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CMBM exam 5 > Anti-neoplastic drugs > Flashcards

Anti-neoplastic drugs Flashcards

1
Q

What does the therapeutic window for a anticancer drug look like?

A

Very small

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2
Q

When you combine cancer drug what should NOT be done?

A

Should not combine ones with the same actions and the same toxicities

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3
Q

Why are multiple cycles of an anti cancer drug needed?

A

Only kills 99% of the cells and the 1% can grow back quickly

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4
Q

Which cells are the most susceptible to chemotherapy?

A

Rapidly growing cells

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5
Q

Which cancer drugs enter at the M phase of the cell cycle?

A

Vincristine
Vinblastine
Vinorelbine
Paclitaxel

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6
Q

Which cancer drugs enter at the S phase of the cell cycle?

A

Cytarabine
6-mercaptopurine
Methotrexate

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7
Q

What are the nitrogen mustards? *

A

Mechlorethamine
Cyclophosphamide
Ifosfamide

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8
Q

What are the platinum complexes? *

A

Cisplatin

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9
Q

What are the nitrosoureas?

A

Lomustine

Carmustine

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10
Q

What are the triazenes?

A

Dacarbazine

Temozolomiden

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11
Q

What are the methylhydrazines?

A

Procarbazine

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12
Q

What are the alkyl sulfonate? *

A

Busulfan

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13
Q

What does cross linked DNA do?

A

Interferes with DNA replication and causes cell cycle arrest

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14
Q

What chemotherapeutic drugs are alkylating agents?

A 
Nitrogen mustards
Platinum complexes
Nitrosoureas
Triazenes
Methylhydrazine
Alkyl sulfonate
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15
Q

What is the mechanism of action for alkylating agents? *

A

Cross links the DNA

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16
Q

Mechloresthamine (Mustargen) *

A

Most reactive nitrogen mustard
Pharm: unstable, given IV immediately after being made up
Toxic: N&V, bone marrow, tissue damage w/ extravesation

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17
Q

Cyclophosphamide (Cytoxan, Neosar) *

A

Pharm: well absorbed orally, prodrug which must be converted by liver cytochrome P450 to active metabolite
Toxic: N&V, cardiotoxic, hemorrhagic cystitis, bladder burn, hematuria, bone marrow toxic

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18
Q

What is the mechanism of platinum complexes? *

A

Covalent crosslink with GG base pairs to bend DNA

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19
Q

Cisplatin (Platinol): Pharmacology *

A

IV, 90% bound to plasma protein, concentrates in liver, kidney, intestine, ovary and excreted in urine

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20
Q

Cisplatin (Platinol): Toxicity *

A

N&V, hypersensitivity rashes, renal damage (hydrate to stop), ototoxicity w/ high frequency hearing loss + tinnitus, peripheral sensory neuropathy and bone marrow depression

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21
Q

Busulfan (Busulfex, Myleran) *

A

Pharm: Oral, half life 2/3 hrs

* Toxicity: N&V, bone marrow depression (stem cells), pulmonary infiltrates and fibrosis

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22
Q

What is the mechanism of antimetabolites?

A

Block formation of DNA
Form abnormal DNA
Cell cycle dependent
Inhibit protein synthesis

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23
Q

What are the antimetabolites?

A 
Methotrexate, Asparaginase
Fluorouracil, 
Capecitabine, 
Cytarabine, 
Mercaptopurine
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24
Q

What is the mechanism for methotrexate?

A

Analog of floic acid
Competitive inhibitor of dihydrofolate reducatse
Blocks dTMP synth which is required for DNA synth
Inhibits the folate-dependent enzymes of de novo purine and thymidylate synth

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25
Q

Methotrexate *

A

Pharm: Oral, IV, IM, Intrathecally, majority excreted unchange in urine
* Tox: Alopecia, N&V, diarrhae, fever, hepatic necrosis, hypersenitivity rxns, oral + Gi ulcers, bone marrow depression, pulmonary infiltrates and fibrosis

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26
Q

What is the mechanism for fluorouracil?

A

Converted to fraudulent F-dUMP
Fraud F-dUMP forms a covalent complex with thymidylate synthase and methylene tetrahydrofolate
Results in inhibition of DNA synth

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27
Q

Fluorouracil

A

Pharm: IV, distributes through body and brain, metabolized in liver, short half life (10-15 min)
* Tox: severe ulceration of oral + Gi mucosa, N&V, diarrhea, alopecia, bone marrow depression

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28
Q

Capecitabine (Xeloda)

A

Pharm: converted to 5-FU by an thymidine phosphorylase which is highly expressed in solid tumors, oral admin

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29
Q

What is the mechanism of Cytarabine (cytosine arabinoside)?

