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Pharmacology for Amjad > EXAM #2: ANTINEOPLASTIC AGENTS > Flashcards

EXAM #2: ANTINEOPLASTIC AGENTS Flashcards

1
Q

What are the three major cell cycle checkpoints?

A

G1/S
G2/M
Metaphase/Anaphase

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2
Q

What are the specific criteria necessary to proceed through the G1/S checkpoint?

A

1) Cell nutrition, size, and environment must be favorable for replication
2) DNA must be intact

This check ensures the cell is prepared for DNA replication and to enter S-phase.

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3
Q

What are the specific criteria necessary to proceed through the G2/M checkpoint?

A

DNA must be completely replicated

This is the checkpoint that ensures the cell is ready to enter mitosis.

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4
Q

What are the specific criteria necessary to proceed through the metaphase/anaphase checkpoint?

A

1) DNA intact must be intact
2) Chromosomes must be attached to the mitotic spindle

This check ensure that the cell is ready for chromatid separation and is prepared for cytokinesis.

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5
Q

What are the three mechanisms of oncogene formation?

A

First, an oncogene is a mutated form of a normal gene that supported cellular proliferation i.e. “proto-oncogenes”

1) Point mutations
2) Chromosomal translocation
3) Proto-oncogene duplication/ amplification

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6
Q

How can point mutations lead to the development of an oncogene?

A
  • Change in an amino acid regulatory region in the proto-oncogene product
  • Amino acid change that makes the proto-oncogene resistant to degradation
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7
Q

How do chromosomal translocations result in oncogenes? Give an example.

A

Chromosomal translocation that causes the fusion of two genes, the product of which is the “fusion gene”

E.g. “Philadelphia” chromosome (9 x 22) ABL and BCR in CML

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8
Q

What is a major oncogene that is found in roughly 30% of all cancers?

A

Ras

Ras in involved in cell signaling/ GPCR signaling; mutations leave Ras permanently turned on.

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9
Q

Define first order killing of cancer cells i.e. what is the cell kill hypothesis?

A

This is the chemotheraputic elimination of a FIXED percentage of cancer cells.

This is first order kinetics*

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10
Q

What are the four goals of cancer drug therapy?

A

1) Curative intent
2) Adjuvant therapy
3) Neoadjuvant therapy
4) Palliation

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11
Q

List the general characteristics of chemotheraputic drug therapy.

A
  • Drugs are cytotoxic and only PARTIALLY selective
  • Low TI

Thus, adverse effects are common.

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12
Q

What are the general mechanisms of resistance to chemotherapeutic agents?

A

1) Genetic instability
2) Drug efflux pumps/ mutated drug transporters
3) DNA damage repair
4) Cell death inhibition
5) Drug inactivation
- Up-regulation of enzymes that metabolize drugs
6) Drug target alteration
7) Epithelial-Mesenchymal Transition

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13
Q

What types of tumors are easiest to treat with chemotherapy?

A

Tumors that are RAPIDLY growing

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14
Q

Define curative intent.

A

Drug therapy is intended to CURE the disease

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15
Q

Define adjuvant therapy.

A
  • Drug given AFTER primary treatment e.g. surgery

- Prevent recurrence

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16
Q

Define neoadjuvant therapy.

A

Drug given FIRST to SHRINK tumor, making it amenable to surgery

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17
Q

Define palliative therapy.

A

Therapy intended to relieve symptoms and improve quality of life.

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18
Q

Do most cancers follow the cell-kill hypothesis? Why or why not?

A

NO

B/c of the cytotoxicity of chemotherapeutic, it is not possible to dose patients in a manner necessary to achieve 1st order kill.

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19
Q

What is a drug efflux pump?

A

A cellular transporter than “pumps” drugs out

E.g. MDR-2

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20
Q

What is Epithelial- Mesenchymal Transition (EMT)?

A
  • Cell loses adhesive properties and becomes motile

- Changes can also cause drug resistance

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21
Q

What are the three general cytotoxic mechanisms to kill cancer cells?

A

1) Perturb normal DNA replication
2) Perturb mitosis
3) Starve cells of amino acids

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22
Q

What are the three targeted mechanisms to kill cancer cells?

A

1) Perturb hormone and growth factor signaling
2) Inhibit blood supply to tumor e.g. VEGF
3) Target activating proteins

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23
Q

What are cell-cycle non-specific drugs?

