Biologic Antineoplastics--Fitz

Question 1

Vina alkyloids

(vincristine, vinblastine)

Answer 1

MOA: binds tubulin, prevents spindle formation Resistance: MDR, tubulin mutations

Toxicity: CNS (esp. vincristine), bone marrow suppresion (esp. vinblastine), N/V, vesicant, alopecia

Dosing: absent deep tendon reflexes in 100% of patients –> proper dose

parasthesias and peripheral neuropathy –> toxic dose, need to reduce

Question 2

Taxanes

(paclitaxel, carbitaxel, docetaxel)

Answer 2

MOA: binds tubulin, stabilizes microtubule formation

Resistance: MDR

PK: extensive CYP450 metabolism

Toxicity: hypersensitivity rxns, BM suppression, peripheral neuropathy, N/V, hypotension, arrhythmias

Question 3

Epilones

(ixabepilone)

Answer 3

MOA: bind tubulin and stabilize microtubule formation

Resistance: NOT MDR

Toxicity: BM suppresion, peripheral neuropathy, cardiac arrhythmias, hypersensitivity

*used when MDR present/anthrocyclines and taxanes fail*

Question 4

Glucocorticoids

(dexamethasone, prednisone)

Answer 4

MOA: downregulate IL-2 and TNF-α production

–> increased neutrophils, decreased T- and B-cells, monocytes, eosinophils, basophils

PK: given in high dose “pulses”

Question 5

Antibiotics

(cyclosporin, tacrolimus)

Answer 5

MOA:

cyclosporin binds cyclophilin

tacrolimus binds FK-binding protein

both are part of IL-2 proliferation cascade

Question 6

Antibiotics

(everolimus, temsirolimus)

Answer 6

MOA: mTOR inhibitors

decrease cell division, bioenergetics, angiogenesis

interfere with IL-2 receptor mediated proliferation via interfering with intracellular tyrosine kinase receptor cascade

Question 7

Antibodies

(rituximab, ibritumomab, tositumomab)

Answer 7

MOA: target CD20 on B-cells

Resistance: target protein alterations

PK: long t_1/2, IV admin

Toxicity: infustion rxns (very common), hypersensitivity, HAMA, infections (esp. TB), cardiac arrhythmias, tumor lysis syndrome

Question 8

Antibodies

(alemtuzumab)

Answer 8

MOA: CD52 on B-cells (CLL)

Resistance: target protein alterations

PK: long t1/2, IV admin

Toxicity: infustion rxns (very common), hypersensitivity, HAMA, infections (esp. TB), cardiac arrhythmias, tumor lysis syndrome

Question 9

Antibodies

(denileukin diftitux)

Answer 9

MOA: inhibits protein translation by inactivating EF2, killing cells with IL-2 receptor

Resistance: target protein alterations

PK: long t1/2, IV admin

Toxicity: infustion rxns (very common), hypersensitivity, HAMA, infections (esp. TB), cardiac arrhythmias, tumor lysis syndrome

Question 10

IFN-α

Answer 10

MOA:

decreases FGF (fibroblast growth factor), antiangiogenic

inhibition of cell division

increases MHC-I presentation on cancer cells

Adverse:

depression*, flu-like Sx, arthralgias, headache, fatigue, hypotension, myelsuppresion

Question 11

IL-2

Answer 11

MOA: expands T-cell response against tumor cells, can also be used to make LAK and CIK cell lines

PK: t_1/2 = 13 min, continuous infusion or multiple daily doses

Toxicity: cytokine storm, fever, chills, diarrhea, weight gain, hand-foot syndrome, fatal hypotension, thrombocytopenia, shock, respiratory response, coma

Question 12

TNF-α

Answer 12

MOA: similar to IL-1

–> increases IL-6 and IL-8 to activate B- and T-cells

PK: intra-arterial admin b/c t_1/2 = very short

Toxicity: hemorrhagic necrosis, malaise, flu-like Sx

Question 13

EPO

Filgrastim

Sagrastim

IL-11

Romiplostim

Answer 13

EPO: RBCs

Filgrastim = G-CSF: neutrophils

Sagrastim = GM-CSF: granulocytes

IL-11: platelets

Romiplostim = thrombopoietin: platelets

Question 14

Cetuximab, panitumumab

Answer 14

MOA: monoclonal antibodies against EGFR, present in many epithelium-derived cancers

Toxicity: skin (rash, photosensitivity, necrotizing fasciitis), lung (interstitial lung disease)

*unique Sx are primarliy epithelial tissues

Question 15

Pertuzumab, trastuzumab, ado-trastuzumab entansine

Answer 15

MOA:

pertuzumab: antibody against Her2/neu–stop and destroy

Trastuzumab: prevents Her2/neu heterodimerization/activation of TK

Ado-trastuzumab entanise: metabolized in lysosome to:

trastuzumab + DM1 (synthetic molecule that binds and blocks tubulin)

Resistance: Her2/neu alteration

Toxicity: ventricular dysfunction, CHF

Question 16

L-aspariginase

Answer 16

MOA: promotes serum conversion of

asparigine –> aspartate

tumor cells lack asparigine synthetase that

aspartate –> asparigine

in cell, so creates selective toxicity

**often used in combination with MTX**

MTX needs to be given first in order to be effective

if L-aspariginase is given first, can’t make DHFR or thymidylate synthase for MTX to be synergistic

(aspariginase is used to make protein)

Question 17

Bortezomib, carfilzomib

Answer 17

MOA: inhibit 26S proteosome of B-cells, ubiquitin-tagged proteins build up and cause apoptosis

bortezomib = reversible

carfilzomib = non-reversible

Toxicity: peripheral neuropathy, thrombocytopenia, neutropenia, and/or anemia

Question 18

Romidepsin, vorinostat

Answer 18

MOA: inhibit histone deacetylases

deaceylation ususally keeps chromatin as heterochromatin

allow to open up –> euchromatin

p53/other tumor suppresor now activated, can cause apoptosis or arrest cell growth

Toxicity: clots, increase warfain effectiveness (bleed)

Question 19

Tertinoin

all-trans retinoic acid

Answer 19

MOA: binds PML-RAR and induces differentation of promyelocytes

*arsenic trioxide kills

Toxicity: differentiation syndrome (fever, dyspnea, weight gain, pulmonary infiltrates)

Question 20

Arsenic trioxide

Answer 20

MOA: heavy metal –> apoptosis

given with tretinoin

Toxicity: leukocyte differentiation syndrome

Question 21

Bexarotene

Answer 21

MOA: activates retinoid X receptors

metabolized by CYP3A4 (drug-drug interactions)

Toxicity: lipid abnormalities, pancreatitis, GI, teratogenic