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Hem-onc > Heme-Onc Drugs 01 06 2015 > Flashcards

Heme-Onc Drugs 01 06 2015 Flashcards

1
Q

Cyclophosphamide

  1. type of drug?
  2. Mechanism of Drug?
  3. Types of Cancers that can be treated with Cyclophosphamide?
  4. how is drug given
  5. TOXICITY?
A

Alkylating agent

Forms DNA- X links, resulting in inhibition of DNA synthesis and function.
-needs to be activated by liver–P450

  • Breast Cancer
  • Ovarian
  • Non-Hodgkin Lymphoma

orally

CARDIOTOXICITY

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2
Q

Acute toxicity vs. Delayed Toxicity for Cyclophosphamide?

A

Acute: nausea, vomitting

delayed: Hemorrhagic Cystisis (infection of bladder)
- Myelosuppression

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3
Q

Ifosfamide

  1. type of drug?
  2. Is it given with anything else?
  3. mechanism of drug?
  4. Does it need to be activated by anything?
  5. what cancers is it used for?
A

Alkylating agent

Forms DNA X-links, resulting in inhibition of DNA synthesis and function

Needs to be given with Mesna

Both Ifosfamide and Mesna needs to be activated by CytP450

Testicular cacner
Lymphoma

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4
Q

What are the acute vs. delayed toxicity of Ifosfamide? (with mesna)

A

Acute: vomitting and nausea

Delayed: mesna is given to prevent cystitis (infection of the bladder.

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5
Q

Busulfan

  1. type of drug?
  2. mechanism of drug?
  3. what cancers is it used for?
  4. What should you be aware of before giving this drug?
A

Alkylating Agent

Cross-links DNA

CML
Bone-Marrow ablation before BMT (transplant)

Glutathione-S transferase Deficiency

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6
Q

Acute and Delayed Toxicity of Busulfan?

A

Acute: nausea and vomiting
Delayed: Pulmonary Fibrosis
- severe myelosuppression
- skin pigmentation

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7
Q

Mechanism of nitrosoureas:

A

cross link DNA at N7 and O6 of guanine

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8
Q

Name of nitrosoureas?

A
  • carmustine
  • Lomustin
  • Semustine
  • Streptozocin
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9
Q

Carmustine and Lomustin

  1. type of drug(s)
  2. Mechanism
  3. Cancers that it is used to treat
A
  • Alkylating agent
  • Nitrosoureas : DNA cross-linking at N7- O6
  • Needs Bioactivation
  • HIGHLY LIPID SOLUBLE = CNS EFFECTIVE

Brain tumors (including glioblastoma multiform)

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10
Q

Toxicity of Nitrosoureas ( Carmustine and Lomustin)

A

CNS toxicity: convulsions, dizziness, ataxia

- Myelosuppression (except of streptozocin)

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11
Q

Procarbazine

  1. type of drug
  2. Mechanism
  3. Does it have to be given with anything else?
  4. cancers
  5. Acute vs. delayed toxicity
A
  • non-classic alkylating agent
  • DNA cross-linking N7 and O6 of guanine
  • Inhibits DNA, RNA and protein synthesis
  • Active metabolites
  • include MAO inhibitor
  • Hodgkin’s Lymphoma
  • Non-hodgkins lymphoma
  • Brain tumors
  • Acute: Nausea, vomitting
  • Delayed: HIGH RISK OF SECONDARY CANCER
  • Myelosuppression
  • CNS toxicity with MAO inhibitors.
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12
Q

Cisplatin

  1. type of drug
  2. drug properties
  3. Mechanism of drug
  4. How is it excreted
  5. Cancers it is used for?
  6. Acute vs. Delayed toxicity
A
  • Alkylating agent: Platinum
  • water soluble
  • Forms intrastrand and inter strand DNA cross-links; binds to nuclear and cellular proteins.
  • RENALY EXCRETED
  • NSCLC; SCLS, breast, bladder, GE Jx cancer, H & N cancer, ovarian cancer (aka testicular, bladder, ovary, and lung carcinomas)

-Acute: Nausea vomiting
- Delayed:
NEPHROTOXICITY
- peripheral sensory neuropathy
-Ototoxicity
- Nerve dysfunction is irreversible

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13
Q

How can you prevent nephrotoxicity of Cisplatin?

