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IHO Mike Rose > Antineoplastics Exam 4 > Flashcards

Antineoplastics Exam 4 Flashcards

1
Q

Vincristine (Oncovin)

A

Class: Vinca Alkaloids

MOA: Bind to tubulin at the forming end of microtubules and terminate spindle assembly.

Resistance: Efflux via P-glycoprotein (MDR), Changes in target proteins (mutated tubulin prevents binding)

Therapeutic Uses: Routinely used in combination therapy due to distinct MOA and toxicities.

Regimens (Oncovin): MOPP (Hodgkin’s), CHOP

Toxicity: Bone marrow suppression (less than vinBlastine); CNS neurotoxicity (vinCristine), N/V (more w/ vinblastine), vesicant

Neurotoxicity –> prominent due to microtubule needs for axonal transport. Common symptoms = motor: loss of reflexes; autonomic: constipation, paralytic ileus, orthrostatic hypotension; sensory: paresthesias ‘pins and needles”

Depression of DTR occurs within 2-3 weeks in 100% of patients –> used as indication of sufficient dose.

Severe paresthesias are used as an indication to decrease the dose.

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2
Q

Vinblastine

A

Class: Vinca Alkaloids

MOA: Bind to tubulin at the forming end of microtubules and terminate spindle assembly.

Resistance: Efflux via P-glycoprotein (MDR), Changes in target proteins (mutated tubulin prevents binding)

Therapeutic Uses: Routinely used in combination therapy due to distinct MOA and toxicities.

Regimens: ABVD (Hodgkin’s) and PVB for testicular cancer

Toxicity: Bone marrow suppression (less than vinBlastine); CNS neurotoxicity (vinCristine), N/V (more w/ vinblastine), vesicant

Neurotoxicity –> prominent due to microtubule needs for axonal transport. Common symptoms = motor: loss of reflexes; autonomic: constipation, paralytic ileus, orthrostatic hypotension; sensory: paresthesias ‘pins and needles”

Depression of DTR occurs within 2-3 weeks in 100% of patients –> used as indication of sufficient dose.

Severe paresthesias are used as an indication to decrease the dose.

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3
Q

Taxanes (Capazitaxel, Docataxel, and Paclitaxel)

A

MOA: Bind to tubulin and enhance and stabilize spindle assembly.

Resistance: Decreased Accumulation via increased P-glycoprotein expression (MDR)

PK: Extensive CYP450 metabolism

Toxicities: Bone marrow suppression, hypersensitivity/ allergic reactions peripheral neuropathy, N/V, hypotension/arrhythmias

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4
Q

Vinorelbine

A

Class: Vinka Alkaloids

MOA: Bind to tubulin at the forming end of microtubules and terminate spindle assembly.

No notes about this drug made by Fitz –> treat like vincristine/vinblastine

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5
Q

Ixabepilone

A

Class: Epilone

MOA: Binds to tubulin and enhance and stabilize spindle assembly (similar to paclitaxel).

Use: Third line for Breast Cancer with Capecitabine

PK: Metabolized in the liver

Toxicities: Bone marrow suppression, peripheral neuropathy, and cardiac arrhthmias, and hypersensitivity

Resistance: P-glycoprotein efflux (MDR)

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6
Q

Prednisone and Dexamethasone

A

Corticosteroids

MOA (immune system): Interfere w/ concentration, distribution, and function of leukocytes. Increases nphils, decreases lymphocytes, monocytes, eosinophils, and basobhils.

End result is a decrease in cytokine release, including decreases in IL-2 and TNF-a

decreases size of lymph nodes and spleen

Given in higher doses, using a “pulse” regimen

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7
Q

Cyclosporine

A

Class: Antirejection antibiotics

MOA: Bind to cyclophilin and inhibit calcineurin. Calcineurin is necessary for the activation of NFAT (T-cell specific transcription factor involved in synthesis of interleukins) which decreases the release of IL-2 –> decrease T cell proliferation.

