Hematology/oncology Flashcards
PT= prothrombin time
Measures extrinsic coagulation
Increased in:
- deficiency of Factors I (fibrinogen), II (thrombin), V, VII, X
- Liver dysfunction–> Factor VII depleted first–> PT increased first
- Warfarin therapy
PTT= Partial Thromboplastin Time
Measures intrinsic, common coagulation
Contains Factor VII–> time increased with deficiency of any other factor
- Increased time in Heparin therapy
- Increased time d/t APLS (antiphospholipid antibody syndrome), sepsis, hemophilia
TT= Thrombin time
Conversion of fibrinogen–> fibrin
- Prolonged by heparin
Ceruloplasmin
Carries Copper (decreased in Wilson's disease) - alpha-2-globulin produced by liver, kidneys
Anaplasia
Loss of cell polarity, architecture
- variation in size, shape (pleomorphic)
- Giant multinucleated cells
- Nuclear hyperchromatism, pleomorphism
- Increased nuclear:cytoplasm ratio, abnL mitoses
Platelet
Life span: 8-10 days Dense granules= ADP, calcium Alpha granules= vWF, fibrinogen - vWF receptor= GpIb; carries/protects factor VIII - Fibrinogen receptor= GpIIb/IIIa
Blood cell differential
Neutrophils (55%) Lymphocytes (30%) Monoctes (5%) Eosinophils (3%) Basophils (0-1%)
Neutrophils
Increased in bacterial infection
- Phagocytic
- Multilobed nucleus
Small granules:
- Alkaline phosphatase
- Collagenase
- Lysozyme
- Lactoferrin
Larger granules: lysosomes:
- Acid phosphatase
- Peroxidase
- Beta-glucuronidase
Hypersegmented polys (5+ lobes) seen in B12/folate deficiency (enlarged nuclei) * Increased band cells in myeloid proliferation states
Macrophages
Precursor= monocyte (kidney-shaped nucleus)
Activated by IFN-gamma
Presents MHC II
Cell marker= CD14
Secretes TNF-alpha
Eosinophil
Protects against helminths (INVASIVE)
- Seen in neoplasia, asthma, allergic processes, collagen vascular diseases, invasive parasites
Contains major basic protein
Bilobate nucleus
Phagocytic for antigen-antibody complexes
Produces:
- Histaminase
- Arylsulfatase
- limits reaction after mast cell degranulation
Basophil
Mediates allergic reaction Contain: - Heparin - histamine (vasodilator) - Leukotrienes (LTD4)
B lymphocyte
Stem cell in bone marrow (matures in marrow) Migrates to: - Follicles of lymph nodes - White pulp of spleen - Unencapsulated lymphoid tissue
MHC II APC
O-negative mothers
Anti-A and Anti-B antibodies produced are IgG (vs other blood types that produce IgM)
- BUT, Hemolytic disease of newborn only occurs in ~3% of O- moms
Rh= IgG antibodies, can cross placenta for all maternal types
- Administer Rho(D) Ig (RhIg) at first delivery to prevent sensitization
- -> Erythroblastosis fetalis seen in subsequent babies of untreated mothers
Factor V Leiden mutation
Factor V resistant to inhibition by APC (activated protein C)
- most common cause of inherited hypercoagulability in whites
ESR
Erythrocyte sedimentation rate
Increased in: infections, autoimmune diseases, malignant neoplasia, GI disease, pregnancy (inflammation)
Decreased in:
- Polycythemia
- Sickle cell anemia
- CHF
- Microcytosis
- Hypofibrinogenemia
Acanthocyte
Spur cell
Seen in:
- Liver disease
- abetalipoproteinemia (cholesterol dysregulation states)
Basophilic stippling
Ribosomal RNA remnants in RBC
Seen in:
- Thalassemia
- Anemia of chronic disease
- Lead poisoning
Heinz bodies
Oxidation of hemoglobin sulfhydryl groups–> denatured hemoglobin precipitation–> damage to RBC membrane–> formation of bite cells (macrophages remove precipitated hemoglobin, part of membrane
Stains with crystal violet stain
Seen in G6PD deficiency, alpha thalassemia
Howell-Jolly bodies
Basophilic nuclear remnants in RBCs
- Normally removed by splenic macrophages