A

Give amifostine (free radical scavenger) and chloride (saline) diuresis

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14
Q

Carboplatin

  1. type of drug
  2. Mechanism
  3. Does it have to be given with anything else?
  4. cancers
  5. Acute vs. delayed toxicity
A
  • Alkylating agent: platinum drug
  • forms intrastrand and inter strand DNA Cross-links; binds to nuclear and cellular proteins
  • more LIPOPHILIC so less renal effects

-Prevent nephrotoxicity with amifostine and chloride (saline) diuresis

testicular, bladder, ovary, and lung carcinomas

Acute: nausea vomitting
Delayed: MYELOSUPPRESSION– THROMBOCYTOPENIA
- peripheral senosry neuropathy

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15
Q

Oxaliplatin

  1. type of drug
  2. Mechanism
  3. cancers
  4. Acute vs. delayed toxicity
A

Alkylating agent: Platinum drug

Forms intra-strand and inter strand DNA cross-links; binds to nuclear and cellular proteins

  • RENALY EXCRETED
  • EFFECTIVE IN CELLS WITH DNA MMR DEFECTS!!! (mis-match repair)

Colorectal cancer
Gastro-esophageal cancer
Pancreatic Cancer

Acute: Nausea, vomitting, laryngopharyngeal dysesthesia (uncomfortable sensation – hypersensitivity)

Delayed: NEUROTOXICITY – COLD SENSITIVITY
- perhipheral sensory neuropathy that is triggered by cold

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16
Q

Methotrexate

  1. type of drug
  2. mechanism
  3. clinical application
  4. Toxicity
A
  • antimetabolite
  • Folic acid analog that competitively inhibits dihydrofolate reductase (DHF reductase) = decrease dTMP = decrease in DNA synthesis
  • inhibits de novo purine nucleotide synthesis
  • Cancers: Leukemias ( ALL), lymphomas, choriocarcinoma (uterine cancer), sarcomas
  • Leucovorin rescue is commonly used.
  • dose adjustments with ASA (aspirin), NSAIDS
  • Leucovorin reverses myelosuppresion

Toxicity:

  • MUCOSITIS (mouth ulcers)
  • Hepatotoxicity
  • Neurotoxicity
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17
Q

5- FU
( 5- Fluorouracil)

  1. type of drug
  2. mechanism
  3. clinical application
  4. Toxicity
A
  1. Pyrimidine Analog that is bioactivated to 5F-dUMP, which covalently complexes folic acid.
  2. Inactive in parent form
    -metabolite inhibits Thymidylate synthetase
    = decresae in dTMP and dna synthesis
    - RNA processing/ translation and DNA synthesis are both disrupted.
  3. Short half-life, catabolized by dihydropyridine dehydrogenase (DPD)
  4. DPD deficiency = SEVERE TOXICITY
    - MYELOSUPPRESSION (not reversible with Leucovorin – folinic acid)
    - n/v/d
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18
Q

Capecitabine

  1. type of drug
  2. mechanism
  3. clinical application
  4. Toxicity
A
  1. Pyrimidine analog that is Oral- 5-FU
  2. Metabolites converted to 5-FU in tumor cells by thymidine phosphorylate
  3. Oral availability, breast, colon cancer
  4. hand-foot syndrome
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19
Q

Cytosine arabinoside ( Ara-C)