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8
Q

Tacrolimus

A

Class: Antirejection antibiotics

MOA: Bind to FK-binding protein and inhibit calcineurin. Calcineurin is necessary for the activation of NFAT (T-cell specific transcription factor involved in synthesis of interleukins) which decreases the release of IL-2 –> decrease T cell proliferation.

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9
Q

Everolimus

A

MOA: MTOR inhibitor which is an intracellular signaling molecule that increases cell division, bioenergetics, and facilitates angiogenesis.

Synergy with drugs that damage DNA.

PK: oral, metabolized by CYP3A4

Substrate for P glycoprotein.

Side effects: hypersensitivity, increased risk of lymphomas and infection, angioedema, kidney arterial and venous thrombosis.

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10
Q

Temsirolimus

A

MOA: MTOR inhibitor which is an intracellular signaling molecule that increases cell division, bioenergetics, and facilitates angiogenesis.

Synergy with drugs that damage DNA.

PK: oral, metabolized by CYP3A4

Substrate for P glycoprotein.

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11
Q

Rituximab

A

MOA: MAB vs. CD20.

Use: B cell non hodgkin’s lymphoma

Resistance: Changes in target protein

PK: IV administration; long half lives (detectable 3-6 months after completion of treatment)

Toxicity: infusion reactions (77% for rituximab), other hypersensitivity reactions: fever, muscle aches, headaches, rashes, anaphylaxis, HAMA, infections (especially reactivation of TB)

Cardiac arrythmias, and tumor lysis syndrome

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12
Q

Ibritumomab

A

MOA: MAB vs. CD20.

Use: B cell non hodgkin’s lymphoma

Resistance: Changes in target protein

PK: IV administration; long half lives (detectable 3-6 months after completion of treatment)

Toxicity: infusion reactions (77% for rituximab), other hypersensitivity reactions: fever, muscle aches, headaches, rashes, anaphylaxis, HAMA, infections (especially reactivation of TB)

Cardiac arrythmias, and tumor lysis syndrome (likely birth defects)

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13
Q

Tositumomab

A

MOA: MAB vs. CD20.

Use: B cell non hodgkin’s lymphoma

Resistance: Changes in target protein

PK: IV administration; long half lives (detectable 3-6 months after completion of treatment)

Toxicity: infusion reactions (77% for rituximab), other hypersensitivity reactions: fever, muscle aches, headaches, rashes, anaphylaxis, HAMA, infections (especially reactivation of TB)

Cardiac arrythmias, and tumor lysis syndrome (likely birth defects)

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14
Q

Alemtuzumab

A

MOA: MAB vs. CD52.

Use: B cell chronic lymphocytic leukemia.

Resistance: Changes in target protein

PK: IV administration; long half lives (detectable 3-6 months after completion of treatment)

Toxicity: infusion reactions (77% for rituximab), other hypersensitivity reactions: fever, muscle aches, headaches, rashes, anaphylaxis, HAMA, infections (especially reactivation of TB)

Cardiac arrythmias, and tumor lysis syndrome, cough, tightness in chest

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15
Q

Denileukin Diftitux

A

Fustion protein that has diptheria toxin coupled to IL-2–> diptheria toxin catalyzes the ADP-ribosylation of elongation factor-2 –> inhibits protein translation by inactivating EF2.

Goal is to kill cells expressing IL-2 receptors (activated T cells, B lymphocytes, and mphages)

Use: T cell lymphoma

Resistance: Changes in target protein

PK: IV administration; long half lives (detectable 3-6 months after completion of treatment)

Toxicity: infusion reactions (77% for rituximab), other hypersensitivity reactions: fever, muscle aches, headaches, rashes, anaphylaxis, HAMA, infections (especially reactivation of TB)

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16
Q

Interleukin 2

A

MOA: induces and expands a T-cell response to tumor cells.