Seen in patients with asplenia, hyposplenia (sickle cell children)
Or, after napthalene (mothball) ingestion
TIBC
Total iron binding capacity= Transferrin (transport of iron in blood)
- increased when body needs more iron
- increased by OCPs, pregnancy
Ferritin
Storage form of iron (in macrophages in bone, liver)
Haptoglobin
Picks up hemoglobin after intravascular hemolysis–> brings to macrophages (“suicide protein”)
- alpha-2-globulin produced by liver, kidneys
Alpha thalassemia
Defective alpha-globin
- cis form in Asians
- trans form in Africans
4 gene deletion= Hb Barts (hydrops fetalis)–> dead in utero
3 gene deletion= HbH disease
- Excess Beta-globin that can’t bind alpha forms B4 (HbH)
1-2 gene deletion: no clinically significant anemia
Beta-thalassemia
Seen in Mediterranean populations
mRNA processing problem leading to underproduction/absent beta-chain
Minor/Intermedia (heterozygote):
- Beta chain under-produced (asymptomatic)
- Confirmed by increased HbA2 (> 3.5% on electrophoresis)
Major: (homozygote)
- Absent beta chain–> anemia (blood transfusion)–> secondary hemochromatosis
- Marrow expansion–> crew cut skull, skeletal deformities, chipmunk face
- Increased HbF (alpha2gamma2)
**HbS/Beta-thal heterozygote–> mild/moderate sickle cell disease (depends on beta production)
Lead poisoning
Inhibits:
- ferrochelatase–> protoporphyrin excess
- ALA dehyratase–> delta-ALA excess
- rRNA degradation–> basophilic stippling
Symptoms:
- Lead lines on gingiva (Burton’s lines), metaphysis of long bones)
- Encephalopathy, Erythrocyte basophilic stippling
- Abdominal colic, sideroblastic Anemia
- Wrist, foot drop
- Adults: H/A, memory loss, demyelination
- Children (lead paint): mental deterioration
Tx: Dimercaprol, EDTA (1st line)
- Succimer in pediatric overdose (chelator)
Sideroblastic anemia
X-linked defect in delta-ALA synthase
- –> Defective heme synthesis
- Glycine, succinyl coA not converted to delta-aminolevulinic acid
- Can also be caused by alcohol, lead, isoniazid, myelodysplastic syndrome
Ringed siderblast with iron-laden mitochondria (have iron, can’t make heme!)
Tx: pyridoxine (B6= cofactor for delta ALA-synthase)
Folate deficiency
Hypersegmented neutrophils
Megaloblastic anemia
- Increased Homocyteine
Symptoms:
- Sore tongue
- Pain on swallowing
- Angular stomatitis
- GI upset
- Hyperpigmentation
B12 deficiency
Increased homocysteine, increased methylmalonic acid (MMA)
Symptoms:
- Neurologic: subacute combined degeneration (involvement of B12 in fatty acid pathways, myelin synthesis
- Peripheral neuropathy with sensorimotor dysfunction
- Posterior column (vibration/proprioception)
- Lateral corticospinal (spasticity)
- Dementia
**Pernicious anemia: older N. European woman; lemon-yellow coloring, shiny smooth tongue (atrophic glossitis), shuffling broad-based gait
Plummer-Vinson syndrome
Triad:
- iron deficiency anemia
- Esophageal webs
- Atrophic glossitis
Hepcidin
Protein released by liver in response to inflammatory state
- Binds ferroportin on intestinal mucosal cells, macrophages–> inhibits iron transport, release of iron from macrophages
- -> anemia of chronic disease
** Body stopping iron release in state of inflammation since bacteria feed off iron to grow
G6PD deficiency
X-linked defect in G6PD
- RBC can’t go into HMP shunt to generate glutathione
- –> increased susceptibility to oxidant stress
Precipitating factors:
- Infections
- Drugs (Sulfa, primiquine, Dapsone)
- DKA
- Favism (fava beans)
Symptoms:
- Back pain, hemoglobinuria
Extravascular hemolysis: bite cells and Heinz bodies on smear (spleen macrophages remove Heinz bodies–> bite cells)