A

DNA alkylating agents that kill cells in ANY stage

Preferentially kill replicating cells

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24
Q

What are the S-phase specific drugs?

A

DNA synthesis inhibitors

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25
Q

What is the mechanism of action of the “antimetabolites?”

A

Inhibiting de novo nucleotide biosynthesis and generally target cells in S-phase

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26
Q

What is the function of ribonucleotide reductase?

A

Turning ribonucleotides into deoxyribnucleotides

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27
Q

What is the mechanism of action of methotrexate?

A
  • Anti-metabolite that targets s-phase
  • Inhibition of dihydrofolate reductase i.e. the enyzme that makes THF from dihydrofolate
  • THF is crucial in the action of thymidylate synthetase (dUMP–>dTMP), which is required for DNA synthesis

Essentially, inhibiting DNA synthesis by preventing the action of folate

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28
Q

Why can extremely high does of Methotrexate be administered to pateints?

A

Leucovorin rescue (folinic acid)

Leucovorin is a reduced form of folic acid. Administration within the proper window can allow for nearly fatal doses of methotrexate do be administered (hopefully targeting cancerous/ rapidly dividing cell), followed by Leucovorin rescue to prevent harmful toxic effects of such a high dose to normal tissue.

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29
Q

What are the mechanisms of Methotrexate resistance?

A

1) Impaired transport
2) Altered DHFR (isozyme) that decrease the affinity of methotrexate’s target
3) Elevated DHFR expression

DHFR= dihydrofolate reductase

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30
Q

What are the unique toxicities seen with Methotrexate?

A
  • Interstitial pneumonitis

- Nephrotoxicity

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31
Q

What is the mechanism of action of 5-fluorouracil?

A
  • Pyrimidine analog
  • Anti-metabolite that targets s-phase
  • 5-FU is metabolized:
    1) 5dUMP, which INHIBITS THYMIDYLATE SYNTHASE and prevents DNA synthesis
    2) FUTP that is falsely incorporated into RNA
    3) FdUTP that is falsely incorporated into DNA

False incorporation causes defects in RNA/DNA function and sturucture leading to cell death.*

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32
Q

What are the unique adverse effects seen with 5-FU administration?

A

Oral and GI ulcers

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33
Q

What is Capecitabine?

A
  • Antimetabolite
  • Targets S-phase

This Prodrug of 5-FU that can be given orally; same mechanism of action as 5-FU (inhibition of thymidylate synthase etc.

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34
Q

What is Cytarabine used to treat?

A

This is the most important antimetabolite for AML

It is only used to treat HEMATOLOGIC MALIGNANCIES*

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35
Q

What is the mechanism of action of Cytarabine?

A
  • Pyrimidine analog/ anti-metabolite
  • Targets cells in S-phase

1) Cytarabine or Ara-C is transported into the cell and converted to Ara-CMP by DEOXYCYTIDINE KINASE
2) Ara-CMP is converted to Ara-dCTP
3) Ara-dCTP is incorporated into DNA and inhibits DNA synthesis

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36
Q

What is the specific toxicity that is associated with Cytarabine?

A

Cerebellar Syndrome

*****Note that inactivation of Ara-C required CYTIDINE DEAMINASE; there are low levels of this enzyme in the brain, making brain more susceptible to adverse effects of drug.

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37
Q

What are the symptoms of Cerebellar Syndrome?

A

1) Dysarthria
2) Nystagumus
3) Ataxia

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38
Q

What are the major mechanisms of cytarabine resistance?

A

1) Loss of DEOXYCYTIDINE KINASE
2) Inability of tumor cells to transport Ara-C into cells
3) Cytidine demainase upregulation

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39
Q

What is the mechanism of action of Gemcitabine?

A
  • Pyrimidine analog/ anti-metabolite that targets S-phase

1) Converted to active form by DEOXYCYTIDINE KINASE, like Cytarabine
1) Incorporated into DNA–inhibits DNA synthesis
3) Inhibits RIBONUCLEOTIDE REDUCTASE, which also inhibits DNA synthesis

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40
Q

What are the mechanisms of Gemcitabine resistance?

A

1) Reduced activity of DEOXYCYTIDINE KINASE

2) Increased production of deoxycytidine b/c of inhibitive effect on deoxycytidine kinase

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41
Q

What is the mechanism of action of 6-MP and 6-TG?