Used along or w/ adoptive cellular therapy (LAK or CIK)

Short half life (13 min.) –> either continuously infused or given as multiple intermittent daily doses.

Side effects: cytokine storm = inflammation, vascular leak; fever/chills, diarrhea, weight gain, or hand-foot syndrome

serious toxicities: thrombocytopenia, shock, respiratory distress, coma, and fatal hypotension.

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17
Q

IFN-a

A

3 MOA’s- 1.) Decrease the production of fibroblast growth factor (FGF). FGF is angiogenic.

  1. ) Inhibition of cell division of both normal and tumor cells
  2. ) increases class I MHC expression on tumor cells –> increased activity of cytotoxic T lymphocytes

Side effects: flu-like symptoms, hypotension, myelosuppression, depression

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18
Q

TNF-a

A

MOA: Similar to IL-1. Cause fibroblast proliferation, chemokine induction (IL-6, IL-8), T and B cell activation. Causes a decrease in rate of proliferation of tumor cells while sparing normal cells.

PK: Intra-arterial administration due to extremely short half-life and toxicity

Toxicity: Malaise and flu-like sx (severe and dose limiting), can cause hemorrhagic necrosis.

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19
Q

Cetuximab

A

MOA: MAB vs. EGFR (a tyrosine kinase) which is overexpressed in a large number of eptihelial-derived cancers. Pretnents actions of EGFR and makes them target of cell mediated immunity.

Side effects: infusion/hypersensitivity rxns, HAMA, infections, skin (rash, photosensitivity, and nec fasc), and lung (interstitial lung disease)

20
Q

Panitumumab

A

MOA: MAB vs. EGFR (a tyrosine kinase) which is overexpressed in a large number of eptihelial-derived cancers. Pretnents actions of EGFR and makes them target of cell mediated immunity.

Side effects: infusion/hypersensitivity rxns, HAMA, infections, skin (rash, photosensitivity, and nec fasc), and lung (interstitial lung disease)

21
Q

Trastuzumab

A

MOA: MAB vs Human Epithelial Growth Factor Receptor 2 (HER2=Neu=ErbB2=CD340) a tyrosine kinase overexpressed in a large number of aggressive breast cancers.

Interferes w/ HER2 signaling, and identifies HER2 overexpressing cells as foreign.

Resisistance: altering HER2

Toxicities: infusion/hypersensitivity, HAMA, infx, birth defects/fetal loss, ventricular dysfunction and CHF.

22
Q

Pertuzumab

A

MOA: MAB vs Human Epithelial Growth Factor Receptor 2 (HER2=Neu=ErbB2=CD340) a tyrosine kinase overexpressed in a large number of aggressive breast cancers.

Considered the first antineoplastic Dimerization inhibitor; it prevents HER2 from dimerizing with other HER receptors.

Resisistance: altering HER2

Toxicities: infusion/hypersensitivity, HAMA, infx, birth defects/fetal loss, ventricular dysfunction and CHF.

23
Q

Ado-Trastuzumab Emtansine

A

MAB vs Human Epithelial Growth Factor Receptor 2 (HER2=Neu=ErbB2=CD340) a tyrosine kinase overexpressed in a large number of aggressive breast cancers.

Internalized and undergoes lysosomal degredation to form 2 components:

  • Trastuzumab
  • DM1 - a small molecule inhibitor that disrupts microtubule networks by binding to tubulin.

Resisistance: altering HER2

Toxicities: infusion/hypersensitivity, HAMA, infx, birth defects/fetal loss, ventricular dysfunction and CHF.

24
Q

L-Asparaginase

A

MOA: Converts Asparagine to Asparate. Some cancer cells lack Asparagine Synthase, so they need extracellular asparagine for protein synthesis.

Side effects: hypersensitivity reactions

Usually used w/ other agents –> order important.

