Antineoplastics Exam 4 Flashcards
Vincristine (Oncovin)
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.
Vinblastine
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.
Taxanes (Capazitaxel, Docataxel, and Paclitaxel)
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
Vinorelbine
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
Ixabepilone
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)
Prednisone and Dexamethasone
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
Cyclosporine
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.
Tacrolimus
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.
Everolimus
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.
Temsirolimus
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.
Rituximab
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
Ibritumomab
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)
Tositumomab
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)
Alemtuzumab
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
Denileukin Diftitux
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)
Interleukin 2
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.
IFN-a
3 MOA’s- 1.) Decrease the production of fibroblast growth factor (FGF). FGF is angiogenic.
- ) Inhibition of cell division of both normal and tumor cells
- ) increases class I MHC expression on tumor cells –> increased activity of cytotoxic T lymphocytes
Side effects: flu-like symptoms, hypotension, myelosuppression, depression
TNF-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.
Cetuximab
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)
Panitumumab
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)
Trastuzumab
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.
Pertuzumab
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.
Ado-Trastuzumab Emtansine
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.
L-Asparaginase
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)
Bortezomib
MOA: Reversible inhibition of 26s proteasome –> increased ubiquitin –> apoptosis.
Side effects: thrombocytopenia, neutropenia, anemia, peripheral neuropathy
Carfilzomib
MOA: Irreversibly inhibition of 26s proteasome –> increased ubiquitin –> apoptosis.
Side effects: thrombocytopenia, neutropenia, anemia, peripheral neuropathy
Romidepsin
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)
Tretinoin (ATRA)
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.
Arsenic Trioxide
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)
Bexarotene
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.
Imatinib (Gleevac)
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:
- ) develop secondary resistance
- ) BCR-ABL1 are not very effective vs. blast phase
- ) 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.
Autologous Peripheral Blood Stem Cell Transplant (PBSC)
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.
Bevacizumab
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.
Sorafinib
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.
Pazopanib and Sunitinib
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.
Thalidomide
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,
Pulse Therapy
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
Rescue Therapy
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
Synergystic effects
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
Recruitment
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
Synchrony
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.
ABVD Regimen
Adriamycin (doxorubicin), Bleomycin, Vinblastine, Decarbazine.
7 + 3
Induction chemotherapy for AML. 7 days of cytarabine followed by 3 days of daunorubicin.
Around 60% remission rate.
Erlotinib
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.
Bosutinib, Dasatinib and Nilotinib
Developed for target cells that have become resistant to Imatinib.
Gefitinib
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.