  1. type of drug
  2. mechanism
  3. clinical application
  4. Toxicity
A
  1. Pyrimidine analog that requires constant infusion
  2. converted to Ara-CMP and Ara-CTP, which inhibits DNA pol alpha and beta
  3. No activity in solid tumors
  4. NEUROTOXICITY (esp. cerebellar) at high doses.
    - rash
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20
Q

Gemcitabine

  1. type of drug
  2. mechanism
  3. clinical application
  4. Toxicity
A
  1. pyrimidine analog
  2. incorporated into RNA and DNA to ermine strand
  3. wide range of solid malignancy
  4. THROMBOCYTOPENIA (low platelet numbers), HEMOLYTIC UREMIC SYNDROME (rare)
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21
Q

6- Meracapto Purine

  1. type of drug
  2. mechanism
  3. clinical application
  4. Toxicity
A
  1. Antimetabolite – purine analog
  2. Inhibit enzymes of purine nucleotide synthesis.
    - Incorporated into DNA and causes STRAND TERMINATION
    * Needs conversion by HGPRT for activation
  • Catalyzed by xanthine oxidase
  • Allopurinol (XO inhibitor) often used for supportive control and can lead to excessive toxicity.
  1. Prevents organ rejection; autoimmune ( SLE, rheumatoid arthritis)

Toxicity:

Deficiency in thiopurine methyl transferase can result in severe toxicities

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22
Q

Cladribine

  1. type of drug
  2. mechanism
  3. clinical application
  4. Toxicity
A
  1. Antimetabolite – purine analog
  2. Inhibits DNA synthesis and repair; inhibitory ribonucleotide reductase.
    - Incorporated into DNA = induces APOPTOSIS
  3. Hairy Cell Leukemia (mature B-cell tumor)
  4. Myelosuppression
    IMMUNOSUPPRESSION : CD4, CD8 T-cells
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23
Q

Vincristine

  1. type of drug
  2. mechanism
  3. clinical application
  4. Toxicity
A
  1. Microtubule agents: destabilizers
  2. Inhibit microtubule polymerization by binding to beta-tubulin to inhibit assembly
  3. Intrathecal administration is lethal
  4. Peripheral neuropathy
    Potent vesicant
    Neurotoxicity
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24
Q

Vinblastine

  1. type of drug
  2. mechanism
  3. clinical application
  4. Toxicity
A
  1. Microtubule Agents- destabilizers
  2. Inhibit microtubule polymerization by binding to beta-tubulin to inhibit assembly
  3. Intrathecal administration is lethal
  4. Peripheral neuropathy
    Potent vesicant
    Neurotoxicity
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25
Q

Paclitaxel

  1. type of drug
  2. mechanism
  3. clinical application
  4. Toxicity
A
  1. Microtubule agents: stabilizing agents
  2. enhances microtubule polymerization
  3. Breast Cancer
  4. Hypersensitivity (5%)
    Neurotoxicity
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26
Q

Abraxane

  1. type of drug
  2. mechanism
  3. clinical application
  4. Toxicity
A
  1. Microtubule agents: stabilizing agents
    - Paclitaxel formulated with albumin.
  2. Microtubule agents: stabilizing agents
  3. enhances microtubule polymerization
  4. Breast Cancer
  5. Neurotoxicity
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27
Q

Etoposide

  1. type of drug
  2. mechanism
  3. clinical application
  4. Toxicity
A
  1. Topoisomerase 2 inhibitors
  2. Double-strand DNA breaks cause cytotoxicity
    G2 phase specific
  3. Small cell lung cancer
    ALL
    Testicular Ca
  4. Myelosuppression
    N/V

Secondary cancers in children

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28
Q

Topotecan

  1. type of drug
  2. mechanism
  3. clinical application
  4. Toxicity
A
  1. Topoisomerase 1 inhibitors
  2. Inhibits topoisomerase 1 inhibitor: single strand breaks cause cytotoxicity
  4. Bone marrow suppression especially neutropenia
29
Q

