Term
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Definition
enzyme that catalyzes addition of phosphate to a protein
protein kinase is an enzyme that catalyzes transfer of a phosphate group from a higher energy small molecule (commonly ATP) to a protein
protein kinases phosphorylate tyrosines (tyrosine kinase) or phosphorylate serines and threonines (serine/threonine kinases)
2 major types of protein kinases are receptor and non-receptor |
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Term
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Definition
| transmembrane protein that has extracellular ligand binding domain which binds ligand and an intracellular domain with intrinsic kinase activity |
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Term
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Definition
| an intracellular (cytoplasmic) kinase |
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Term
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Definition
has very specific epitope recognition and is produced by a clonal cell lineage
monoclonal antibodies are usually produced in mice
a single cell lineage (derived from a single cell, a clone) is isolated from the mouse and the clone produces a single type of antibody with a very specific binding recognition |
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Term
| humanized and chimeric antibody |
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Definition
a monoclonal antibody that is genetically engineered to contain primarily human amino-acid sequence, but retain mouse epitope binding sequence
a small part of the antibody (epitope binding region) contains the original mouse amino acid sequence) |
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Term
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Definition
| growth of new blood vessels from pre-existing blood vessels (vessel sprouting) |
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Term
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Definition
after binding extracellular ligand (growth factor) cell division and survival pathways are activated
growth factor receptors control cell division, survival, and sometimes differentiation
cancer cells are usually very dependent on activation of growth factor receptors |
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Term
| growth factor receptor model |
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Definition
growth factor -> receptor -> signal transduction -> gene transcription -> cell division/survival
a growth factor binds a receptor
the receptor is activated by growth factor binding and the receptor (with or without intrinsic kinase activity) initiates intracellular signal tranduction
transcription of genes is activated by the signaling cascade
these genes promote cell survival and progression through the cell cycle (division) |
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Term
| growth factor receptors with intrinsic kinase activity |
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Definition
[image]
some types of extracellular growth factors act through receptor kinases
in this example epidermal growth factor (EGF) activates the tyrosine kinase domain in the cytoplasmic tail of the receptor
EGF receptor is an example of a receptor kinase
1. GROWTH FACTOR (LIGAND) BINDING
the growth factor binds to the extracellular domains (ligand binding domains) of the receptors
2. RECEPTOR DIMERIZATION
ligand binding causes the receptors to form dimers (2 members of the same family (a homodimer) or 2 members of different receptor families (a heterodimer)
3. ACTIVATION OF RECEPTOR KINASE ACTIVITY
conformational change is transmitted through the transmembrane region to the intracellular domain
the tyrosine kinase domain is activated (undergoes autophosphorylation)
4. PHOSPHORYLATION OF INTRACELLULAR (TARGET) PROTEINS
the kinase domain of the receptor phosphorylates tyrosines on intracellular target proteins which initiates intracellular signaling pathways leading to cell division and survival |
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Term
| growth factor receptors without intrinsic kinase activity |
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Definition
[image]
other types of growth factors activate receptors that do not have intrinsic kinase activity
in this example erythropoietin (EPO) activates a receptor that associates (non-covalently binds) to other intracellular proteins that possess tyrosine kinase activity (for example, JAK2, a non-receptor kinase)
