Monday 1 - fitz - Antineoplastics Flashcards
Vincristine
other name
used in what combinations for what disease
Onvcovin
MOPP for Hodgkin’s disease
CHOP for non-Hodgkin’s lymphoma
vinblastine
used in what combination for what disease
ABVD for Hodgkin’s disease
PVB for testicular cancer
toxicity of vincristine vs vinblastine
toxicity of both
vinCristine - more CNS tox (fatal if intrathecal)
vinBlastine - more Bone marrow suppression
vesicant, alopecia, depression of deep tendon reflexes within 2-3 weeks in 100% of patients (this sign is used to tell that its working)
Taxanes
capazitaxel, docataxel, paclitaxel
stabilize tubulin, too much spindle activity
pumped out by p-glycoprotein
hypersensitivity RXN can occur, new forms of paclitaxel are albumin bound and cause less of this4peripheral neuropathy
Ixabepilone
main points,
3rd line Tx for what
enhances stability of tubules, like paclitaxel but it is an antibiotic
DOESN’T produce a multidrug resistant tumor, like most other natural products do (via upregulation of P-glycoprotein)
used with capecitabine to Tx breast cancer (third line Tx)
DEXAMETHASONE, PREDNISONE
Glucocorticoids, immunosuppressants
treatment of cancers that express the requisite receptors
CYCLOSPORINE, TACROLIMUS
Antibiotics, mTOR inhibitors. immunosuppressants
used to prevent rejection following bone marrow transplants
CYCLOSPORINEbinds tocyclophilin, inhibitscalcineurin, stops NFAT, which usually helps produce IL-2
TACROLIMUSbinds toFK-binding protein, inhibitscalcineurin, stops NFAT
EVERLOLIMUS, TEMSIROLIMUS)
Antibiotics, mTOR inhibitors . immunosuppressants, angiogenesis inhibitor
mTOR upregulates cell growth and angiogenesis, and regulates the synthesis of D1
ALEMTUZUMAB
antibody mimmunosuppressant\
used for specific leukemia and lymphomas because they target unique CDs
targets CD52
Specific SE: cough, tightness in chest
DENILEUKIN DIFTITUX
fusion protein immunosuppressant
used for specific leukemia and lymphomas because they target unique CDs
diphtheria toxin coupled to IL-2
diphtheria toxin catalyzes the ADP-ribosylation of elongation factor-2inhibits protein translationby inactivating EF2
IBRITUMOMAB
antibody
immunosuppressant\
used for specific leukemia and lymphomas because they target unique CDs
targets CD20
may be more likely to cause birth defects
RITUXIMAB
antibody
immunosuppressant
used for specific leukemia and lymphomas because they target unique CDs
targets cd20
TOSITUMOMAB
antibody
immunosuppressant
used for specific leukemia and lymphomas because they target unique CDs
targets CD20
may be more likely to cause birth defects
Mechanism of immunosuppressive antibiotics
immunosuppressive antibiotics interfere with intracellular processes that are key for cell proliferation and cytokine production and release
the 1st step in the process that leads to IL-2 mediated cell proliferation is activation ofreceptor tyrosine kinases (RTKs)
immunosuppressive antibiotics do not interfere with this process; they interfere with one of two intracellular signaling cascades
calcineurin
necessary for activation of NFAT, a T cell-specific transcription factor that is involved in the synthesis of interleukins by activated T cells
If we have decreased cacimurin then we get decreased releaseofIL-2→decreased activation of IL-2 receptor → decreased cell proliferation
Cyclosporine and tacrolimus inhibit this
Do a mantoux test before giving what for cancer
anthing anti immune, esp antibodies apparently
Toxicities of anti CD antibodies
cardiac arrhythmias
tumour lysis syndrome
INTERLEUKIN 2
side effects of high doses:
activation and expansion of lytic lymphocytes causes inflammation, vascular leak and secondary release of other cytokines (such as TNF, interferon α) = cytokine storm
can produce mild/moderate symptoms such as fever/chills, diarrhea and weight gain or hand-foot syndrome (palmar-plantar erythrodysesthesia)
serious toxicities such as thrombocytopenia, shock, respiratory distress, coma andfatal hypotension
INTERFERON α
three mechanisms of anti-tumour activity
unique SE
decreasesthe production offibroblast growth factor (FGF)
anti-FGF actions may be responsible for actions against leukemic stem cells inchronic myeloid leukemia
FGF isangiogenic
inhibition of cell division of both normal and tumour cells
increases class I MHC expression on tumour cells(actually restores normal MHC expression levels>increased activity of cytotoxic T lymphocytes)
SE: depression
TUMOUR NECROSIS FACTOR α
similar to IL-1 in terms of actions: causes fibroblast proliferation, chemokine induction (IL-6, IL-8), T and B cell activation
effects on many cell types (at least 17 different kinds) - causes a decrease in the rate of proliferation of tumour cells while sparing normal cells
intra-arterial administrationdue to extremely short half-life and toxicity
severe dose-limiting toxicity ismalaise and flu-like symptoms- can cause hemorrhagic necrosis
Erythropoietin
makes RBCs
Filgrastim (g-csf)
makes neutrophils
Sargramostim (gm-csf
Makes Granulocytes, eosinophils, basophils, monocytes
Interleukin 11
makes platelets
Thrombopoietin
makes platelets
PDGF-R, VEGF-R, and VEGF inhibitors of tyrosine kinase
Bevacizumab (VEGF) - first line treatment, can be used for glioblastoma,
STIs: PAZOPANIB, SORAFENIB, SUNITINIB (VEGF-R) - these are not as specific in which kinases they inhibit - first line Tx for renal cell carcinoma
Very expensive
Tyrosine kinase inhibitors - inhibitors of EGFR
Cetuximab, panitumumab - bind EGFR
erlotinib, gefitinib - bind to the ATP binding site on the receptor for EGFR
epithelial derived cancers
Tyrosine kinase inhibitors - inhibitors of HER2
pertuzumab (first antineoplastic dimerization inhibitor),
trastuzumab (makes HER2 overexpressing cells seem foreign. SE: ventricular dysfunction and CHF.