Pyruvate kinase deficiency
Autosomal recessive
Defect in pyruvate kinase–> decreased ATP–> can’t reshape after going through vessels (rigid RBCs)
- See hemolytic anemia in NEWBORN
HbC defect
Glutamic acid–> Lysine at beta-globin residue 6 (vs Glu–> val in SC)
- HbSC have milder disease than HbSS
Paroxysmal Nocturnal Hemoglobinuria
Impaired synthesis of GPI anchor or Decay-Accelerating Factor to protect RBC from complement-mediated lysis
- Complement binds RBC–> intravascular hemolysis
Symptoms:
- Hemolytic anemia
- Pancytopenia
- Venous thrombosis
Lab:
- CD55/59 negative RBCs
Tx: eculizumab
Sickle Cell anemia
Glu–> val at position 6 on beta-chain
Beta chain can fit into complementary alpha chain on another hemoglobin molecule–> aggregation of hemoglobin monomers
- see Howell-Jolly bodies in children as the spleen is infarcted
- First crisis after HbF no longer being made (8-12 months post-partum)–> dactylitits (sausage fingers)
Warm agglutination
IgG
- Chronic anemia in SLE, CLL, certain drugs
Cold agglutination
IgM
- Acute anemia triggered by cold
- Seen in CLL, Mycoplasma pneumoniae, Infectious mono
Direct Coomb’s
Test Patient RBCs
- Add anti-Ig antibody–> RBC agglutination= positive test
Indirect Coomb’s test
Test patient plasma
- add normal RBCs to patient serum–> agglutination= anti-RBC surface Ig
Acute intermittent porphyria
Defect in porphobilinogen deaminase
- accumulate porphobilinogen, delta-ALA, uroporphyrin (urine)
Symptoms:
- Painful abdomen
- Port-wine urine (uroporphyrin)
- Polyneuropathy
- Pscyhological disturbances
- Precipitated by drugs: phenobarbital, griseofulvin, hepatitis C; EtOH, low-calorie diet
Treatment:
- Glucose, heme (inhibit ALA synthase)
Porphyria cutanea tarda
Defect in uroporphyrinogen decarboxylase
- Congenital or acquired= aromatic hydrocarbon exposure, estrogen, hepatitis C
- Accumulate uroporphyrin (tea-colored urine)
Symptoms:
- Blistering cutaneous photosensitivity
- most common porphyria
Bernard-Soulier syndrome
Decreased GpIb–> defect in platelet to vWF adhesion
Decreased platelet count, increased bleeding time
Glanzmann’s thombasthenia
Decreased GpIIb/IIIa–> defect in platelet-platelet aggregation (can’t bind fibrinogen
- Increased bleeding time
Labs: blood smear w/ no platlet clumping
Idiopathic thrombocytopenic purpura
Anti-GpIIb/IIIa antibodies–> splenic macrophages consume platelets (bound to Abs)
–> purpura (no platlets!)
Labs: increased megakaryocytes
Thrombotic thrombocytopenic purpura
Deficiency of ADAMTS13 (vWF metalloprotease)–> decreased degradation of vWF multimers
Large vWF multimers–> platelet aggregation, thrombosis
- decreased platelet survival
Labs: schistocytes, increased LDH
Symptoms:
- Neurological, renal
- Fever, thrombocytopenia
- microangiopathic hemolytic anemia
von Willebrand’s disease
Autosomal dominant
- Diagnosis: ristocetin cofactor assay
Decreased vWF–> normal to increased PTT; increased bleeding time
- vWF protects factor VIII
- Defect in platelet-to-vWWF adhesion
Tx: DDAVP (desmopressin)–> releases stored vWF in endothelium
Prothrombin gene mutation
3’ untranslated region mutation–> increased production–> increased plasma levels, clots
Antithrombin deficiency
Inherited deficiency–> thromboses
- Put patient on heparin to treat thrombosis–> abnormally LOW increase in PTT (would expect longer for clot to form)
Protein C/S deficiency
Inability to inactivate factors V, VIII
- Increased thrombotic skin necrosis with hemorrhage following Warfarin administration (Warfarin given to try and correct hypercoagulable state)
- Warfarin blocks C, S–> thrombotic skin necrosis
Cryoprecipitate
Contains:
- Fibrinogen