1. LIGAND BINDING
2. RECEPTOR DIMERIZATION
3. ACTIVATION OF ASSOCIATED KINASE (JAK2, A NON-RECEPTOR KINASE)
the associated kinase (a non-receptor kinase (JAK2)) is not part of the intracellular domain of the receptor
JAK2 binds the intracellular domain of the receptor (through non-covalent interaction)
receptor dimerization causes activation of associated tyrosine kinase (JAK2 becomes phosphorylated)
4. PHOSPHORYLATION OF TARGET PROTEIN
JAK2 phosphorylates intracellular target proteins (for example, STAT) |
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Term
| growth factor receptor signaling and examples of drug action |
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Definition
[image]
signaling events that occur between growth factor receptor (the example above is a receptor kinase, an epidermal growth factor receptor) activation and gene transcription:
1. RECEPTOR ACTIVATION
ligand binds and activates receptor
2. RAS (A SMALL GTP-ASE) ACTIVATION
step leads to activation of RAS (a proto-oncogene, a small GTPase)
2 other intracellular kinases can activate RAS (ABL and SCR)
3. MAP KINASE PATHWAY ACTIVATION
RAS in turn, activates a series of kinases (the MAP kinase pathway)
4. GENE TRANSCRIPTION
MAPK moves into the nucleus and activates gene transcription
5. CELL CYCLE PROGRESSION
the transcribed genes cause progression through the cell cycle (proliferation) and promote cell survival
CETUXIMAB AND TRASTUZUMAB: monoclonal antibodies that bind the EGF receptor (EGFR) and block ligand binding
GEFITINIB AND ERLOTINIB: inhibit the kinase domain of the receptor
FARNESYLTRANSFERASE INHIBITORS: prevent RAS activation
IMATINIB AND DASATINIB: inhibit ABL (a non-receptor kianse)
SORAFENIB: inhibits the RAF kinase (another non-receptor kinase) which is part of the MAP kinase pathway |
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Term
| angiogenesis: required for growth of tumors beyond 1-2 mm diameter |
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Definition
the process is sometimes referred to as the "angiogenic switch" during which tumors convert from antiogenesis independent growth to angiogenesis dependent growth
tumors smaller than 1-2 mm in diameter can obtain nutrients and oxygen by diffusion
growth larger than 1-2 mm requires angiogenesis (diffusion is insufficient)
blood vessels near the tumor sprout new vessels that support tumor grwoth
angiogenesis also promotes entry of tumor cells into circulation which can lead to secondary tumors (metastases)
the newly formed blood vessels that feed tumors are more permeable compared to normal vessels in our body |
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Term
| major steps in angiogenesis |
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Definition
1. TUMOR RESPONSE TO LOW OXYGEN
when tumors reach their maximal size the cells experience low O2 tension
this triggers a transcriptional response
2. VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) PRODUCTION BY TUMOR (AND OTHER FACTORS)
as a result of transcriptional response, the tumor produces pro-angiogenic factors such as VEGF
3. VESSEL FORMATION (ENDOTHELIAL CELL PROLIFERATION, MIGRATION, AND ORGANIZATION)
tumor production of VEGF (and other factors) causes sprouting of new blood vessels from pre-existing vessels (angiogenesis) nearby
the process of vessel formation is characterized by certain endothelial cell activities (proliferation, migration, and organization into tubules) |
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Term
| tumor response to low oxygen tension |
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Definition
[image]
1. HYPOXIA
2. ACTIVATION OF TRANSLOCATION OF HIF
3. TRANSCRIPTION OF PROANGIOGENIC GENES (VEGF, PDGF, TGF)
the trigger in the angiogenic switch is low oxygen (hypoxia) supply to the tumor cells
hypoxia causes activation of a certain transcription factor (hypoxia inducible factor-1 alpha, HIF-1alpha) which translocates to the nucleus and dimerizes with HIF-1beta and then HIF1alpha-HIF1beta complex transcribes genes that encode for factors that induce angiogenesis (VEGF, PDGF, TGF)
this response is regulated by the prolyl hydroxylase ubiquitination pathway |
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Term
| vascular endothelial growth factor (VEGF) production by tumor |
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Definition
[image]
