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Pharmacology > Cancer Drugs > Flashcards

Cancer Drugs Flashcards

1
Q

Methotrexate

  • MOA
  • IND
  • SE
  • CON
A
  • MOA:
    • Inhibit purine synthesis
    • Kills cells in S phase
    • Folic Acid analog
      • inhibits dihydrofolate reductase
    • Conversion to polyglutamates (MTX-PG)
      • inhibits thymidylate synthase
      • prevents egress from cell
  • IND
    • Chemo
      • ALL in children
      • Choriocarcinoma
      • osteosarcoma
      • breast cancer
    • Immunosuppressant
      • RA
      • psoriasis
  • SE
    • Bone marrow suppression
    • Neurotoxic at high dose
  • CON
    • Ascites and pleural effusion
      • disseminates to all body water and can slow excretion
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2
Q

What is the benefit of using Trimetrexate over Methotrexate?

A

Trimetrexate:

  • more lipid-soluble (doesn’t need transporter)
  • use in transporter-deficient resistant cells
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3
Q

What drug is used to minimize bone marrow supression by methotrexate?

A

Leucovorin (5-formyl-THF)

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4
Q

6-Mercaptopurine

  • MOA
  • IND
  • SE
A
  • MOA
    • Purine (hypoxanthine) analog
    • Converted to thio-IMP
      • inhibits de novo purine synthesis
      • (-) PRPP amidotransferase
      • (-) IMP dehydrogenase (conversion to AMP and GMP)
      • Converted to thio-GTP which is incorporated into DNA => instability
    • Metabolized by xanthine oxidase
      • Chemo
        • ALL
        • non-Hodgkins lymphoma
      • Immunosuppressant
        • IBD
        • psoriasis
  • IND
    • Not in notes
  • SE
    • Bone marrow suppression
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5
Q

6-Thioguanine

  • MOA
  • IND
  • SE
A
  • MOA
    • Purine (guanine) analog
    • Converted to 6-thio-GTP by HGPRT
    • inhibits de novo purine synthesis
    • (-) PRPP amidotransferase
    • (-) IMP dehydrogenase (conversion to GMP)
    • incorporated into DNA => instability
    • (-) DNA polymerase
  • IND
    • Not in notes
  • SE
    • Bone marrow suppression
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6
Q

What drug may increase levels of 6-Mercaptopurine in the body?

A

Allopurinol: inhibits xanthine oxidase

Used to treat gout and hyperuricemia

Must decrease oral dose 75% to reduce toxicity

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7
Q

Fludarabine

  • MOA
  • IND
  • SE
A
  • MOA
    • Purine antimetabolite
    • phosphorylated to triphosphate form (2-fluoro-ara-ATP)
    • Incorporated into DNA
      • chain termination
    • Incorporated into RNA
      • (-) processing and translation
  • IND
    • CLL
  • SE
    • Myelosuppression

Fludarabine = Arab = ATP

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8
Q

What is the mechanism of resistance against Fludarabine in cancer cells?

A

decreaed activity of deoxycytidine kinase, which phosphorylates Fludarabine

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9
Q

5-Fluorouracil

  • MOA
  • IND
  • SE
A
  • MOA
    • converted to 5-FdUMP
      • inhibits thymidylate synthase (in presence of THF)
      • (-) thymidine synthesis => (-) DNA synthesis
    • incorporated into RNA
      • not processed
  • IND
    • Adenocarcinoma of colon
    • Radiation sensitizer
  • SE
    • used w/Leucovorin = GI tox
    • Skin hyperpigmentation
      • lessened with Vit B6 (pyridoxine)
    • Hand-foot syndrome (lesions on palms and soles)
    • Cerebellar Tox
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10
Q

Ara-C

  • MOA
  • IND
  • SE
A
  • MOA
    • analog of deoxycytidine
    • active form: ara-CTP
    • Acts in S phase
    • (-) DNA polymerase
    • incorporated into DNA
      • (-) transcription and elongation
  • IND
    • AML
  • SE
    • Myelosuppression
    • Cerebellar/ Liver Tox (high dose)

Ara-C

A = AML

C = CTP

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11
Q

What is the mechanism of resistance affecting Ara-C function in cancer cells?