A

2’-deoxycytidine analog; phosphorylated to aracytidine triphosphate
2’-hydroxyl trans tp 3’hydroxyl hunders rotation of base and inhibits DNA chain elongation
Inhibits DNA pol

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30
Q

How does DNA chain elongation work?

A

The OH group of the 3’ carbon of the sugar of one nucleotide forms an ester bond to the phosphate of another nucelotide eliminating a molecule of water
Next nucleotide added to 3’ end

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31
Q

Cytarabine (ctosine arabinoside)

A

Pharm: IV, rapidly inactivated by cytidine deaminase in GI and liver
* Tox: bone marrow depression, oral ulcers, hepatic damage, N&V, diarrhea, anaphylaxis, fever, pulmonary edema, high does = sudden respiratory distress and CNS toxicity

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32
Q

What is the clinical use of cytarabine?

A

Acute myelocytic leukemia (AML)
Lymphoblastic leukemia (ALL)
Chronic myelogenous leukemia (CML)

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33
Q

What is the mechanism of 6-mercaptopurine?

A

Converted to 6-mercaptopurine ribose phosphate; inhibits purine (guanine) synth
Triphosphate form can be incorperated into DNA resulting in DNA strands and breaks
Used for leukemia in children

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34
Q

6-mercaptopurine

A
  • Pharm: oral bioavailability - 5-37%, IV half life 50 min, metabolized in liver
  • Tox: bone marrow depression, N&V (25%), hepatic enzyme elevate (33%)
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35
Q

If a pt is receiving oral doses of 6-mercaptopurine how much should it be reduced to if the pt is also receiving Xanthine oxidase inhibitors (allopurinol)? *

A

75%

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36
Q

What are the thymine pyrimidine antimetabolites?

A

Fluorouracil (5-FU), capecitabine, floxuridine, idoxuridine

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37
Q

What are the cytosine pyrimidine antimetabolites?

A

Cytarabine (Ara-C, cytosine arabinoside), 5-azacytidine, decitabine, gemcitabine

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38
Q

What are the guanine purine antimetabolites?

A

6-mercaptopurine, azathioprine

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39
Q

What are the adenine purine antimetabolites?

A

Fludarabine, cladrabine, pentostatin

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40
Q

What is a purine antimetabolite (non-specified)?

A

Methotrexate

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41
Q

What are the three phosporylation events of a nucleoside analog?

A

First is rate-limiting nucleoside kinase
Triphosphorylated analongue can incorporate into DNA/RNA and/or inhibit enzymes
Active nucleoside analogues catabolized by 5’-nucleotidase and deaminase

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42
Q

What is the mechanism of Asoarginase Erwinia chrysanthemi (Erwinaze)? *

A

Hydrolyze asparagine to aspartic acid and ammonia
Some lymphoid malignancies require L-asparagine from plasma
Inhibits protein synth

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43
Q

Asoarginase Erwinia chrysanthemi (Erwinaze)

A

Pharm: IV

* Tox: risk of anaphylaxis, minimal effect on bone marrow and GI mucous, hyperglycemia, clotting deficiency

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44
Q

What is the clinical use for Asoarginase Erwinia chrysanthemi (Erwinaze)?

A

Acute lymphoblastic leukemia

45
Q

Microtubule inhibitors; taxanes

A

Paclitaxel

Docetaxel

46
Q

What is the shared mechanism of paclitaxel and docetaxel? *

A

Taxanes stabilize or freeze polymerized microtubules

Block mitosis metaphase arrest

47
Q

Paclitaxel and docetaxel

A

Pharm: IV, metabolized in liver

* Tox: bone marrow toxicity, peripheral sensory neuropathy (dose limited) and hypersensitivity rxn

48
Q

What is the mechanism of anthracycline antibiotics?

A

Intercalates into DNA and blocks the resealing action of topoisomerase II, generates free radical

49
Q

What are the toxicities of anthracycline antibiotics?

A

Acute cardiac toxicity; arrhythmias ST & T wave alterations
Chronic cardiac toxicity; cardiomyopathy leading to congestive heart failure unresponsive to digitals related to total cumulative dose
Severe local tissue damage

50
Q

Topoisomerase inhibitors; Anthracycline antibiotics

A

Doxorubicin

51
Q

What are the topoisomerase inhibitors?

A

Anthracycline antibiotics
Dactinomycin
Etoposide
Camptothecins

52
Q

Topoisomerase inhibitors; Camptothecins

A

Irinotecan

53
Q

What is the mechanism of topoismerase inhibitors?