1. TUMOR VEGF PRODUCTION
2. NEARBY ENDOTHELIAL CELL STIMULATION
3. ENDOTHELIAL CELLS ALSO PRODUCE PROANGIOGENTIC FACTORS
the tumor cells produce VEGF (among other factors such as basic fibroblast growth factor (bFGF)) that stimulate nearby endothelial cells of pre-existing blood vessels
binding of VEGF to its receptor on endothelial cells activates gene transcription in endothelial cells
the endothelial cells produce other factors (autocrine and paracrine) that are part of the angiogenesis process (they stimulate progression through the cell cycle, cell migration and organization of endothelial cells into tubules that will mature into functional blood vessels) |
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Term
| vessel formation (endothelial cell proliferation, migration, and organization) |
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Definition
1. VEGF BINDING TO RECEPTOR ON ENDOTHELIAL CELLS
2. SIGNAL TRANSDUCTION
3. ENDOTHELIAL CELL EFFECTS
the receptor for VEGF has intrinsic tyrosine kinase activity (a receptor kinase)
the maine point is VEGF produces several different responses in endothelial cells which is mediated by intracellular signal transduction
know that the end result of VEGF effect is increased vascular permeability, greater endothelial cells survival (less apoptosis), progression through the cell cycle (proliferation), migration of endothelial cells and organization of endothelial cells into tubules |
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Term
| inhibitors of receptor tyrosine kinase |
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Definition
erlotinib
gefitinib
lapatinib
sunibinib |
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Term
| inhibitors of non-receptor tyrosine kinases |
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Definition
nilotinib
dasatinib
ruxolitinib |
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Term
| inhibitors of mixed kinases |
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Definition
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Term
| inhibitors of serine-threonine kinases |
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Definition
everolimus
temsirolimus
vemurafenib |
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Term
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Definition
trastuzumab
alemtuzumab
bevacizumab
cetuximab
gemtuzumab ozogamicin
ibritumomab tiuxetam
ofatumumab
panitumumab
rituximab
tositumomab and iodine I-tositumumab
ipilimumab |
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Term
| gefitinib, erlotinib, and lapatinib |
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Definition
inhibitors of receptor tyrosine kinases
use: non-small cell lung cancer (most common type of lung cancer in which malignant cells develop from epithelial (non-small) cells) and breast cancer (lapatinib)
cancer treatment efficacy depends on extent the tumor cell is dependent on epidermal growth factor for proliferation and survival
MOA:
1. BLOCK ATP BINDING
2. INHIBIT TYROSINE KINASE ACTIVITY OF EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR)
3. CELL CYCLE ARREST AND APOPTOSIS
these drugs are specific for epidermal growth factor receptors (a type of receptor kinase)
they act on the intracellular domain of the receptor to inhibit the tyrosine kinase activity
gefitinib is known to block ATP binding to the kinase domain (erlotinib likely does the same) which probably inhibits the autophosphorylation step, thus preventing phosphorylation of intracellular target proteins
ADRs and other considerations:
RASH, ACNE, AND DIARRHEA COMMON
uncertain mechanism underlying these ADRs (could be due to lack of EGF action on epiethelial cells)
potential for drug-drug interaction through CYP3A4 and 3A5
inducers or inhibitors of CYP3A4 will affect metabolism of gefitinib and erlotinib
lapatinib metabolized by CYP3A4 AND 3A5 |
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Term
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Definition
inhibitor of receptor tyrosine kinases
use: gastrointestinal stromal tumors (GIST); renal cell carcinoma
MOA:
INHIBITS MANY DIFFERENT RECEPTOR TYROSINE KINASES (PDGF, VEGF, KIT, CSF RECEPTORS AND OTHERS)
resulting from many different molecular tartest, this drug is likely to have diverse physiologic effects
sunitinib inhibits phosphorylation (probably the auto-phosphorylation step)
platelet derived growth factor (PDGF) receptor and vascular endothelial growth factor (VEGF) receptors are involved in angiogenesis