- Factor VIII
- Factor XIII
- vWF
- Fibronectin
Use:
- Treat coagulation factor deficiency of fibrinogen, factor VIII (hemophilia A)
Fresh frozen plasma
Increased coagulation factor levels
Use:
- Treat DIC, cirrhosis, Warfarin overdose
Leukemoid reaction
Acute inflammatory response to infection
- increased WBCs, neutrophils, band cells (left shift)
- Increased Leukocyte alkaline phosphatase (also seen in PV, essential thrombocytosis, primary myelofibrosis)
- Contrast with decrease leukocyte alkaline phophatase in CML (increased WBC, left shift)
Hodgkin’s lymphoma
Localized, Single group of nodes (neck)
- Rare extranodal involvement
- Contiguous spread (stage= prognosis)
- Bimodal: young adults and 55+
- More common in men
- 50% associated with EBV t(8;14)
Reed Sternberg cells: B cells; CD30+, CD15+
- Needed for Hodgkin’s diagnosis
- Prognosis better with strong stomal/lymphocytic reaction against cells
- Most common form= nodular sclerosing (M=W)
- Lymphocyte mixed/depleted= poor prognosis
“B” signs/symptoms: low grade fever, night sweats, weight loss
Non-Hodgkin’s Lymphoma
Multiple, peripheral nodes
- Commonly see extranodal involvement
- May have lymphoblastic T-cell origin
Incidence peaks 20-40 years
- associated with HIV, immunosuppression
Fewer constiutional signs/symptoms
Burkitt’s lymphoma
Neoplasm of mature B cells (non-Hodgkin’s)
Adolescents, young adults
t(8;14): c-myc (transcription factor regulator on chrom 8) and heavy chain Ig (chrom 14)
- High proliferation index= Ki167 fraction
Endemic form (Africa): jaw lesion Sporadic: pelvis or abdomen
Diffuse large B-cell lymphoma
Older adults, 20% in children
- most common adult NHL
May be T-cell in origin (20%)
Presentation: tumor lysis syndrome
Genetics: bcl-2 (18), c-myc (8), bcl-6
Mantle cell lymphoma
Older males
Mantle= pre-germinal center (naive B cells)
Presentation: SICK; tumor lysis syndrome, Waldeyer’s ring, bone marrow, GI tract involvement
Genetics:
- t(11;14): cyclin D1 (chrom 11) with heavy chain Ig (14)
- CD5+ B cells
Poor prognosis
Follicular lymphoma
Adults
Genetics: t(14;18): heavy chain Ig (chrom14) and bcl-2 (inhibits apoptosis, chrom 18)
Difficult to cure; indolent course
Adult T-cell lymphoma
HTLV-1
Cutaneous lesions, hypercalcemia, opportunistic infections
- Japan, West Africa, Carribbean
Aggressive
Mycosis fungoides/Sezary syndrome
Adults: cutaneous patches/nodules
CD4+
indolent course
MGUS
Monoclonal Gammopathy of Undetermined Significance
- M protein < 30 g/dL (no other Ig abnormalities)
- Bone marrow plasma cells < 10%
- NO end-organ damage (no CRAB)
1-2% convert to multiple myeloma/year
Smoldering MM
M protein > 30g/dL (IgG, IgA, light chain and/or 10%+ plasma cells in bone marrow
- NO CRAB (end-organ damage
51% convert in 5 years, 73% at 20 years)
Multiple myeloma
Plasma cells produce IgG (55%) or IgA (25%)
- Most common tumor in ppl > 45 years
Associated symptoms:
- infections
- Primary amyloidosis AL
- M spike
- Ig light chains in urine (Bence Jones proteinuria)
- Rouleaux formation (RBC stacking)
- CRAB: hyperCalcemia, Renal insufficiency (due to light chains), Anemia, Bone lesions/Back pain
Waldenstrom’s macroglobulinemia
M-spike= IgM
–> hyperviscosity
NO lytic bone lesions
Acute lymphoblastic leukemia/lymphoma
Most common leukemia in people < 20 years
- Seen again in 60+
T-cell ALL= mediastinal mass (leukemic infiltration of thymus)
Features:
- Peripheral blood, bone marrow have increased lymphoblasts
- TdT+ (marker of pre-T and pre-B cells)
- CALLA+ (common ALL antigen) (CD10+)
- May spread to CNS, testes
- CD22+: ALL with B-cell lineage
- t(12;21)= better prognosis: seen in Down syndrome, NF-1, Ataxia telangiectasia