Irinotecan

  1. type of drug
  2. mechanism
  3. clinical application
  4. Toxicity
A
  1. Topoisomerase 1 inhibitors
  2. Inhibits topoisomerase 1 inhibitor: single strand breaks cause cytotoxicity.
    - Prodrug (converted in the liver in S-38 metabolite -1000x more potent)
  3. first line drug for colorectal cancer
  4. DIARRHEA
    Early cholinergic event
    late 2-10d post treatment
    can be severe
30
Q

Doxorubicin

  1. type of drug
  2. mechanism
  3. clinical application
  4. Toxicity
A
  1. Anthracyclines
  2. Inhibits topoisomerase II
    DNA intercalation
    *Generation fo semi-quinone free radicals
  3. Widely USed
    IV administration
    Not Oral
  4. CARDIAC TOXICITY (caused by free radicals)
    early vs late
    - NEUTROPHENIA

prevention with iron chelator: Dexrazoxane; Vesicant

31
Q

Daunorubicin

  1. type of drug
  2. mechanism
  3. clinical application
  4. Toxicity
A
  1. Anthracyclines
  2. Inhibits topoisomerase II
    DNA intercalation
    *Generation fo semi-quinone free radicals
  3. NOT for solid tumors
  4. Cardiac toxicity (caused by free radicals)
    early vs late

prevention with iron chelator: Dexrazoxane; Vesicant

32
Q

Mitomycin- C

  1. type of drug
  2. mechanism
  3. clinical application
  4. Toxicity
A
  1. Antitumor Antibiotics
  2. Potent DNA X-linker through alkylation

Requires reduction for activation

  1. Anal cancer
  2. Hemolytic Uremic Syndrome
33
Q

Bleomycin

A
  1. Antitumor Antibiotics
  2. Binds DNA and to metal so that it creates superoxide free radicals and damages DNA ( ss and ds breaks)

G2 specific

Renally excreted

  1. Hodgkins lymphoma
    Testicular cancer
  2. Pulmonary Fibrosis
    Hyperpigmentation
34
Q

Antimetabolites are cell-cycle specific?

A

S phase

35
Q

Epipodophyllotoxin are cell cycle specific?

A

G2-S phase

36
Q

Taxanes are cell cycle specific?

A

M phase – prevent microtubule disassembly

37
Q

Vinca Alkaloids are cell cycle specific

A

M phase – prevent microtubule assembly

38
Q

who are cycle cycle non-specific drugs?

A
  • Alkylating agents
  • Camptothecins
  • Platinum Analogs
39
Q

Imantinib

  1. mechanism/target
  2. Cancers
  3. Resistance?
A

Aka Gleevac

  1. tyrosine kinase inhibitor that binds to catalytic cleft of ABL t(9:22) (BCR-ABL protein)
  2. CML and c-Kit ( GIST- gastrointestinal stromal tumors– usually chemotherapy resistant)
    * inhibits platelet derived growth factor receptor ( PDGFR)
  3. mutations in cleft that abrogate binding of drug (The 315 Ile)
40
Q

Tratuzumab

  1. type of drug
  2. mechanism/target
  3. Cancers
  4. Toxicity?
A

Herceptin

    • humanized IgG kappa monoclonal antibodu tjat selectivly binds with high affinity the extraceullar domain of HER-2
  2. Interfering with HER2- dependent signaling
    - - antibody dependent cellular toxicity (immune related)
  3. Her2 + breast cancers
  4. CARDIOTOXICITY - decline in left ventricular cardiac function
41
Q

Lapatinib

  1. target
  2. cancer
  3. side effects?
A

Competitive inhibitor of HER1 and HER2

Approved for combination with chemotherapy treatment of herceptin-refractory HER2+ breast cancer

  • rash, diarrhea
42
Q

Neratinib

  1. mechanism
A

irreversible inhibitor of HER1 and HER2

43
Q

Pertuzumab

  1. target
  2. cancer
A

Blocks dimerization of HER2

Metastatic Breast cancers (in combination with Trastuzumab and Docetaxel)