KIT (CD117) is the receptor from stem cell factor (SCF) and a mutation in this receptor is commonly found in gastrointestinal stromal tumors (GIST, malignancy thought to arise from GI pacemaker cells)
elevated CD117 in the tumor is diagnostic for GIST
colongy stimulating factor (CSF) is traditionally known for effects on blood cell maturation
ADRs and other considerations:
hypertension, asthenia, DERMATOLOGIC AND GASTROINTESTINAL effects common
WOUND HEALING concern
CYP3A4 metabolism, fecal elimination
side effects are likely due to interference of growth factor action on epithelial or other cells in these tissue; although this drug inhibits VEGF receptor no wound healing problems have been reported |
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Term
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Definition
inhibitors of non-receptor tyrosine kinases
use: chronic myelogenous leukemia (CML) when a particular gene translocation between chromosomes 9 and 22 is present (includes nearly all CML cases)
this particular translocation results in what is called the Philadelphia chromosome (the fusion of the BCR and ABL genes)
the result of this gene fusion is a product with high constitutive (always in activated state) ABL kinase activity
MOA:
1. INHIBITS ABL KINASE
2. EFFICACY AGAINST CML ATTRIBUTED TO BCR-ABL GENE FUSION (CALLED PHILADELPHIA CHROMOSOME) PRODUCT
3. ALSO INHIBITS SRC KINASE
Src can phosphorylate RAS (resulting in activation of RAS) which is at the beginning of the MAP kinase pathway
ADRs and other considerations:
myelosuppression
prolonged Q-T interval
CYP3A4 metabolism |
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Term
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Definition
inhibitor of non-receptor tyrosine kinases
use: myelofibrosis
MOA:
INHIBITS JAK KINASE
myelofibrosis is associated with actating mutations in JAK2
myelofibrosis is a myeloproliferative disorder in which bone marrow is replaced by fibrotic tissue
ADRs and other considerations:
myelosuppression
prolonged QT interval
CYP3A4 metabolism
anemia and thrombocytopenia(sometimes dose-limiting) are common with ruxolitinib |
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Term
| gene translocation in CML |
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Definition
[image]
this is a reciprocal translocation between chromosomes 9 and 22:
A. NORMAL CHROMOSOME
normal 9 and 22 chromosomes showing location of ABL kinase and BCR genes
B. AFTER TRANSLOCATION
nearly all CML patients have the t (9,22) translocation
the reciprocal exchange of DNA sequence results in a long chromosome 9 (called der 9) and a short chromosome 22 with fusion of ABL and BCR genes (called Philadelphia chromosome)
c. BCR-ABL GENE FUSION
the fused genes result in protein fusion of ABL and BCR
the ABL-BCR protein has increased ABL kinase activity resulting in hypoer-proliferation of granulocytes (CML) |
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Term
| development of chronic myelogenous leukemia |
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Definition
[image]
1. HEMATOPOIETIC STEM CELLS (HSC) ACQUIRE PHILADELPHIA CHROMOSOME
2. MATURATION OF HSC INTO GRANULOCYTES
3. HYPER-PROLIFERATION OF GRANULOCYTES
HSCs can differentiate into common myeloid progenitors (CMP), which ten differentiate into granulocytes/macrophase progenitors (GMP)
GMP cells produce granulocytes (G) and macrophases (M)
MEP cells differentiate into red blood cells (RBC) and megakaryocytes (MEG)
the initial chronic phase of CML (CML-CP) is characterized by a massive expansion of the granulocytic cell series
self renewing stem cells have potential to produce all mature blood cell types
in normal cells, a growth factor must bind a receptor on the cell surface to turn activate kinase activity of ABL
t (9,22) translocation resulting in the BCR-ABL fusion causes the kinase activity of ABL to be constitutively active (does not require presence of growth factor)
the constitutive activity of ABL in turn causes selective proliferation of granulocytes resulting in CML |
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Term
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Definition
mixed kinase inhibitors
use: chronic myelogenous leukemia (CML); HYPEREOSINOPHILIC SYNDROME (HES); gastrointestinal stromal tumors (GIST)
MOA:
INHIBITS MULTIPLE KINASE: BCR-ABL, PDGF, KIT
BCR-ABL mutation is associated with CML