Small lymphocytic lymphoma, chronic lymphocytic leukemia (SLL, CLL)
60+ years
- Asympomatic; may have lymphadenopathy, splenomegaly, fatigue
- Autoimmune hemolytic anemia
Features:
- Smudge cells in periphery
- CLL= increased peripheral blood lymphocytosis/bone marrow involvement (vs SLL in periphery)
- increased Bcl-2 expression (protoncogene)
- CLL= deletion of 13q (good prognosis)
Hairy cell leukemia
Older men; rare
- Mature B cell tumor
Features:
- Hair-like projections on cells
- Stains TRAP (tartrate-resistant acid phosphatase)
Tx: cladribine= adenosine analogue
Acute mylogenous leukemia (AML)
Neonates and 65+
Features: increased circulating myeloblasts
- Adults: t(15;17)–> M3 AML subtype
- PML/RAR fusion: blocks myeloid precursor differentiation
- Responsive to ATRA (all-trans retinoic acid)–> pushes myeloid cells to differentiate
Presentation:
- Auer rods= peroxidase-positive inclusions in granulocytes, myeloblasts (ATRA–> auer rod release–> DIC)
- DIC: cells larger, sticker–> coagulation
Chronic myelogenous leukemia (CML)
30-60 years
- Philadelphia chromosome= t(9;22) bcr-abl fusion
- Bcr= breakpoint cluster region (chrom 22)–> increase P210 when fused with abl (chrom 9)–> tyrosine kinase activated–> protected from apoptosis
Features:
- increased neutrophils, metamyelocytes, basophils
- Splenomegaly (red pulp infiltration)
- Smaller megakaryocytes with hypolobulated nuclei (dwarfs)
- increased myeloid:erythroid ratio (decreased RBCs)
- Can accelerate and transform to AML/ALL (blast crisis)
- Low leukocyte alkaline phosphatase) due to immature granulocytes
Tx:
Imatinib: small molecule inhibitor of bcr-abl tyrosine kinase
Langerhans cell histiocytosis
Proliferative disorder of dendritic (Langerhans) cells from monocyte lineage
- Children: lytic bone lesions, skin rash
- Cells immature, do not efficiently stimulate T-lymphocytes via antigen presentation (increased skin infections?)
Cells:
- S-1000 (neural crest derived)
- CD1a
- Birbeck granules= “tennis rackets” on EM
Polycythemia vera
JAK2 positive
- Increased RBC and plasma volume
Abnormal clone of hematopoietic cells with constitutively active JAK 2 (V16F)
- erythrocytosis, thrombocytosis (low/no EPO)
Symptoms:
- Erythromelalgia, splenomegaly, thrombotic complications
- Excess histamine–> peptic ulcers, intense itching after hot shower
TxL phlebotomy
Essential thrombocytosis
Specific expansion of megakaryocytes Symptoms: - Hemorrhagic, thrombotic symptoms (easy bruisin, microangiopathic occlusion) - Thrombocytosis - Megakaryocyte hyperplasia
Myelofibrosis
Fibrotic obliteration of bone marrow
- Teardrop cells
- Fatigue, spleno/hepatomegaly (extramedullary hematopoeisis)
- Anemia
- Early satiety
- Dry tap due to marrow fibrosis
Appropriate vs inappropriate polycythemia
Relative: sweating/volume loss (decrease plasma) with no change in RBC mass
Approptiate absolute: increased RBC mass due to decreased O2 saturation
- Lung disease
- congenital heart disease (shunting)
- High altitude
Inappropriate absolute: increased RBC mass due to ectopic EPO-producing disease:
- Renal cell carcinoma
- Wilm’s tumor
- Cyst
- Hepatocellular carcinoma
- Hydronephrosis
Heparin
Co-factor for activation of antithrombin
- Decreases thrombin, factor Xa (in blood)
Use:
- Short half-life: immediate anticoagulation
- PE, ACS, MI, DVT
- Can be used in pregnancy (won’t cross placenta- water soluble)
- Prophylaxis in surgery for DVT
Monitoring: PTT
Tox:
- osteoporosis
- bleeding
- HIT= heparin-induced thrombocytopenia: IgG antibodies against heparin bound to PF4 (platelet factor 4)
- -> thrombosis, cytopenia