MTX first = synergistic cytotoxicity

MTX second = decreased cytotoxicity (no DHFR enzymes needed for MTX’s MOA)

25
Q

Bortezomib

A

MOA: Reversible inhibition of 26s proteasome –> increased ubiquitin –> apoptosis.

Side effects: thrombocytopenia, neutropenia, anemia, peripheral neuropathy

26
Q

Carfilzomib

A

MOA: Irreversibly inhibition of 26s proteasome –> increased ubiquitin –> apoptosis.

Side effects: thrombocytopenia, neutropenia, anemia, peripheral neuropathy

27
Q

Romidepsin

A

MOA: Inhibit histone de-acetylases (HDACs) causing more eurchromatin (stopping the silencing of p53). Increase transcription and lead to cell cycle arrest and apopotosis.

Side effects: hematologic: PE, DVT, drug-drug interactions (PT and INR are prolonged if given w/ Warfarin)

28
Q

Tretinoin (ATRA)

A

MOA: Promotes degredation of the PML-RAR fusion protein allowing differentiation of promyelocytes in M3 acute promyelocytic leukemia. Doesn’t kill cells.

Co-administered w/ arsenic trioxide or anthracycline antibiotics to cause cell death.

Toxicities: CNS toxicity, differentiation syndrome (formerly called retinoic acid syndrome): fever, dyspnea, weight gain, pulmonary infiltrates. +/- plueral/pericardial effusion and +/-leukocytosis., birth defects. dry skin, hepatic enzyme abnormalities, hyperlipidemia.

29
Q

Arsenic Trioxide

A

MOA: Heavy metal toxin that promotes cell death through both apoptosis and necrosis. Given in conjunction w/ tretinoin to kill granulocytes.

Also approved for relapsed APL.

Toxicities: arrhthmias (prolonged QT), leukocyte maturation syndrome (similar to differentiation syndrome)

30
Q

Bexarotene

A

MOA: selectively activates retinoid X receptors which are involved in the regulation of cell growth and diff.

Use: cutaneous T cell lymphoma.

PK: metabolized by CYP3A4.

Side effects: lipid abnormalities, and pancreatitis. Teratogenic.

31
Q

Imatinib (Gleevac)

A

MOA: BCR-ABL specific tyrosine kinase inhibitors. Specifically inactivating ABL1 kinase by blocking ATP binding. Inactivation of BCR-ABL causes apoptosis.

Loss of BCR-ABL mutant cells allows normal cells to repopulate.

5 year survival 85-90%

Resistance:

  1. ) develop secondary resistance
  2. ) BCR-ABL1 are not very effective vs. blast phase
  3. ) CML stem cells are resistant to tyrosine kinase inhibitors.

Must be taken for life –> chronic disease.

Toxicity: Edema, bone marrow suppression, CHF, MI, teratogenic

Bosutinib, dasatinib and nilotinib are for cells resistant to Imatinib.

32
Q

Autologous Peripheral Blood Stem Cell Transplant (PBSC)

A

Hematopoeitic stem cells from peripheral blood. Growth factors are given after transplantation.

Safe - 1-2% death rate from the transplant

Problem if contamination of the autologous graft by myeloma cells.

33
Q

Bevacizumab

A

MOA: Humanized MAB directed against VEGF.

Uses: First-line treatment of metastatic CRC, lung, and breast cancer. Also macular degeneration and diabetic neuropathy.

Side effects: common antibodiy side effects, GI perforation, wound dehiscence and hemoptysis –> can be fatal. Possible worsen CAD or peripheral artery disease.

Very expensive

PK: oral, highly plasma bound, metabolized in liver CYP3A4. Excreted in feces.

34
Q

Sorafinib

A

MOA: Signal trasduction inhibitors of RAF receptor for VEGF and PDFG which is a receptor tyrosine kinases

Very costly. 1st line treatment for renal cell carcinoma.

PK: oral, highly plasma bound, metabolized in liver CYP3A4. Excreted in feces.