Ado-trastuzumab emtansine (makes trastuzumab and DM1 (small molecule inhibitor that binds tubulin - like vincristine) in cancer cells)
L-asparaginase
what other drug is given with and what is the dosing order
“alterer of intracellular processes”
depletes asparagine
L=asparaginase converts all of the asparagine into aspartate, which the cancer cells (ALL) cannot convert back to asparagine if they have no asparagine synthetase
if methotrexate is given first, you get synergy
If L-asparaginase is given first, MTX is not as effective
Bortezomib, carfilzomib
inhibit proteosome
build up of ubiquitin
bort - reversible
car - irreversible
SE: thrombocytopenia, neutropenia, anemia, peripheral neuropathy
Romidespin, Vorinostat
inhibit histone deacetylases (HDAC) which are sometimes more active in cancers to silence p53 and other tumor suppressor genes
(deacetylation causes heterochromatin)
IT FREES THE TUMOR SUPPRESSOR GENES
se: pulmonary embolism, deep vein thrombosis
severe thrombocytopenia and GI bleeding result from coadministration with valproic acid
PT and INR are prolonged if given withWARFARIN
What type of leukima does differentiation block occur in a lot?
What drugs can you give that help differentiate the cells, leading to their apoptosis?
acute promyelocytic leukemia (APL)
bexarotine - retinoid that activates retinoid X receptors. doesn’t kill cells
Tretinoin (atra) (promotes degredation of PML-RAR fusion protein) - doesn’t kill cells. SE: differentiation syndrome (fever, dyspnea, weight gain, pulminary infiltrates), CNS tox, teratagenic.
Co administered with *arsenic trioxide or *anthracyclin antibiotic to cause cell death. SE: arrhythmias, leukocyte maturation syndrome
Bexarotene
Retinoid that activates retinoid X receptors
used for cutaneous T-cell lymphoma
metabolized by CYP3A4
SE: lipid abnormalities, pancreatitis, TERATOGENIC
inhibitors of BCR-ABL
bosutinib, dasatinib, imatinib, nilotinib
the complicated thing that mTOR does
mTOR regulates translation of p21, which in normally under the control of p53.
mTOR usually stops the cell from progressing through the cell cycle if DNA is damaged.
If we stop mTOR, the cell will keep going and die
Immunomodulatory drugs
Lenalidomide
Pomalidomide
Thalidomide - developmental toxin approved for use in Tx of hansen’s disease and MM - SIGNIFICANTLY TERATOGENIC - ALMOST KILLED FITZ AS A FETUS - sedating, restores appetite and decreases wasting “wonder drug to prevent morning sickness” - SE: peripheral neuropathy, DVT, Phocomelia (abbreviated arms and legs in fetuses)
MOPP
Mechlorethamine, oncovin = vincristine, prednisone, procarbazine
hodgkin lymphoma
COP +/-D
Cyclophosphamide, oncovin = vincristine, prednisone, doxorubicin
non hodgkin lymphoma
PVB
testicular cancer
platin (carbo or cis), vinblastine, bleomycin
FAC and CMF
breast cancer
5-FU, cyclophosphamide, adriamycin = doxo, methotrexate
R-CHOP
rituximab, cyclophosphamide, adriamycin (hydroxydanorubicin - or doxorubicin), vincristine (oncovin), prednisone
diffuse large b-cell lymphoma pearls
40% of lymphomas
average age 67
Tx - CHOP
what do you do if you suspect lymphoma?
EXCISIONAL BIOPSY OF THE LYMPH NODE