44
Q

T-DM1

  1. make up of drug
  2. toxicities:
A

DM1 (poison) + Linker (thioether)+ Trastuzumab

  • improved trastuzumab
    2. throbocytopenia, elevated transaminases
45
Q

Gefitinib

  1. type of drug
  2. cancer
A
  1. small molecular tyrosine kinase inhibitors specific for EGF-R
  2. Non small cell lung cancer ( NSCLC)
46
Q

Erlotinib

  1. type of drug
  2. resistance
  3. metabolism
  4. side effect
A
  1. small molecular tyrosine kinase inhibitors specific for EGF-R

improves survival in advanced non small cell lung carcinoma

  1. resistance arises by 2nd mutation
  2. CYP3A4 system – be wary of war fin, phenytoin and grapefruit products
  3. ACNEIFORM RASH: corelates to efficacy of the drug : the worse the rays, the better the drug is working.
47
Q

Crizotinib

  1. mechanism of drug
A

Inhibits ALK1, ROS1, HGFR, and other tyrosine Kinases

ALK1 inhibition in NSCLC = diseaes shrinkage

48
Q

Cetuximab (erbitux)

  1. type of drug
  2. clinical activity
  3. Resistance
A
  1. Engineered chimeric monocolonal antibody to EGFR (extracellular domain)
  2. modest clinical activity in advanced (metastatic) colon cancer when combined with chemotherapy.
    Very modest activity in NSCLC
  3. K-Ras and BRAF mutations
49
Q

Vemurafenib

  1. type of drug
  2. cancers
  3. side effect?
  4. how is it recommended to take Vemurafenib?
A
  1. Small molecule RAF inhibitor that targets V600E BRAF mutation
  2. MELANOMA (50%), colon cancer, papillary thyroid cancer, non-small cell lung cancer, hairy cell leukemia
  3. causes other skin cancers
    - cutaneous SQUAMOUS CELL CARCINOMAS
    - transactivate wtBRAF in setting of RAF mutations

Colon cancers

  1. combine BRAF inhibitor with a MEK inhibitor (downstream RAF)
50
Q

Dabrafenib

What type of drug?
The problem with this drug?

A
  1. BRAF inhibitor

2. Causes other skin cancers

51
Q

Tremetinib

  1. type of drug
  2. cancer
A

MEK inhibitor
- Mek is downstream RAF –> ERK = cell growth, proliferation, and survival

mutant squamous cell carcinomas

52
Q

Poly (ADP- Ribose) Polymerase in Tumors from BRCA Mutations

PARP

A

use = inhibition

- leads to accumulation of lethal DNA ds breaks during S-phase if there is a defect in BRCA 1/2 related repair pathway

53
Q

Platinum

A

used for: BRCA mutations!

54
Q

ATRA (A-Trans Retioic Acid)

  1. type of drug
  2. Cancer
  3. Complication of cancer to chemotherapy
A
  1. Target nuclear receptor via high Dose of VITAMIN A (target RAR)
  2. Acute promyelocytic Leukemia (PML) to mature neutrophils (differentation is blocked due to PML-RAR fusion protein)

PML is characterized by 15:17 translocation

  1. Chemotheray causes DIC due to the release of contents from AUER RODs into circulation and degranulation of promyelocytes

= ATRA SYNDROME: leukocytosis (high WBC count – because all immature cancer cells matured with ATRA) and capillary leak syndrome ( pulmonary edema + respiratory failure)

55
Q

Dasatinib

  1. type of drug
  2. mechanism
  3. cancer
  4. side effect
A
  1. & 2. inhibitor of several tyrosine kinases: BCR-ABL, Src, C-kit, and PDGFR-alpha

Differs from imatinib in that it binds to active AND inactive conformation of ABL.