a certain PDGF mutation (gene fusion) is associated with hypereosinophilic syndrome (persistent elevation of eosinophils causes multiple organ damage)
a mutation in the KIT kinase is associated with gastrointestinal stromal tumors (GIST)
the mutations result in a constitutively active kinase
Drug resistance mechanism:
kinase domain mutations, gene amplification
acquired resistance (loss of response) is due to mutations in the kinase domains of ABL, PDGF, or KIT
ADRs and other considerations:
dermatologic, gastrointestinal, edema
CYP3A4 metabolism
metabolites in feces |
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Term
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Definition
mixed kinase inhibitor
use: advanced renal cell carcinoma; hepatocellular carcinoma
MOA:
1. INHIBITS MULTIPLE KINASES: RAF (PART OF MAP KINASE PATHWAY), KIT, VEGF, PDGF
2. CELL CYCLE INHIBITION, DECREASES CELL SURVIVAL, INTERFERES WITH ANGIOGENESIS
this drug has multiple targets: it inhibits B- and C-RAF (serine/threonine kinases) at the beginning of the MAP kinase pathway
KIT is inhibited, but soRAFenib is not indicated for GIST (gastrointestinal stromal tumors)
activity against VEGF and PDGF will block the process of angiogenesis
ADRs:
CYP3A4 metabolism
HAND-FOOT reaction common
WOULD HEALING CONCERN
since soRAFenib inhibits the VEGF receptor kinase activity wound healing is a concern |
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Term
| temsirolimus and everolimus |
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Definition
inhibitors of serine/threonine kinases
use: renal cell carcinoma
MOA:
[image]
1. GROWTH FACTORS STIMULATION
growth factors such as insulin growth factor (IGF) and epidermal growth factor (EGF) can activate the PI3-kinase pathway
2. ACTIVATION OF PI3-KINASE PATHWAY
3. MTOR ACTIVATION PROMOTES CELL DIVISION (BLOCKED BY TEMSIROLIMUS AND EVEROLIMUS)
mTOR (mammalian target of rapamycin, a serine/threonine kinase) mediates production of proteins that promote cell cycle progression (division) and angiogenesis (hypoxia inducible factor, HIF)
rapamycin is the prototype inhibitor of mTOR (temsirolimus and everolimus also inhibit mTOR)
ADRs and other considerations:
HYPERGLYCEMIA common - mechanism of hyperglycemia is unclear (may reduce insulin production by pancreatic beta cells)
wound healing difficult (decreased HIF)
metabolic drug interactions (CYP3A4) |
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Term
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Definition
inhibitor of serine/threonine kinases
use: melanoma
MOA
INHIBITS B-RAF KINASE
restricted to use in melanoma patients with B-RAF V600E mutation |
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Term
| monoclonal antibody suffixes |
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Definition
-ximab = chimeric
-zumab = humanized
-momab = mouse
-mumab = human |
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Term
| general structure of chimeric and humanized antibodies |
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Definition
[image]
the problem of immune response to foreign (mouse) antibodies is alleviated by engineering chimeric, humanized, or complete human antibodies
the variable region of the light chain and heavy chain mediate antibody binding (VL and VH)
the Fc domain can activate complement or activate other immune cells
a chimeric antibody is mostly human amino acid sequence (contains the VL and VH mouse sequences)
the humanized antibody contains minimal mouase amino acid sequences (the complementary determining regions, CDR) needed for antigen binding
complete human monoclonal antibodies are also produced using transgenic mice or using phage display libraries |
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Term
| potential mechanisms of anti-tumor monoclonal antibodies |
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Definition
1. ANTIBODY-DEPENDENT CELL MEDIATED TOXICITY
the antibody binds to antigen on the tumor cell and a cytotoxic T cell binds to the Fc portion of the antibody causing activation of the T cell
2. COMPLEMENT-DEPENDENT CYTOTOXICITY
antibody binds antigen on the surface of the tumor cell and complement is activated which kills the tumor cell
3. RECEPTOR ACTIVATION AND INDUCTION OF APOPTOSIS
the antibody binds a transmembrane proteins (a receptor) and activates a signaling event that induces tumor cell apoptosis
4. BLOCK GROWTH FACTOR ACTIVITY
antibodies can compete with growth factor binding to receptors
