite acrolein that is secreted in the urine.
    • This can be prevented by aggressive hydration or (more commonly) MESNA (2-mercaptoethane sulphonate) that binds and inactivates acrolein in the urine.
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13
Q

What is cisplatin?

A

Cisplatin is a bifunctional alkylating agent that is a commonly used analogue

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14
Q

How does cisplatin work?

A

Cisplatin enters cells by passive diffusion then becomes ionized

  • It binds to DNA to form interstrand and intrastrand cross links
    • Cell cycle specific
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15
Q

What types of cancers is cisplatin used in?

A
  • Lung
  • Breast
  • Ovarian
  • Head and Neck cancers
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16
Q

What are the major side effects of cisplatin?

A
  • Renal insufficiency
  • Neuropathy
    • Both are reversible
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17
Q

What is a “secondary” malignancy?

A
  • Secondary malignancy are a side effect of drugs used to treat a primary or initial cancer
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18
Q

What is a common phenomena associated with secondary malignancy?

A
  • Polycythemia vera

- Leukemia is also a side effect

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19
Q

Treatment of lymphoma leads to risk of what secondary condition?

A
  • Treatment of lymphoma with intense therapy has lead to approximately 10% of patients being at risk of secondary leukemia and breast cancer
    • Risk is greatly increased when alkylators and XRT are combined
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20
Q

What are the most common secondary malignancies?

A
  • AML
  • MDS
    • These are usually highly resistant to any therapy
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21
Q

How does chemotherapy cause emesis?

A
  • Enterochromaffin cells release serotonin in response to emetic chemotherapy agents
    • When serotonin binds its receptor it acts on the vagus nerve leading to emesis/nausea
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22
Q

What is Ondansetron (Zofran)?

A

Ondansetron is a selective serotonin receptor blocking agent that is though to block 5HT stimulation of the vagus nerve

  • It may also work by blocking CNS serotonin receptors
  • HELPS TO PREVENT VOMITING AND NAUSEA
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23
Q

How is Ondansetron administered?

A

Ondansetron is given IV or po about 1/2 hour before chemo

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24
Q

What can Ondansetron be combined with for maximal benefit?

A
  • Can be combined with steroids for maximal benefit
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25
Q

What is aprepitant?

A

Aprepitant, a nerokinin1 agonist that blocks substance P binding is a new antiemetic that can be combined with 5-HT inhibitors.

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26
Q

What are antimetabolite agents?

A
  • Broadly antimetabolite agents inhibit the normal metabolic functions of cells
    • Most antimetabolite drugs are targeted to DNA or RNA synthesis
    • These agents commonly resemble normal metabolic intermediates
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27
Q

Which phase are antimetabolite agents specific for?

A

Most antimetabolites are specific for the S phase

28
Q

How should antimetabolites be administered?

A

Antimetabolites should be given by continuous IV infusion or hyper fractionated IV bolus

29
Q

Which cells are particularly sensitive to antimetabolites?

A

– Rapidly cycling normal cells (bone marrow and gut epithelium) are often highly sensitive to these agents

30
Q

What is methotrexate?

A

Methotrexate is a direct descendant of aminopterin

- this is a an analogue of folic acid and inhibits DHFR by competitive inhibition

31
Q

How is methotrexate administered?

A
  • Low dose => oral immuno-suppresion

- High dose => IV

32
Q

What cancers are methotrexate commonly used for?

A
  • Lymphoma
  • Braset cancer
  • Head and neck cancer
  • Lung cancer
33
Q

How is methotrexate given to treat CNS cancers?

A

Methotrexate is give intrathecally to treat CNS cancers

34
Q

What are common side effects of methotrexate?

A
  • Marrow suppression
  • Gi toxicity (mucositis, diarrhea)
  • Renal failure
35
Q

How is renal failure caused by methotrexate?

A
  • Renal failure is caused by precipitation of the drug in the renal tubules
    • Decreased clearance of the drug will increase other side effects
    • Urine is alkalinized to prevent this
36
Q

What is also give with methotrexate to prevent lethal side effects?

A
  • Methotrexate is often given at lethal doses to achieve greater tumor cell kill
    • This must be followed by LEUCOVORIN rescue to prevent lethal side effects
37
Q

How do tumors become resistant to methotrexate?

A
  • Decreased transport
  • Gene amplification
  • Mutation of DHFR => so that it is no longer inhibited by Methotrexate but is able to utilize folic acid
38
Q

For what diseases is methotrexate used for immunosuppresion?

A

Methotrexate is used in rheumatoid arthritis and lupus

39
Q

What is 5 fluoroucil?