A

Inhibits resealing of nicked DNA

54
Q

What is the mechanism of doxorubicin? *

A

Intercalates into DNA and blocks the resealing action of topoisomerase II

55
Q

Doxorubicin (Adriamycin)

A

Pharm: rapid infusion IV, distributes widely except to CNS, metabolized in liver and excreted in bile
* Tox: N&V, red urine (not hematuria), severe local tissue damage with extravasation, diarrhea, fever, transient ECG changes, ventricular arrhythmia, cardiotoxicity

56
Q

What is the mechanism for the toxicity of Doxorubicin?

A

Free radical damage: doxorubicin + Fe(+2) can generate hydroxyl radicals from peroxide
Dexrazoxane: to protect from cardiotoxicity and treat extravastion from IV doxorubicin

57
Q

What is the mechanism if irinotecan (camptosar)? *

A

Blocks the resealing action of topoisomerase I

58
Q

Irinotecan (camptosar)

A

Pharm: IV
* Tox: dose limiting myelosuppression and severe GI toxicity life-threatening
Limited use of UGT1A1*28 polymorphism of Uridine disphoate

59
Q

What is the therapeutic use of irinotecan?

A

Metastatic and recurrent colon cancer; small cell lung cancer

60
Q

What is the free radical generator?

A

Bleomycin (blenoxane) - mixture of 2 cooper chelating glycopeptide antibodies

61
Q

What is the mechanism of bleomycin? *

A 
DNA-bleomycin-Fe(2+) complex forms 
DNA-bleomycin-Fe(2+) interacts with oxygen
Forms superoxide (O2-) and hydroxyl free (OH-) radicals
Radials produce DNA breaks (DNA fragmentation) 
DNA repair mechanism determine cytotoxicity
62
Q

Bleomycin

A

Pharm: IV, subQ or IM, localized to skin, lymph, lung, lymphatic and peritoneum tissue, excreted in urine
* Tox: N&V, fever, anaphlazis and phlebitis at injection site, degraded by hydrolysis which is low in lungs - pulmonary fibrosis, ulcers, hyperpigment

63
Q

What are the hormone inhibitors?

A

Aromatase inhibitors

Hormone analogs

64
Q

What are the aromatase inhibitors

A

Exemestane
Letrozole
Anastrozole

65
Q

What is the mechanism of aromatase inhibitors?

A

Block the conversion of androgens to estrogen

66
Q

What is the pharm and tox of aromtase inhibitors?

A

Oral

Musculoskeltal pain, headache, joint pain, hot flashes, fatigue, difficulty breathing, bone density, hot flashes

67
Q

What is the therapeutic use for aromatase inhibitors?

A

Breast cancer, postmenopausal women

68
Q

What are the hormone analogs?

A

Goserelin acetate

Megestrol acetate

69
Q

What is the mechanism of goserelin acetate (Zoladex)?

A

Decapeptide analong of LHRH prolonged adminstration inhibits gonadotropin secretion = dec extradiol

70
Q

What are the side effects of goserelin acetate?

A

Headache, hot flashes, emotional lability, depression, vaginitis

71
Q

What is the therapeutic use for goserelin acetate?

A

Prostate cancer, advanced breat cancer in pre/peri-menopausal women

72
Q

What is the mechanism for pamidronate disodium (Aredia)? *

A

Synthetic bisphosphate pamidronate

adsorb to calcium phosphate crystals in bone, blocks their dissolution by inhibiting osteoclast-mediated bone resorption

73
Q

What are the side effects for pamidronate disodium?

A

Fever, severe joint, bone and muscle pain, seizure

74
Q

What are the tyrosine kinase inhibitors?

A

Monoclonal antibodies

Chemical agents

75
Q

What are the monoclonal antibodies?

A

Trastuzumab
Bevacizumab
Cetuximab
Rituximab

76
Q

What are the chemical agents?

A

Tamoxifen

Imatinib

77
Q

Suffix for chimeric antibodies

A

-ximab

78
Q

Suffix for humanized antibodies

A

-umab

79
Q

Suffix for nonhuman host antibodies

A

-omab

80
Q

What is the mechanism for monoclonal antibodies?