deprivation of growth factor signaling causes slow cell proliferation of apoptosis
5. DERIVATIZED (TOXIN OR RADIOACTIVE ISOTOPE)
antibody can be conjugated (derivatized) to a cytotoxic chemical or a radioactive isotope |
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Term
| cetuximab and panitumumab |
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Definition
monoclonal antibodies
target: EGFR
use: colorectal cancer
MOA:
1. INHIBITS LIGAND BINDING TO EGFR
probable mechanism is blocking of growth factor binding to receptor, thereby inhibiting the effects on tumor growth
2. APOPTOSIS, INTERFERES WITH CELL PROLIFERATION
the end result in induction of cell apoptosis or at least slowed progression through the cell cycle
other potential mechanism such as antibody-dependent cytotoxicity mediated by T cells is uncertain
beneficial effect depends on expression of EGFR (this principle applies to many other drugs that specifically target a receptor or intracellular protein
ADRs:
INFUSION REACTION (MOST MONOCLONAL ACTIBODIES), SOMETIMES SERIOUS
overall, infusion reactions are very common (all monoclonal antibodies carry this risk to some extent)
serious reactions rarely occur (airway obstruction, severe hypotension, cardiac arrest)
acne, rash common (ANTI-EGFR EFFECT(
there is a correlation between development of rash and drug benefit
rash manifested by acne formation is common
adverse effect on skin is likely related to epithelial cell dependence on EGFR for normal skin homeostasis |
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Term
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Definition
monoclonal antibody
target: VEGF
MOA:
1. BINDS VEGF
this antibody binds vascular endothelial cell growth factor (VEGF) and thereby blocks activation of receptor by VEGF
2. INHIBITS ANGIOGENESIS
without VEGF stimulation of endothelial cells angiogenesis is inhibited
ADRs (attributed to anti-VEGF activity):
angiogenesis is needed for normal processes in the body and VEGF is needed for maintenance of vascular integrity
GASTROINTESTINAL PERFORATION
GI perforation may occur any time during treatment
intestinal contents enter the abdominal cavity
this condition is a surgical emergency
bacterial contamination of the abdominal cavity causes peritonitis which can be fatal
abnormal/slow wound healing
angiogenesis is required for wound healing
this effect is a concern for surgical pateitns
hemorrhage
can be minor (epistaxis, nose bleed) or serious (pulmonary) |
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Term
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Definition
monoclonal antibody
target: HER2
use: breast caner
MOA:
1. HER2 MEMBER OF EPIDERMAL GROWTH FACTOR RECEPTOR FAMILY
2. COMMONLY EXPRESSED IN BREAST CANCER
HER2 receptor is expressed in 20-30% of primary breast caner tumors and expression level in tumor predicts response to trastuzumab
3. ANTIBODY BLOCKS GROWTH FACTOR EFFECTS
inhibits proliferation and induces apoptosis
4. FC MEDIATED CYTOTOXICITY
the antibody binds the receptor on tumor cells and a killer T cell binds the Fc domain of the antibody
ADRs:
congestive heart failure
due to dysfunction of the left ventricle (decline in ejection fraction)
knock out mice studies consistent
mice deficient in HER2 receptor (knock-out mice) develop cardiomyopathy
left sided heart failure: edema occurs in the lungs; left side is pumping to the tissues, but blood back up in the lungs
right sided heart failure: edema occurs in the periphery; right side is pumping to the lungs, but blood backs up in the periphery |
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Term
| rituximab, toxitumomab, and I-tositumomab |
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Definition
monoclonal antibodies
target: CD20
use: B-cell non-Hodgkin lymphoma (NHL)
MOA:
1. CD20 SPECIFIC FOR B-CELL LINEAGE
these antibodies bind CD20 antigen which is expressed through pre-B cell stage to mature plasma cells
CD20 is found in 90% of B cell neoplasma
some studies report that CD20 mediates calcium ion flux, but the significance of this is uncertain
2. INDUCES IMMUNE ATTACK (ANTIBODY-DEPENDENT CELL MEDIATED TOXICITY)
antibody induces an immune attack by T cells through Fc domain activation and activation of signaling through CD20 that leads to cell apoptosis
3. DIRECT APOPTOSIS
4. I131 EMITS BETA AND GAMMA RADIATION; CD20 NOT INTERNALIZED
131-I emits beta (electrons) and gamma (photons) radiation