A

high levels of cytidine deaminase

(forms Ara-U or Ara-UMP)

Present in the GI, so must give Ara-C by IV

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12
Q

Gemcitabine

  • MOA
  • IND
  • SE
A
  • MOA
    • difluoro analog of deoxycytidine
    • dFdCDP: (-) ribonucleotide reductase
      • decreases dNTPs available for DNA
      • incorporation of gemcitabine
    • dFdCTP: (-) dCMP deaminase
      • increases t 1/2 of dFdCTP
  • IND
    • solid tumors
  • SE
    • myelosuppression
    • radiation sensitizer
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13
Q

Hydroxyurea

  • MOA
  • IND
  • SE
A
  • MOA
    • inhibits ribonucleotide reductase
      • decreased dNTP
      • decreased DNA synthesis
    • arrests cells at S phase
    • increases fetal Hb
  • IND
    • Myeloproliferative
      • CML
      • Polycythemia vera
    • Melanoma
    • Sickle cell
  • SE
    • Myelosuppression
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14
Q

What is the MOA of alkylating agents?

A

Structural:

  • form carbonium ion intermediate (strong electrophile)
  • covalently link to side chains

Chemical:

  • N7 of guanine particularly susceptible
    • changes base pairing (G pairs with T, substituting A-T for G-C)
  • Mutagenesis
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15
Q

How do monofunctional vs bifunctional alkylating agents differ in their actions on DNA?

A

Monofunctional:

  • Changes base pairing
    • ex: N7 of guanine - G pairs with T
  • Mutagenesis and carcinogenesis

Bifunctional

  • Changes base pairing and cross-links nucleic acid chains together or to proteins
  • Cytotoxicity
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16
Q

What are the resistance mechanism of cells against alkylating agents?

A

Develops rapidly when used as a single agent

  • mutant/absent p53
    • Don’t undergo cell cycle arrest or apoptosis
  • Decreased uptake
  • increased glutathione in cell
    • scavenges electrophiles
  • increased DNA repair activity
  • increased rates of metabolism
    • aldehyde dehydrogenase
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17
Q

What effect does glutathione have on alkylating agents?

A

it promotes resistance by scavenging carbonium ion intermediate (electrophiles)

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18
Q

What toxicities are associated with alkylating agents?

A
  1. Myelosuppression
  2. Neurotoxicity
  3. Pulmonary fibrosis
  4. leukemogenesis
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19
Q

Why is Mechlorethamine (nitrogen mustard) given by rapidly-flowing IV?

A

it has vesicant properties (blister agent)

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20
Q

Cyclophosphamide

  • MOA
  • IND
  • SE
A
  • Nitrogen Mustard
  • MOA
    • metabolized by P-450 in liver to hydroxylated active form
    • alkylating agent (x-links DNA)
  • IND
    • hematologic malignancy
  • SE
    • myelosuppression
    • **Hemorrhagic cystitis **
      • caused by accumulation of acrolein (metabolite)
      • treat with MESNA
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21
Q

Mechlorethamine

  • MOA
  • IND
  • SE
A
  • MOA
    • alkylating agent
    • x-links DNA (N7 of guanine)
  • IND
    • hematologic malignancy
  • SE
    • vesicant (blisters)
      • give by rapid-flow IV
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22
Q

Busulfan

  • MOA
  • IND
  • SE
A
  • MOA
    • alkyl sulfonate
    • alkylating agent
    • x-links DNA strands together or to protein
  • IND
    • None listed in notes
    • CML (cards)
  • SE
    • Myelosuppression leading to loss of bone marrow function
    • Pulmonary fibrosis (cards)
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23
Q

What is the clinical use of Chloroethyl Nicrosoureas (CENUs)?