- Tx: argatroban, lepirudin, bivalrudin
Tx for overdose: protamine sulfate (positively charged)
Enoxaparin, dalteparin, fondiparinux
Low-molecular weight heparins (LMWH)
- Act more on Xa
- Better bioavailability, 2-4 time longer t1/2
- Less incidence of HIT, but not easily reversible
Lepidrudin, bivalrudin, argatroban
Derivative of hirudin (anticoagulant in leeches)
- Inhibits thrombin
- Alternative to heparin for anticoagulating patients with HIT
Warfarin
Interferes with vitamin k gamma-carboxylation by blocking epoxide reductase conversion of vitamin k (inactive K1–> K2)
- Can’t synthesize factors II, VII, IX, X, proteins C, S (in liver)
- Monitor PT (extrinsic pathway) and INR values
Use:
- Chronic anticoagulation
- NOT in pregnant women (lipid soluble, bound to albumin- crosses placenta)
Tox:
- CytP450 pathway: metabolism increased by Rifampin, phenobarbital, phenytoin
- Cyp450 inhibitors (increase Warfarin conc): amiodarone, cimetidine
- Cholestyramine bind warfarin in intestine–> decreased activity
- Bleeding
- Skin/tissue necrosis (protein C/S deficiency)
Tx for overdose:
- vitamin K
- Severe, rapid reversal: fresh frozen plasma
Alteplase (tPA), reteplase (rPA), tenecteplase (TNK-tPA)
Thrombolytics: directly/indirectly convert plasminogen to plasmin–> cleave thrombin, fibrin clots
- Increased PT, PTT, no change in platelet count
Use:
- Early MI, ischemic stroke (first 4 hours)
- Thrombolysis in severe PE
Tox: Bleeding (avoid in active bleeds, intracranial bleed, severe HTN)
- Tx toxicity with aminocaproic acid= inhibits fibrinolysis
Aspirin (ASA)
Irreversible inhibition of COX (1 and 2): covalent acetylation
- Increases bleeding time, decreases TXA2, prostaglandins
- no effect on PT, PTT
Use: antipyretic, antiinflammatory, antiplatelet (decrease aggregation)
Tox:
- Gastric ulcers
- tinnitus (CNVIII)
- Chronic use: acute renal failure (interstitial necrosis/nephritis), upper GI bleed
- Reyes syndrome (fatty liver) in children with viral infection
Overdose: respiratory alkalosis, metabolic acidosis
Intolderance: asthma, nasal polyps (10% of asthma patients have NSAID/ASA intolderance–> bronchospasm, nasal congestion due to increased leukotrienes)
- Leukotrienes= Lipooxygenase products of arachidonic acid metabolism
Clopidogrel, ticlopidine, prasugrel, ticagrelor
ADP receptor inhibitors: block receptor–> irreversible platelet aggregation inhibition as platelet won’t express GpIIb/IIIa
- Inhibit fibrinogen binding: prevent Glycoprotein IIb/IIIa from binding to fibrinogen
Use: ACS, coronary stenting, decreased incidence/recurrence of thrombotic stroke
Tox: Ticlopidine–> neutropenia (fever, mouth ulcers); only used when pt can’t tolerate aspirin, clopidogrel)
Cilostazol, dipyridamole
PDEIII inhibitor
- Increased cAMP in platelet–> inhibit aggregation; vasodilation
Use: intermittent claudication, prevent stroke/TIA, angina prophylaxis
Tox: nausea, headache, flushing, hypotension, abdominal pain
Abciximab, eptifibatide, tirofiban
GP IIb/IIIa inhibitors: bind on activated platelets (so fibrinogen can’t bind)–> prevent aggregation
- Abciximab= monoclonal Ab to Fab fragments
Use: ACS, percutaneous transluminal coronary angioplasty
Tox: bleeding, thrombocytopenia
Methotrexate
Folic acid analog: inhibits dihydrofolate reductase
–> decreased dTMP–> decreased DNA and protein synthesis
Tox:
- Myelosuppression; reversed with Leucovorin (folinic acid rescue)
- Macrovesicular fatty changes in liver (cirrhosis with chronic use)
- Mucositis
- Teratogen (duh)
5-FU
Pyrimidine analog bioactivated to 5F-dUMP–> complexes with folic acid–> inhibits thymidylate synthase (FU thymidylate synthase!)