CD20 is not internalized which means antibody will not be taken up by the cell
ADRs and other concerns:
infusion reactions
especially first time infusion is common and can be serious
TUMOR LYSIS SYNDROME (RITUXIMAB); RENAL TUBULE URIC ACID CRYSTALS
TLS can occur with rituximab
TLS is manifested by hyperkalemia, hyperuricemia, hypocalcemia, can can lead to acute renal failure
TLS is associated with rapid reduction in tumor (mostly hematological) volume and is thought to be caused by rapid destruction of tumor cells and release of their intracellular contents
TLS can also occur without (spontaneous) chemotherapy
cytopenias
especially thrombocytopenia is a concern with tositumomab
HYPOTHYROIDISM (131-derivative)
free 131-I can accumulate in the thyroid and cause hypothyroidism |
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Term
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Definition
[image]
rituximab mediating antibody-dependent cell mediated cytotoxicity and inducing apoptosis
1. immune attack is mediated by an activated immune cell (usually a CD8 T cell)
this mechanism occurs when the antibody is bound to the antigen (in this case CD20 on a malignant B cell)
the immune cell binds the Fc domain of the antibody resulting in activation of the immune cell
the immune cell releases factors that destroy the B cell
2. binding of antibody can also directly activate the CD20 antigen and activate signaling leading to apoptosis
the exact nature of this signaling pathway is uncertain |
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Term
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Definition
[image]
metabolic imbalances due to TLS
hyperuricemia, hyperkalemia, and hyperphosphatemia result from rapid destruction of malignant cells and release of intracellular ions, nucleic acids, and proteins and their metabolites leading to acute renal failure
rapid destruction of tumor cells is the initiating factor in tumor lysis syndrome (TLS)
release of intracellular contents cause primary metabolic imbalances (hyperkalemia and hyperphosphatemia) which in turn can cause secondary metabolic imbalances (hyperuricemia and hypocalcemia)
the very high demand on the kidneys to correct the plasma concentrations combined with uric acid crystals and calcium phosphate crystal formation in tubules can cause acute renal failure
hypocalcemima is caused by precipitation with phosphate in soft tissues |
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Term
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Definition
monoclonal antibody
target: CD33
use: AML (acute myelogenous leukemia)
MOA:
1. CD33 EXPRESSED ON AML CELLS
CD33 is expressed on myeloblast cells in 80% of patients with AML
the antibody is derivatized with calicheamicin which is a potent anti-tumor antibiotic that binds the minor grove of DNA
2. ANTIBODY-CD33 INTERNALIZED
the CD33 receptor is internalized and calicheamicin is released in the cell lysosome
3. CALICHEAMICIN RELEASED AND BINDS IN THE DNA GROOVE
the antibiotic enters the cell nucleus and binds the DNA minor grove causing strand breakage and cell death
ADRs:
infusion reaction
myelosuppression
hepatotoxicity and veno-occlusive disease
most concerning is severe hepatotoxicity which is manifested by hepatic veno-occlusion |
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Term
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Definition
monoclonal antibody
target: CD52
use: chronic lymphocytic leukemmia (B-cell)
MOA:
1. ANTIBODY DEPENDENT CELL MEDIATED CYTOTOXICITY
2. COMOPLEMENT ACTIVATION
MOA is not certain but thought to induce immune attack and local activation of complement
CD52 is expressed in T and B lymphocytes and neutrophils
ADRs:
infusion reaction
NEUTROPENIA, RISK OF INFECTION
this antibody causes decrease of WBCs which puts patients at risk for infection (bacterial, viral, and protozoan)
complete blood count must be monitored |
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Term
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Definition
monoclonal antibody
target: CD152
use: melanoma
MOA:
1. BINDS CD 152
2. ENHANCES T CELL MEDIATED RESPONSE
mediates inhibitory signals in T lymphocytes
blocking CD152 is thought to promote immune system activity against melanoma cells
ADRs:
serious immune-mediated reactions
severe reactions attributed to activation and proliferation of T cells are enterocolitis, hepatitis, dermatitis, neuropathy, and endocrinopathy |
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