A

Brain tumors

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24
Q

What is the MOA of CCNUs (nitrosoureas)?

A
  • Forms breakdown products:
  1. chloroethyl-carbonium ion
    • alkylating agent
    • x-links DNA
  2. isocyanate
    • reacts with lysine to inactivate enzymes
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25
Q

What side effects are associated with Nitrosoureas? What is the cause?

A

Severe delayed myelosuppression

Cause: carbamoylating breakdown products

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26
Q

Methylnitrosourea (Streptozotocin)

  • MOA
  • IND
A
  • MOA
    • methylates DNA (at guanine O-6)
  • IND
    • human pancreatic cell carcinoma (insulinoma)
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27
Q

What drugs are in the Triazenes-Methylhydrazines class? What is their MOA?

A
  • Drugs:
    • Dacarbazine
    • Procarbazine
  • MOA:
    • methylate DNA
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28
Q

Dacarbazine

  • MOA
  • SE
A
  • MOA
    • Methylating agent
    • requires activation in liver to MTIC
    • Kills at all phases of cell cycle
  • SE
    • nausea and vomiting (GI tox)
    • Myelosuppression (bone marrow tox)
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29
Q

Procarbazine

  • MOA
  • IND
  • SE
A
  • MOA
    • DNA methylation by active metabolite
      • Liver
    • DNA breaks, chromatid breaks, translocation
  • IND
    • Hodgkin’s disease
    • Brain tumor
  • SE
    • metabolite is MAOI
      • no tyramine in diet
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30
Q

Cisplatin

  • MOA
  • IND
  • SE
A
  • contains platinum
  • MOA
    • sequential aquation to DDP
    • x-links between DNA strands and within strands
  • IND
    • Genitourinary tumors
    • Lung cancer
  • SE
    • Nephrotoxicity
      • decreased with amifostine
    • Ototoxicity
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31
Q

Carboplatin

  • MOA
  • IND
  • SE
A
  • contains platinum
  • MOA
    • sequential aquation
    • x-links between DNA strands and within strands
  • IND
    • Genitourinary tumors
    • Lung cancer
  • SE
    • Ototoxicity
    • Some nephrotoxicity
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32
Q

Oxaliplatin

  • MOA
  • IND
  • SE
A
  • MOA
    • sequential aquation (to active metabolite)
  • IND
    • Colon cancer
  • SE
    • Peripheral neuropathy
    • Acute nephrotoxicity
      • exacerbated by cold temp
33
Q

What is the mechanism of resistance for the platinum drugs (cisplatin, carboplatin, oxaliplatin)?

A
  • overexpression of nucleotide excision repair proteins (NER)
  • Cisplatin: overexpression of mismatch repair proteins (MMR)
34
Q

Tamoxifen

  • Class
  • MOA
  • IND
  • SE
A
  • Class
    • Selective Estrogen-Receptor Modulator (SERM)
  • MOA
    • competitive estrogen-receptor antagonist
    • effects are organ specific
    • halts cell cycle in G0 or G1
    • Active metabolite: 4-OH-Tamoxifen
  • IND
    • ER+ Breast cancer
  • SE
    • Endometrial hyperplasia and cancer
    • Thromboembolism
    • Hot flashes
35
Q

What is the mechanism of resistance of cancer cells to SERMS?

A
  • Loss/ modification of ER
  • Overexpression of EGFR, HER2, etc.
36
Q

Anastrozole

  • MOA
  • IND
  • SE
A
  • MOA
    • Aromatase inhibitor (converts androgens to estrogen)
    • Decreased estradiol
  • IND
    • ER+ breast cancer
  • SE
    • Osteoporosis

Used over tamoxifen due to fewer thromboembolic events

37
Q

What is the benefit of using anastrozole instead of Tamoxifen in ER+ breast cancer?