A
  • Purine analogs/ antimetabolites that inhibit s-phase of the cell cycle

1) Activated by HGPRT into thio-IMP and thio-GMP respectively
2) thio-IMP converted into thio-GMP
3) thio-GMP blocks BOTH SALVAGE and DE NOVO purine synthesis i.e. inhibits DNA replication

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42
Q

What is the common mechanism of resistance in 6-MP and 6-TG?

A

Decreased HGPRT activity

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43
Q

What enzymes inactivates 6-MP? Why is this important?

A

Thiopurine methyltransferase (TPMT)

Polymorphism causes reduced TPMT activity that can lead to life-threatening toxicity and need for lower doses

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44
Q

What is the mechanism of action of Fludarabine?

A
  • Purine analog/ antimetabolite that targets cells in s-phase

1) Activated by DEOXYCYTIDINE KINASE and incorporated into DNA and RNA
2) Inhibits RIBONUCLEOTIDE REDUCTASE and DNA POLYMERASE
3 Inhibits RNA function and mRNA translation

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45
Q

What is the common mechanism of Fludarabine resistance?

A

Decreased of DEOXYCYTIDINE KINASE

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46
Q

What is the mechanism of action of Cladribine?

A
  • Purine analog/ antimetabolite that targets cells in s-phase

1) Activated by DEOXYCYTIDINE KINASE and incorporated into DNA
2) Causes DNA strand breaks
3) Inhibitor of RIBONUCLEOTIDE REDUCTASE

47
Q

List the alkylating agents.

A

Nitrogen mustards

  • Mechlorethamine
  • Cyclophosphamide

Nitrosureas
- Carmustine (BCNU)

48
Q

What is the general mechanism of action of the alkylating agents? What phase of the cell cycle do they target?

A
  • Alkylation of the N7 position on guanine to cause DNA cross-linking and strand breakage
  • Cytotoxic to the WHOLE cell cycle
49
Q

What is the mechanism of action of Cyclophosmphamine?

A
  • Prodrug that is metabolized to active form
  • Alkylating agent

Note that the active drug can be converted to another drug, “Acrolein” which is specifically cytotoxic to the bladder

50
Q

What are the specific toxicities associated with Cyclophosphamide?

A

Hemorrhagic cystitis

Recall, it is a prodrug that is converted to an active form; active form is converted to ACROLEIN, which is specifically toxic to the bladder.

51
Q

What drug can be administered with Cyclophosphamine to reduce the risk of hemorrhagic cystitis?

A

Mensa

This drug INACTIVATES ACROLEIN

52
Q

What is Carmustine (BCNU) commonly used to treat? Why?

A
  • Alkylating agent
  • Used to treat BRAIN TUMORS b/c it is highly lipophilic

Often included in wafers that are placed post-op*

53
Q

List the general adverse effects of alkylating agents.

A

1) Mutagenic, teratogenic, myelosuppressive
2) Dose-limiting factor is bone marrow suppression and damage to intestinal mucosa
3) Cause Leukemia
4) Strong vesicant/ blistering properties

54
Q

What are the mechanisms of resistance to the alkylating agents?

A
  • Inactivation by GLUTATHIONE/ increased production of
  • Reduced uptake
  • Accelerated DNA repair/ double strand break repair
  • Increased expression of MGMT, which removes alkyl groups from guanine before cross-links form
55
Q

What is the function of MGMT?

A

Prevention of DNA damage by removing alkly groups from guanine i.e. prevents drugs from “alkylating”

56
Q

List the non-classical alkylating agents.

A

Platinum compounds

  • Cisplatin
  • Carboplatin
  • Oxaliplatin
57
Q

What is the mechanism of action of the platinum compounds?

A
  • Generally, these drugs cause DNA cross-linking WITHOUT actually alkylating DNA
  • Active throughout the whole cell cycle

Note that these compounds are actively transported into the cell via the Cu++ transporter

58
Q

What are the side effects that are specific to Cisplatin?

A
  • Neurotoxicity i.e. peripheral motor and sensory neuropathy
  • Nephrotoxicity
  • Anaphylaxis
59
Q

What are the side effects that are specific to Carboplatin?