Toxicities: Increased risk of hemorrhage, hypertension, CHF, MI, teratogenic.

35
Q

Pazopanib and Sunitinib

A

MOA: Signal trasduction inhibitors of c-kit receptor for VEGF and PDFG which is a receptor tyrosine kinases

Very costly (Sunitinib is the most expensive of any drug!) 1st line treatment for renal cell carcinoma.

PK: oral, highly plasma bound, metabolized in liver CYP3A4. Excreted in feces.

Toxicities: CHF, MI, teratogenic.

Pazopanib- severe (fatal) hepatotoxicity, hemorrhage, QT prolongation and torsades de points, GI perf, and hypertension

Sunitinib - skin discoloration, hand and foot syndrome.

36
Q

Thalidomide

A

MOA: unknown, complex. Alters the ratios of various types of immune cells and changes the expression of molecular markers. Antiangiogenic. Also causes decreased cell movement. Most effect anti-TNF agent.

Side effects: positive - sedation/ no N/V

PK: oral, renal excretion of metabolites.

Toxicity: relatively few, peripheral neuropathy, DVT (most patients are placed on warfarin), phocomelia!, miscarriage,

37
Q

Pulse Therapy

A

Intermittent treatment with very high doses of a drug, followed by drug-free periods.

Allow hematologic and immunologic recovery between treatment cycles.

I.e. MTX for the treatment of choriocarcinoma

38
Q

Rescue Therapy

A

Following adminstration of toxic doses of chemo, normal cells can be rescued by giving antidotes that only they can use.

I.e. Leucovorin folling high dose MTX

39
Q

Synergystic effects

A

Effect greater than sum of parts. Allows lower doses and decreased toxicity. Decreased resistance.

Broader cell kill in cancers that consist of heterogenous tumors.

I.e. Cytarabine and 6-TG

40
Q

Recruitment

A

Use a CCNS drug to achieve a significant log kill which causes cancer cells in G-0 to be recruited back into cell cycle. Then give CCS drug to kill dividing cells.

Examples: Daunorubincin and Cytarabine in AML

41
Q

Synchrony

A

Using CCS drugs to synchronize cells into simultaneous cell division so they are more sensitive to other drugs or radiation.

Timing the delivery of drugs so that the action of one drug doesn’t interfere with the actions of another.

Examples: Hydroxyurea followed by radiation. Vinka alkaloids followed by Etoposide. MTX followed by L-Asparaginase.

42
Q

ABVD Regimen

A

Adriamycin (doxorubicin), Bleomycin, Vinblastine, Decarbazine.

43
Q

7 + 3

A

Induction chemotherapy for AML. 7 days of cytarabine followed by 3 days of daunorubicin.

Around 60% remission rate.

44
Q

Erlotinib

A

Competitive antagonists of the ATP-binding site of epithelial growth factor (EGFR) kinase, which is overexpressed in a large number of epithelial-derived cancers.

Resistance: change in target proteins. Overexpression

Use: Metastatic NSCLC. Less than 25% success rate.

Toxicity: relatively minor, CHF, MI, teratogenic, rare interstitial pneumonia.

PK: Oral administration, highly plasma protein bound, metabolized in liver by CYP 3A4 and excreted in feces.

45
Q

Bosutinib, Dasatinib and Nilotinib

A

Developed for target cells that have become resistant to Imatinib.

46
Q

Gefitinib

A

Competitive antagonists of the ATP-binding site of epithelial growth factor (EGFR) kinase, which is overexpressed in a large number of epithelial-derived cancers.

Resistance: change in target proteins. Overexpression

Use: Metastatic NSCLC. Less than 25% success rate.

Toxicity: relatively minor, CHF, MI, teratogenic, rare interstitial pneumonia.

PK: Oral administration, highly plasma protein bound, metabolized in liver by CYP 3A4 and excreted in feces.

IHO Mike Rose (20 decks)

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