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Cancer Drugs Flashcards

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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
What side effects are associated with Nitrosoureas? What is the cause?
Severe delayed myelosuppression Cause: carbamoylating breakdown products
26
Methylnitrosourea (Streptozotocin) * MOA * IND
* MOA * methylates DNA (at guanine O-6) * IND * human pancreatic cell carcinoma (insulinoma)
27
What drugs are in the Triazenes-Methylhydrazines class? What is their MOA? ## Footnote
* Drugs: * Dacarbazine * Procarbazine * MOA: * methylate DNA
28
Dacarbazine * MOA * SE
* 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)
29
Procarbazine * MOA * IND * SE
* 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
30
Cisplatin * MOA * IND * SE
* 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**
31
Carboplatin * MOA * IND * SE
* contains platinum * MOA * sequential aquation * x-links between DNA strands and **within strands** * IND * Genitourinary tumors * Lung cancer * SE * Ototoxicity * Some nephrotoxicity
32
Oxaliplatin * MOA * IND * SE
* MOA * sequential aquation (to active metabolite) * IND * Colon cancer * SE * Peripheral neuropathy * Acute nephrotoxicity * exacerbated by cold temp
33
What is the mechanism of resistance for the platinum drugs (cisplatin, carboplatin, oxaliplatin)?
* overexpression of nucleotide excision repair proteins (NER) * Cisplatin: overexpression of mismatch repair proteins (MMR)
34
Tamoxifen * Class * MOA * IND * SE
* 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
What is the mechanism of resistance of cancer cells to SERMS?
* Loss/ modification of ER * Overexpression of EGFR, HER2, etc.
36
Anastrozole * MOA * IND * SE
* MOA * Aromatase inhibitor (converts androgens to estrogen) * Decreased estradiol * IND * ER+ breast cancer * SE * Osteoporosis Used over tamoxifen due to fewer thromboembolic events
37
What is the benefit of using anastrozole instead of Tamoxifen in ER+ breast cancer?
Anastrozole causes fewer thromboembolic events
38
What are the mechanisms of resistance to Aromatase Inhibitors?
* Insensitivity to estrogen * Ineffective inhibition of aromatase * Sources of estrogen independent of aromatase
39
Fulvestrant * MOA * IND * SE
* MOA * Selective Estrogen-Receptor Downregulator (SERD) * inhibits dimerization leading to increased turnover * given IM * IND * ER+ Breast cancer * SE * hot flashes * asthenia (weakness)
40
Leuprolide * MOA * IND * SE
* 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
Gosrelin * MOA * IND * SE
* 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
Flutamide * MOA * IND * SE
* MOA * competitive antagonist at the androgen reeptor * inhibits AR nuclear translocation * IND * not in notes * SE * gynecomastia * abnormal liver function * teratogen
43
Interferon 2-alpha * MOA * IND * SE
* MOA * enhances host immune responses * antiproliferative effects * IND * Hairy cell leukemia * CML * Melanoma * Kaposi's sarcoma * SE * Flu-like symptoms * neurotoxicity
44
Tretinoin * MOA * IND * SE
* 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
Imatinib * MOA * IND * SE
* MOA * abl, c-kit, PDGF tyrosine kinase inhibitor * IND * CML * GIST (GI stromal tumor) * SE * edema * neutropenia * thrombocytopenia
46
Gefitinib * MOA * IND * SE
* MOA * EGFR tyrosine kinase inhibitor * IND * non-small cell lung carcinoma * responders are female, Asian nonsmokers * SE * mild
47
Erlotinib * MOA * IND * SE
* MOA * EGFR tyrosine kinase inhibitor * IND * non-small cell lung cancer * SE * mild
48
Trastuzumab * MOA * IND * SE
* MOA * monoclonal antibody against HER-2/neu receptor * IND * Her-2-positive Breast cancer * SE * Cardiotoxicity * especially when used with doxirubicin
49
Bevacizumab * MOA * IND * SE
* MOA * monoclonal Ab against VEGF * inhibits angiogenesis * IND * metastatic colorectal cancer * SE * NOT myelo-suppressive * GI perforation * Pulm hemorrhage Be**_v_**acizumab = V = VEGF
50
Cetuximab * MOA * IND * SE
* 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
Rituximab * MOA * IND * SE
* 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
What are the targets of the following drugs? * Trastuzamab * Cetuximab * Bevacizumab * Imatinib
53
Glucocorticoids in Cancer Treatment * MOA * IND * SE
* MOA * activate glucocorticoid receptor and initiate apoptosis * IND * ALL treatment in children * Malignant lymphoma * SE * glucose intolerance * osteoporosis * psychosis
54
Vorinostat * MOA * IND * SE
* MOA * histone deacetylase inhibitor * can't unwind DNA * apoptosis * IND * T cell lymphoma * SE * Fatigue * Pulm embolism * DVT * Blood dyscrasias
55
Bortezomib * MOA * IND * SE
* MOA * Proteosome inhibitor * downregulates NF-kß * IND * Multiple Myeloma * SE * Neuropathy * Shingles * **Acyclovir** is prophylactic
56
Increased DNA repair (such as MGMT activity) causes resistance to which cancer drugs?