A

Anastrozole causes fewer thromboembolic events

38
Q

What are the mechanisms of resistance to Aromatase Inhibitors?

A
  • Insensitivity to estrogen
  • Ineffective inhibition of aromatase
  • Sources of estrogen independent of aromatase
39
Q

Fulvestrant

  • MOA
  • IND
  • SE
A
  • MOA
    • Selective Estrogen-Receptor Downregulator (SERD)
    • inhibits dimerization leading to increased turnover
    • given IM
  • IND
    • ER+ Breast cancer
  • SE
    • hot flashes
    • asthenia (weakness)
40
Q

Leuprolide

  • MOA
  • IND
  • SE
A
  • MOA
    • GnRH agonist
    • Ultimately decreases lvls of estrogen and testosterone
  • IND
    • Not in notes
  • SE
    • Gynecomastia
    • loss of bone density
    • loss of muscle mass
    • Hot flashes
41
Q

Gosrelin

  • MOA
  • IND
  • SE
A
  • MOA
  • GnRH agonist
    • Ultimately decreases lvls of estrogen and testosterone
  • IND
    • Not in notes
  • SE
    • Gynecomastia
    • loss of bone density
    • loss of muscle mass
    • Hot flashes
42
Q

Flutamide

  • MOA
  • IND
  • SE
A
  • MOA
    • competitive antagonist at the androgen reeptor
    • inhibits AR nuclear translocation
  • IND
    • not in notes
  • SE
    • gynecomastia
    • abnormal liver function
    • teratogen
43
Q

Interferon 2-alpha

  • MOA
  • IND
  • SE
A
  • MOA
    • enhances host immune responses
    • antiproliferative effects
  • IND
    • Hairy cell leukemia
    • CML
    • Melanoma
    • Kaposi’s sarcoma
  • SE
    • Flu-like symptoms
    • neurotoxicity
44
Q

Tretinoin

  • MOA
  • IND
  • SE
A
  • MOA
    • all-trans retinoic acid (ATRA)
    • acts on translocation PML-RAR to stimulate terminal differentiation
    • natural progression to apoptosis
  • IND
    • Acute Promyelocytic Leukemia
      • PML-RAR translocation product
  • SE
    • Retinoic Acid Syndrome
      • Dyspnea
      • Pulmonary infiltrates
      • fever
      • phypotensino
45
Q

Imatinib

  • MOA
  • IND
  • SE
A
  • MOA
    • abl, c-kit, PDGF tyrosine kinase inhibitor
  • IND
    • CML
    • GIST (GI stromal tumor)
  • SE
    • edema
    • neutropenia
    • thrombocytopenia
46
Q

Gefitinib

  • MOA
  • IND
  • SE
A
  • MOA
    • EGFR tyrosine kinase inhibitor
  • IND
    • non-small cell lung carcinoma
    • responders are female, Asian nonsmokers
  • SE
    • mild
47
Q

Erlotinib

  • MOA
  • IND
  • SE
A
  • MOA
    • EGFR tyrosine kinase inhibitor
  • IND
    • non-small cell lung cancer
  • SE
    • mild
48
Q

Trastuzumab

  • MOA
  • IND
  • SE
A
  • MOA
    • monoclonal antibody against HER-2/neu receptor
  • IND
    • Her-2-positive Breast cancer
  • SE
    • Cardiotoxicity
      • especially when used with doxirubicin
49
Q

Bevacizumab

  • MOA
  • IND
  • SE
A
  • MOA
    • monoclonal Ab against VEGF
    • inhibits angiogenesis
  • IND
    • metastatic colorectal cancer
  • SE
    • NOT myelo-suppressive
    • GI perforation
    • Pulm hemorrhage