A

Less nausea, neuropathy and nephrotoxicity, but can induce anaphylaxis like Cisplatin

60
Q

How is the nephrotoxicity of Cisplatin decreased?

A

Coadministration of IV saline

61
Q

What is Procarbazine used to treat?

A

This is a non-classical alkylating agent used to treat Hodgkin’s Disease

62
Q

What is Dacarbazine used to treat?

A

This is a non-classical alkylating agent used to treat Hodgkin’s lymphoma, melanoma, and sarcoma

63
Q

What is Temozolamide used to treat?

A

This is a non-classical alkylating agent used to treat Glioblastomas and metastatic melanoma

64
Q

Describe microtubule dynamic instability.

A
  • Equilibrium between forming and falling apart

- MTs need to be able to do BOTH function normally

65
Q

List the antimicrotubule agents.

A

Vinblastine
Vincristine
Paclitaxel
Docetaxel

66
Q

What is the mechanism of action of Vinblastin and Vinctistine? What cell cycle phase do they kill in?

A
  • Vinblastine and Vincristine prevent MT polymeratiztion

- Without properly forming MTs, the mitotic spindle cannot form; thus, these compounds kill in MITOSIS

67
Q

What is the major adverse effect of vincristine?

A

Neurotoxicity

Note that this is NOT seen with Vinblastine but does have myelosuppression*

68
Q

What is the mechanism of action of the Taxanes? What cell cycle phase do they kill in?

A
  • Prevent MT destruction/ depolymerization

- Thus, the mitotic spindle can form in MITOSIS, but the PULLING phase is inhibited

69
Q

What is the major adverse effect of Paclitaxel?

A

1) Peripheral neuropathy
2) Mylosuppression
3) Anaphylaxis in ~5% of patients

70
Q

What drugs are commonly given with Paclitaxel?

A

1) Filgrastim= G-CSF to reduce myelosuppression

2) Dexamethasone and antihistamines that prevent hypersensitivity reactions

71
Q

What is the normal function of Topoisomersase in the cell?

A
  • Recall that DNA is normally stored in a condensed form

- TOPOISOMERASE cuts DNA for replication, unwinds it, and repairs the cut

72
Q

List the Topoisomerase I inhibitors.

A

Irinotecan

Topotecan

73
Q

List the Topoisomerase II inhibitors.

A

Etoposide

74
Q

What is the mechanism of action of Doxorubicin?

A

Anthracycline antibiotic

  • Intercalates with DNA and inhibits DNA polymerase
  • Inhibits topoisomerase II
75
Q

What is the major adverse effect seen with Doxorubicin?

A
  • Binds iron and generates ROS

- Causes irreversible CARDIOMYPOATHY

76
Q

What can reduce the cardiotoxicity of Doxorubicin?

A

Dexrazoxane

This is an iron chelator that reduces the formation of free radical formation

77
Q

What is the mechanism of action of Bleomycin?

A

This is a small peptide that binds DNA and causes single and double strand breaks

78
Q

What phase of the cell cycle does Bleomycin target?

A

G2

79
Q

What is unique about the toxicity of Bleomycin?

A

Cumulative, irreversible PULMONARY toxicity

Only minimally myelosuppressive*

80
Q

What is the clincal utility of Glucocorticoids in cancer treatment?

A

1) Inhibit lymphocyte proliferation
2) Reduce ICP w/ brain tumors
3) Reduce nausea and vomiting associated with chemotherapy

81
Q

What is the mechanism of action of Tamoxifen?

A

Partial estrogen receptor antagonist

82
Q

What cancer is Tamoxifen used to treat?

A

Breast cancer

83
Q

How is estrogen synthesized in post-menopausal women?

A

In post-menopausal women, AROMATASE converts testosterone into estrogen in peripheral tissues

84
Q

What is the mechanism of action of Anastrazole? What cancer is it used to treat?

A

Anaztrazole is an aromatase antagonist used to treat breast cancer that is estrogen receptor positive in post-menopausal women

85
Q

What are androgen receptor inhibitors used to treat? What is the mechanism of action?

A

Prostate cancer

These drugs prevent DHT from binding to androgen receptors, which normally drives prostate cancer growth

86
Q

What are Leuprolide and goserelin?

A
  • GnRH AGONISTS
  • Causes DESENSITIZATION of the GnRH receptor in the pituitary in the long-term
  • Decreases LH and FSH
  • Decreases Testosterone

Used to treat prostate cancer*

87
Q

What is the mechanism of Degarelix?