A

5 Fluoroucil works in the same metabolic pathway as methotrexate
- It inhibits the enzyme thymidylate synthase by a suicide mechanism

40
Q

For what cancers is 5 fluoroucil used?

A
  • Breast

- GI malignancies

41
Q

What are the common side effects of 5 fluoroucil?

A

Bone marrow and GI toxicities

42
Q

What drug is used to potentiate the action of 5 Fluoroucil (5FU)?

A

Leucovorin

43
Q

What is cytarbine?

A

Cytarbine is the clinically most used member of the nucleoside analogues
- It is the analogue of cytidine with a sugar molecule arabinose

44
Q

What is the mechanism of action of cytarbine?

A
  • Cytarbine is taken int o the cell and metabolized just as the normal compound
    • Once converted to ara-CTP it binds to and competitively inhibits DNA polymerase alpha
      • This interferes with DNA replication
    • Some of the drug is incorporated into DNA where it acts to slow chain elongation and inhibits DNA ligation
45
Q

At what phase does cytarbine work?

A

Cytarbine (ara-C) acts on the S phase

46
Q

What is ara-c most commonly used for?

A

Cytarbine (ara-c) is most commonly used to treat acute myeloid leukemia (AML)
- It is also used to treat lymphoma

47
Q

How is ara-c administered?

A

Ara-c is give by continuous IV for seven days as par tot the AML induction chemotherapy along with Daunarubicin (7+3 regimen)

48
Q

What are the side effects of cytarbine?

A
  • Marrow aplasia
  • GI toxicity
  • Alopecia
49
Q

What dangerous toxicity is associated with high dose ara-c?

A

HiDAC can cause acute severe cerebellar toxicity

50
Q

How do topoisomerase inhibitors act?

A
  • Topoisomerases are involved in the unwinding of the supercoiled DNA during DNA replication and mRNA synthesis
    • If topoisomeraseas are inhibited DNA damage results and induces apoptosis
51
Q

What are two major members of anthracycline antibiotics?

A
  • Doxorubicin

- Daunarubicin

52
Q

How do anthracycline antibiotics work?

A
  • Anthracycline antibiotics consist of a sugar molecule attached to a tetracycline backbone
    • The drug is able to intercalate into DNA
    • This inhibits DNA replication and mRNA synthesis
    • Also inhibits topoisomerase II
53
Q

How do anthracycline antibiotics act on topoisomerase Ii?

A
  • Anthracyclines stabilize a DNA-TopII intermediate and inhibit relegation of DNA ends
    • This results in DNA fragmentation and cell death
54
Q

What are anthracyclines generally used for?

A
  • Hematologic malignancies
  • Breast
  • Lung
  • GI and GU cancers
55
Q

How are anthracyclines administered?

A

IV infusion

56
Q

How are anthracyclines metabolized?

A

Hepatic metabolism

- Give decreased dose in liver failure

57
Q

What are the major side effects of anthracyclines?

A
  • GI
  • Marrow
  • Cardiac
  • Anthracyclines are vesicants (blister agents)
58
Q

What are the cardiac effects of anthracyclines?

A
  • Anthracyclines produce a cumulative dose dependent cardiomyopathy
    • Increased dose leads to increase risk of cardiomyopathy (esp 550mg/m^2)
  • The cardiomyopathy is reversible
  • Patients are subject tot congestive heart failure and arrhythmias
59
Q

What are epidophyllotoxins?

A
  • Epidophyllotoxins complex with topoisomerase II and cause DNA breaks
60
Q

What dose limiting toxicity is associated with epidophyllotoxins?

A
  • Neutropenia
61
Q

What are the main drugs in the epidophyllotoxin class?

A
  • PV-16

- Etoposide

62
Q

What is VP-16 used to treat?

A
  • Testicular
  • Ovarian
  • Lung
  • Lymphoid cancers
63
Q

What are topoisomerase I inhibitors?

A
  • Topotecan/irinotecan are topoisomerase I inhibitors which inhibit the enzymes ability to relegate DNA during replication
    • This results in double strand breaks which are strong activators of DNA damage dependent apoptosis pathways
      -
64
Q

What phase of the cell cycle do topoisomerase I inhibitors work?

A

S phase

65
Q

What cancers are treated with topoisomerase I inhibitors?

A
  • Lung
  • Ovarian
  • Colorectal
66
Q

What is a lethal side effect of topoisomerase I inhibitors (topotecan/irinotecan)?

A

Diarrhea

Pharm Block 2 (15 decks)

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