Bevacizumab = V = VEGF

50
Q

Cetuximab

  • MOA
  • IND
  • SE
A
  • MOA
    • monoclonal Ab against EGFR
    • increased lvls of EGF leads to apoptosis
  • IND
    • metastatic, EGF-positive, KRAS wild-type colorectal cancer
  • SE
    • infusion reaction
    • severe rash
51
Q

Rituximab

  • MOA
  • IND
  • SE
A
  • MOA
    • monoclonal Ab against CD20 (B cell surface)
    • immune response against B cells only
  • IND
    • B cell non-Hodgkin’s lymphoma
  • SE
    • infusion reaction
    • Tumor lysis syndrome
      • causes acute renal failure
    • Hep B reactivation
52
Q

What are the targets of the following drugs?

  • Trastuzamab
  • Cetuximab
  • Bevacizumab
  • Imatinib
A
53
Q

Glucocorticoids in Cancer Treatment

  • MOA
  • IND
  • SE
A
  • MOA
    • activate glucocorticoid receptor and initiate apoptosis
  • IND
    • ALL treatment in children
    • Malignant lymphoma
  • SE
    • glucose intolerance
    • osteoporosis
    • psychosis
54
Q

Vorinostat

  • MOA
  • IND
  • SE
A
  • MOA
    • histone deacetylase inhibitor
    • can’t unwind DNA
    • apoptosis
  • IND
    • T cell lymphoma
  • SE
    • Fatigue
    • Pulm embolism
    • DVT
    • Blood dyscrasias
55
Q

Bortezomib

  • MOA
  • IND
  • SE
A
  • MOA
    • Proteosome inhibitor
    • downregulates NF-kß
  • IND
    • Multiple Myeloma
  • SE
    • Neuropathy
    • Shingles
      • Acyclovir is prophylactic
56
Q

Increased DNA repair (such as MGMT activity) causes resistance to which cancer drugs?

A
  • CENU (chloroethylnitrosureas)
    • alkylates DNA at O6
57
Q

Alteration in target site (ex: DHFR) causes resitance to which cancer drug?

A

Methotrexate

58
Q

Decreased drug activation causes resistance to which cancer drug?

A

decreased GHPRT expression causes decreased activation of 6-MP to T-IMP

59
Q

Increased drug inactivation causes resistance to which cancer drug?

A

Alkylating agents are inactivated by glutathion or GST

eliminated by a drug transporter (MRP)

60
Q

Increased drug sequestration (ex: by metallothionein) causes resistance to which cancer drug?

A

Cisplatin and other platinum-containing drugs

61
Q

Increased drug efflux causes resistance to which cancer drugs?

A
  • alkaloids
  • anthracyclines
  • metal drugs
62
Q

Irinotecan

  • MOA
  • IND
  • SE
A
  • MOA:
    • Stabilizes Topoisomerase-I and prevents DNA religation
  • IND:
    • Colorectal Cancer
  • SE:
    • Diarrhea
    • Myelosuppression
63
Q

Topotecan

  • MOA
  • IND
  • SE
A
  • MOA:
    • Stabilizes Topoisomerase-I and prevents DNA religation
  • IND:
    • Ovarian
    • small-cell lung
  • SE:
    • Neutropenia
64
Q

Etoposide

  • MOA
  • IND
  • SE
A
  • MOA:
    • Inhibits Topoisomerase II and blocks religation
    • inhibits nucleotide transport
    • apoptosis
    • acts in late S-G2
  • IND
    • Small cell lung cancer
    • Hematologic
  • SE
    • Myelosuppression
65
Q

Teniposide

  • MOA
  • SE
A
  • MOA:
    • Inhibits Topoisomerase II and blocks religation
    • inhibits nucleotide transport
    • apoptosis
    • acts in late S-G2
  • SE
    • Myelosuppression
66
Q

Paclitaxel

  • MOA
  • IND
  • SE
A
  • MOA:
    • binds beta-tubulin and promotes stabilization
    • anaphase cannot occur
  • IND:
    • Ovarian
    • breast
    • small cell lung
    • leukemia
  • SE
    • Neutropenia
    • Neurotoxicity
67
Q