A

GnRH ANTAGONIST used to treat prostate cancer

88
Q

What is the mechanism of action of Trastuzumab?

A

Monoclonal antibody that targets HER-2 (EGFR TRK amplified in invasive breast cancer) and prevents signaling

Used to treat HER-2+ breast cancer

89
Q

What is the major toxicity associated with Trastuzumab?

A

Cardiotoxicity

90
Q

What is the mechanism of Cetuximab?

A

Monocolonal antibody used to treat EGFR+ COLORECTAL tumors

91
Q

What is a mechanism of Cetuximab resistance?

A

Activating mutations in Ras

Thus, Ras activity is tested prior to use of this drug*

92
Q

What is Bevacizumb’s mechanism of action?

A

Monoclonal antibody for VEGF i.e. prevent angiogenesis

93
Q

What are the adverse effects assocaited with Bevacizumb?

A
  • HTN
  • Increased risk of bleeding/ thrombosis
  • Increased risk of GI perforation
  • Decreased wound healing
94
Q

What is the mechanism of action of Lapatinib?

A

Small molecule that inhibits EGFR and HER-2 kinase activity in THE CELL

Used specifically with capecitabine to treat HER-2+, Trastuzumab refractory breast cancer*

95
Q

What is the mechanism of action of Erlotinib?

A

Small molecule EGFR inhibitor as a first line treatment for NON-SMALL CELL LUNG CARCINOMA

96
Q

What is Imatinib used to treat?

A

CML caused by Philadelphia chromsome translocation

97
Q

What is Imatinib’s mechanism of action?

A

Small molecular inhibitor BCR-ABL constitutively active Tyrosine Kinase

98
Q

What are the mechanisms of resistance to Imatinib?

A

Point mutations in BCR-ABL that causes reduced drug affinity

99
Q

What is the mechanism of action of Asparaginase?

A
  • This is an enzyme used to treat childhood ALL
  • Hydrolyzes plasma L-asparagine into L-aspartate

Tumor cells cannot synthesize enough L-asparagine, but normal cells can; thus, this drug starves the tumor of essential nutrients

100
Q

What is the unique toxicity assocaited with Asaparaginase?

A

Anaphylaxis

101
Q

What is the mechanism of action of Bortezomib?

A

Proteasome inhibitor that elevates levels of p53 (important tumor suppressor)

p53 causes apoptosis in cancer cells*

102
Q

What is the major toxicity seen with Bortezomib?

A

Peripheral neuropathy

103
Q

What is the mechansim of action of Temsirolimus?

A
  • Inhibition of mTOR complex 1 (mTORC1)
  • mTORC1 is normally involved in protein translation
  • Thus, this drug it inhibits protein translation in rapidly dividing cells
104
Q

What are the unique side effects of Temsirolimus?

A

Hyperglycemia

Hypertriglyceridemia

105
Q

What is the resistance mechansim of Temsirolimus?

A
  • There are two mTORs, mTORC1 and mTORC2

- Temsirolimus inhibits mTORC1, which can cause an upregulation of mTORC2

106
Q

Which antineoplastic agents are nephrotoxic?

A

Cisplastin

Methotrexate

107
Q

Which antineoplastic agents are neurotoxic?

A 
Vincristine 
Cytarabine
Cisplastin
Bortezomib 
Paclitaxel
108
Q

Which antineoplastic agents are cardiotoxic?

A

Doxorubicin

Trastuzumab

109
Q

Which antineoplastic agents cause bladder toxicity?

A

Cyclophosmphamide

110
Q

Which antineoplastic agents cause hypersensitivity reactions/ anaphylaxis?

A

Asparaginase

Paclitaxel

111
Q

What are 6-mercaptopurine and 6-thiguanine commonly used to treat?

A

These are purine analogs/ antimetabolites that inhibit s-phase; commonly used to treat AML and ALL

112
Q

What is Fludarabine commonly used to treat?

A

This is a purine analog/ antimetabolite that inhibits s-phase; it is commonly used to treat CLL

113
Q

What is Cladribine commonly used to treat?

A

This is a purine analog/ antimetabolite that inhibits s-phase; it is commonly used to treat Hairy Cell Leukemia

Pharmacology for Amjad (64 decks)

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