  1. CML, ALL with resistance to Imatinib
  2. pulmonary edema and fluid retention
56
Q

Nilotonib

  1. drug type and mechanism
  2. Resistance
  3. Cancer
A

inhibits BCR-ABL, C-Kit, and PDGFR beta tyrosine kinases.

  • higher binding affinity
  • resistance to T315I mutation

CML as first line therapy OR resistance/intolerance

57
Q

How are Imatinib, Dasatinib, and Nilotinib metabolized?

A

Absorbed orally and metabolized in the liver mainly by CYP3A4 – CAUTION with patients taking other drugs (phenytoin, warfarin and grapefruit)

-avoid “ibs” –small molecule inhibitors

58
Q

Panitumumab

  1. type of drug and mechanism
  2. Cancer
  3. resistance
  4. side effects
A
  1. Fully human monoclonal antibody directed against EGFR
  2. Refractory metastatic colorectal cancer
  3. K-Ras muations = resistance
  4. Acneiform skin rash and hypomagnesemia
59
Q

Bevacinzumab

  1. type and mechanism of drug
  2. cancers
  3. side effects
A

Recombinant humanized monoclonal antibody that targets all forms of VEGF-A.

In combination with chemotherapy for metastatic colorectal cancer, metastatic NSCLC and metastatic breast cancer

hypertension, increased arterial throboembolic events (stroke, angina, transient ischemic attack, MI), wound healing complications

60
Q

Sorafenib

  1. type of drug and target
  2. Cancer
  3. Side effects
A

Small molecule that inhibits receptor tyrosine kinases especially VEGF-2 and VEGF-3 and RAF

Advanced renal cell cancer and advanced hepatocellular cancer

Side effects: rash (hand-foot-syndrome), diarrhea, HYPERTENSION

61
Q

Sunitinib

  1. what type of drug is it/ mechanism
  2. cancer it is used to treat?
A

Inhibits multiple RTKs

Advanced renal cell cancer and for treatment of GIST after disease progression on or with intolerance to imatinib

62
Q

Name the mTOR signinalin inhibitors:

A

Sirolimus
Tacrolimus
Temsirolimus
Everolimus

63
Q

Bortezomib (Velcade)

  1. drug mechanism
  2. cancer
  3. side effect
A

Proteosome inhibitor

Multiple Myeloma

Peripheral Neuropathy

64
Q

Rituximab (Rituxan)

  1. type of drug
  2. cancer
  3. Given alone?
  4. reactions?
A

chimerica monoclonal antibody that targets CD20 (B-lymphocytes)

B-lymphomas and leukemais

can use either alone or with chemotherapy

Infusion rxn is common

65
Q

Alemtuzumab

  1. type of drug and mechanism
  2. Side effects
A

L-Asparaginase: enzyme used to treat childhood ALL
- because tumor cells lack asparagine synthetase they require an exogenous source of L-asparagine. Thus, by depletion of 1- asparagine = effective inhibition of protein synthesis

Side effects: DIC (increasing risk of clotting)
Pancreatitis
Neurological toxicity

66
Q

Who are the selective Estrogen receptor Modulators:

A

Tamoxifen:
- prevent breast cancer recurrence in pre-menopausal women.
side effect: increases risk of thromboemoblism

Raloxifen

67
Q

What do aromatase inhibitors do and what is their significant side effect

A

prevent breast cancer recurrence in POST-menopausal women

  • Anastrazole, Letrozole ( second generation is Exemestane)

OSTEOPOROSIS

68
Q

Androgen Receptor Modulator

A

Flutamide – prostate cancer

69
Q

Who are the DNA damaging drugs (chemotherapy)

A

Alkylators – non cell cycle specific – cause intercalation of DNA

Platinum (Cisplatin, Carboplatin, Oxaliplatin) – grab onto DNA and prevent transcription

Hem-onc (3 decks)

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