Vincristine

  • MOA
  • IND
  • SE
A
  • MOA:
    • Binds beta-tubulin
    • promotes depolymerization
  • IND
    • Lymphoma
    • breast carcinoma
    • peds: leukemia and solid tumor
  • SE:
    • Peripheral neuropathy
    • No Myelosuppression
68
Q

Vinblastin

  • MOA
  • IND
  • SE
A
  • MOA
    • Binds beta-tubulin
    • promotes depolymerization
  • IND:
    • Lymphoma
    • Testicular cancer
  • SE:
    • myelosuppression
69
Q

What is the MOA of Mitomycin?

A
  • reduced in hypoxic tissue
  • ROS generation
  • alkylating agent
    • DNA x-links
70
Q

Bleomycin

  • MOA
  • IND
  • SE
A
  • MOA:
    • Contains Fe2+ which is converted to Fe3+
    • e- forms ROS (strand breaks)
  • IND:
    • Testicular tumors
    • Hodgkins lymphoma
    • solid tumors
  • SE:
    • Pulmonary fibrosis
    • No myelosuppression
71
Q

Mitoxantrone

  • MOA
  • IND
  • SE
A
  • MOA:
    • DNA intercalators
    • DNA strand breaks
    • (-) topoisomerase II
  • IND:
    • MS
    • Leukemia
    • Breast cancer
  • SE:
    • Myelosuppression
    • Less cardiotoxicity than doxorubicin (less able to produce ROS)
72
Q

Doxorubicin

  • MOA
  • IND
  • SE
A
  • MOA:
    • Inhibits topoisomerase II
      • Block DNA/RNA Synthesis
    • produce ROS
  • IND:
    • Solid tumors
    • hematologic malignancy
    • bladder cancer
    • metastatic thyroid carcinoma
  • SE:
    • Cardiac Toxicity
    • CON: Herseptin
73
Q

Daunorubicin

  • MOA
  • IND
  • SE
A
  • MOA:
    • Inhibits topoisomerase II
      • Block DNA/RNA Synthesis
    • produce ROS
  • IND:
    • Acute leukemia
  • SE:
    • Cardiotoxicity
74
Q

Idarubicin

  • MOA
  • IND
  • SE
A
  • MOA:
    • Inhibits topoisomerase II
      • Block DNA/RNA Synthesis
    • produces ROS
  • IND:
    • AML
  • SE:
    • Cardio and GI toxicity
    • IV only due to tissue necrosis
75
Q

When is Epirubicin prefered over Doxorubicin?

A

When the patient has heart problems

Doxorubicin = cardiotox

76
Q

Plicamycin

  • MOA
  • IND
  • SE
A
  • MOA:
    • x-linkage in CG-rich regions
    • inhibits DNA, RNA, protein synthesis
  • IND:
    • Testicular cancer
    • Paget bone disease
  • SE:
    • Lowers Ca2+ lvls
      • (-) bone resorption
    • Use in hypercalcemia
77
Q

Dactinomycin

  • MOA
  • IND
  • SE
A
  • MOA:
    • x-linkage in CG-rich regions
    • inhibits RNA synthesis
    • ROS (DNA ss breaks)
  • IND:
    • Wilm’s tumor
    • rhabdomyosarcoma
    • choriocarcinoma
  • SE:
    • Myelosuppression
    • GI upset
78
Q

L-asparaginase

  • MOA
  • IND
  • SE
A
  • MOA:
    • Hydrolysis of Asn to Asp
    • Deprives lymphoid tumors of Asp
  • IND:
    • ALL
    • some lymphomas
  • SE:
    • Allergy
    • Hyperglycemia
    • Clotting abnormalities
      • (-) protein synthesis in all tissues

Pharmacology (12 decks)

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