A

Antibody-dependent cell-mediated cyotoxicity
Complement-mediated cytotoxicity
Direct induction of apoptosis

81
Q

What is the mechanism for trastuzumab? *

A

Recombinant DNA-derived humanized monoclonal antibody that recognizes the HER2 receptors that can be overexpressed on breast cancer cells
HER2 receptor overexpression causes cells to grow, divide and multiply

82
Q

What is the therapeutic use for trastuzumab? *

A

HER2 overexpressing metastatic breast cancer (25%)

83
Q

What is the toxicity for trastuzumab? *

A

Weakening for the heart muscle, congestive heart failure, anemia

84
Q

What is the mechanism for bevacizumab? *

A

Humanized monoloncal antibody that reconginzes vascualr-endothelial growth factor and inhibits ineteraction of VEGF with its receptors

85
Q

What is the therapeutic use for bevacizumab? *

A

Treatment for metastatic colorectal cancer

86
Q

What is the toxicity of bevacizumab? *

A

Proteinuria, hypertension, congestive heart failure, gastrointestinal perforations, pulmonary hemorrhage

87
Q

What is the mechanism of cetuximab? *

A

Monoclonal antibody that binds to the epidermal growth factor receptor (EGFR or HER1)
Block binding of epidermal growth factor and other ligands (TGF-a) to the receptor on normal and tumor cells
Inhibits cell growth and induces apoptosis

88
Q

What is cetuximab used for? *

A

Metastatic colorectal cancer

Resitricted in pts w/ wildtype KRAS

89
Q

Cetuximab

A

Pharm: give IB every 2 weeks
Tox: severe infusion rxn, acneiform rash, hypomagnesemia

90
Q

What is the side effect of EGFR inhibitors?

A

Severe acneiform rash/eruption

91
Q

What is Rituximab?

A

Chimeric human-mouse monoclonal that recognizes CD20

92
Q

What is the mechanism of rituximab?

A

Complement-mediated cytoxicity
Antibody dependent cell mediated cytotoicity
Induction of apoptosis in malignant lymphoma cells

93
Q

What is the clinical use for rituximab?

A

First line of treatment for CD20 B-cell malignancies
Replased B-cell non-hodgkin’s lymphoma
Chronic lymphocytic leukemia

94
Q

What are the side effects of rituximab? *

A

Infusion rxns, fever, chills, lymphopenia, infection, asthenia, hep B reactivation, leukoencephalopathy

95
Q

What are immunoconjugates?

A

Attach radioisotope to monoclonal antibody (gamma or beta)
Antibody binds target
Cytotoxic ionizing radiation delivered to antigen expressing cells

96
Q

What are the tyrosine kinase inhibitors?

A 
Tamoxifen 
Lapatinib
Imatinib
Nilotininb
Ponatinib
97
Q

What is the mechanism of tamoxifen? *

A

Binds estrogen receptor

Competitive inhibitor of estradiol binding the estrogen receptor

98
Q

Tamoxifen (nolvadex)

A

Pharm: oral, metabolized in liver w/ active metabolites (N-desmethyltamoxifen and trans 4-hydroxytamoxifen
* Tox: N&V, hot flush, vag discharge, endometrial cancer, venous thrombosis + pulmonary emboli, stroke

99
Q

What is the therapeutic use for tamoxifen? *

A

Estrogen-dependent breast cancer

100
Q

What is the side effect to tamoxifen?

A

Reduced serum cholesterol and reduced maintenance of bone density

101
Q

What is the mechanism of lapatinib? *

A

HER2 and EGFR (HER1) inhibitor

102
Q

What is the mechanism of imantinib? *

A

Inhibitor of constitutively active Bcr-Abl tyrosine kinase (product of the Philadelphia chromosome)
Blocks the ATP binding site on the kinase.

103
Q

What is the mechanism of nilotinib (tasigna)? *

A

Inhibitor of Bcr-Abl tyrosine kinase
Binds to and stabilizes the inactive conformation of the kinase domain of the Abl protein of the Bcr-Abl fusion protein
Inhibits platelet-derived growth factor receptor (PDGF-R) and c-kit

104
Q

What is the mechanism for ponatinib? *

A

Inhibits unmutated and all mutated forms of Bcr-Abl, including T315I, the highly drug therapy-resistant missense mutation of Bcr-Abl.
Inhibits other tyrosine kinases associated with VEGFRs and FGFRs
Inhibits the tyrosine kinase receptor TIE2 and FMS-related tyrosine kinase receptor-3 (Flt3)

105
Q

Tretinoin toxicity *

A

“Retinoic acid syndrome”

(fever, dyspnea, weight gain, pulmonary infiltrates, pleural or pericardial effusions), onset 2-21 days, potentially lethal

106
Q

What is the target of tretinoin? *

A

Acute promyelocytic leukemia (APL), high rate complete remission as a single agent

107
Q

Arsenic trioxide toxicity *

A

Atrial or ventricular arrhythmias - lengthening of QT interval on ECG (40% patients)

108
Q

What is the target of arsenic troxide (ATO)?

A

Relapsed acute promyelocytic leukemia (APL), complete responses in >85% patients

CMBM exam 5 (19 decks)

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