* CENU (chloroethylnitrosureas) * alkylates DNA at O6
57
Alteration in target site (ex: DHFR) causes resitance to which cancer drug?
Methotrexate
58
Decreased drug activation causes resistance to which cancer drug?
decreased GHPRT expression causes decreased activation of 6-MP to T-IMP
59
Increased drug inactivation causes resistance to which cancer drug?
Alkylating agents are inactivated by glutathion or GST eliminated by a drug transporter (MRP)
60
Increased drug sequestration (ex: by metallothionein) causes resistance to which cancer drug?
Cisplatin and other platinum-containing drugs
61
Increased drug efflux causes resistance to which cancer drugs?
* alkaloids * anthracyclines * metal drugs
62
Irinotecan * MOA * IND * SE
* MOA: * Stabilizes Topoisomerase-I and prevents DNA religation * IND: * Colorectal Cancer * SE: * Diarrhea * Myelosuppression
63
Topotecan * MOA * IND * SE
* MOA: * Stabilizes Topoisomerase-I and prevents DNA religation * IND: * Ovarian * small-cell lung * SE: * Neutropenia
64
Etoposide * MOA * IND * SE
* 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
Teniposide * MOA * SE
* MOA: * Inhibits Topoisomerase II and blocks religation * inhibits nucleotide transport * apoptosis * acts in late S-G2 * SE * Myelosuppression
66
Paclitaxel * MOA * IND * SE
* MOA: * binds beta-tubulin and promotes stabilization * anaphase cannot occur * IND: * Ovarian * breast * small cell lung * leukemia * SE * Neutropenia * Neurotoxicity
67
Vincristine * MOA * IND * SE
* MOA: * Binds beta-tubulin * promotes depolymerization * IND * Lymphoma * breast carcinoma * peds: leukemia and solid tumor * SE: * Peripheral neuropathy * No Myelosuppression
68
Vinblastin * MOA * IND * SE
* MOA * Binds beta-tubulin * promotes depolymerization * IND: * Lymphoma * Testicular cancer * SE: * myelosuppression
69
What is the MOA of Mitomycin?
* reduced in hypoxic tissue * ROS generation * alkylating agent * DNA x-links
70
Bleomycin * MOA * IND * SE
* 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
Mitoxantrone * MOA * IND * SE
* 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
Doxorubicin * MOA * IND * SE
* 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
Daunorubicin * MOA * IND * SE
* MOA: * Inhibits topoisomerase II * Block DNA/RNA Synthesis * produce ROS * IND: * Acute leukemia * SE: * Cardiotoxicity
74
Idarubicin * MOA * IND * SE
* MOA: * Inhibits topoisomerase II * Block DNA/RNA Synthesis * produces ROS * IND: * AML * SE: * Cardio and GI toxicity * IV only due to tissue necrosis
75
When is Epirubicin prefered over Doxorubicin?
When the patient has heart problems Doxorubicin = cardiotox
76
Plicamycin * MOA * IND * SE
* 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
Dactinomycin * MOA * IND * SE
* 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
L-asparaginase * MOA * IND * SE
* 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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