Tox:
- Myelosuppression; rescue with thymidine
- Photosensitivity
Cytarabine (arabinofuranosyl cytidine), capecitabine, gemcitabine
Pyramidine analog–> inhibits DNA polymerase
Tox: myelosuppression, megaloblastic anemia
Azathiopurine, 6-mercaptopurine (6-MP), 6-thioguanine (6-TG)
Purine analog–> decreases de novo purine syntheis (blocks PRPP amidotransferase)
- Activated by HGPRT
Tox:
- Bone marrow, GI liver (abdominal pain, jaundice)
- Metabolized by xanthine oxidase–> increased toxicity with allopurinol administration
Dactinomycin
Intercalates DNA (antitumor antibiotic)
Tox: myelosuppression
Doxorubicin (adriamycin)
Danorubicin
Anthracycline (antitumor antibiotic)
Generates free radicals
- Noncovalently intercalate DNA–> breaks–> decreased replication
Tox: cardiotoxicity (dilated cardiomyopathy)–> CHF
** Dexrazoxane (iron chelating agent) used to prevent cardiotoxicity
Resistance:
- MDR1= human multidrug resistance gene; codes for P-glycoprotein
- P-glycoprotein= ATP-dependent drug efflux pump: pumps substances out of intestinal, renal tubular epithelium, capillary endothelium at BBB (thus removes chemotherapeutic drugs in tumor cells)
Bleomycin
Antitumor antibiotic: free radical formation–> breaks in DNA strands
Tox: Pulmonary fibrosis, skin changes
Cyclophophamide, ifosfamide
Alkylating agent: death in rapidly dividing cells
MOA: covalently x-link (interstrand) DNA at guanine N-7
- Activated by p450 system in liver
Tox:
- Hemorrhagic cystitis: partially prevent with mesna (thiol binds toxic metabolites)
Carmustine
Lomustine
Semustine
Streptozocin
Nitrosureas Require bioactivation (non-enzymatic hydroxylation) to cross BBB--> CNS
Tox: CNS (dizziness, ataxia)
Trastuzumab (Herceptin)
Monoclonal antibody against HER-2 (c-erbB2)= tyrosine kinase
Tox: cardiotoxic
Vincristine, Vinblastine
Alkaloids
Bind tubulin in M phase–> mitotic spindle can’t FORM
Vincristine= neurotoxic (areflexia, peripheral neuritis, paralytic ileus) Vinblastine= myelosuppression (blasts bone)
Paclitaxel, Taxols
Hyperstabilize microtubules in M phase–> mitotic spindle can’t BREAK DOWN
Use: ovarian, breast cancer
- Drug-eluting stents (inhibits intimal hyperplasia)
Tox: myelosuppression, hypersensitivity
Cisplatin, carboplatin
Cross-link DNA; hydrated to form cytotoxic metabolite in environment with low Cl- concentration
Tox: nephrotoxic, acoustic nerve (cochlear hair cell) damage
- Nephrotoxicity prevented with amifostine (free radical scavenger), chloride diuresis (normal IV saline)
Etoposide, teniposide
Inhibit Topoisomerase II–> can’t repair ds DNA breaks (positive or negative supercoils)
Use:
Etoposide= testicular, SCLC
Teniposide= genital warts
Tox: myelosuppression, GI irritation, alopecia
Hydroxyurea
Inhibits ribonucleotide reductase–> decreased DNA synthesis
Use: melanoma, CML, sickle cell disease (increase HbF)
Tox: bone marrow, GI upset
Irinotecan, topotecan
Topoisomerase I inhibitors (block ss breaks to relieve supercoiling
Tamoxifen, Raloxifene
SERM:
- Breast= receptor antagonist (breast cancer tx)
- Bone= receptor agonist (osteoporosis tx)
- Endometrium: Tamoxifen= partial agonist (increased risk of endometrial cancer)
- Raloxifene= antagonist (no risk of cancer)
Busulfan
Alkylates DNA
Tox: pulmonary fibrosis, hyperpigmentation
Trastuzumab (Herceptin)
Monoclonal antibody against HER-2 (c-erbB2)
Irinotecan, topotecan
Topoisomerase I inhibitors (block ss breaks to relieve supercoiling
Imatinib (Gleevec)
bcr-abl tyrosine kinase inhibitor
TOx: fluid retention
Rituximab
Monoclonal ab against CD20 (B-cell neoplasms)
Use: non-Hodgkin’s lymphoma, RA (with MTX)
Vemurafenib
Small molecule inhibitor of B-Raf kinase with V600E mutation
Use: metastatic melanoma
Bevacizumab
Monoclonal Ab against VEGF–> prevents angiogenesis
Osler-Weber Rendu= Hereditary hemorrhagic telangiectasia
Inherited disorder of blood vessels
- Telangiectasia of skin and mucosa
- Recurrent epistaxis
- GI bleeds
- Skin discolorations
- AV malformations
Hemoglobin A2
2 alpha, 2 delta chains
- Comprises 2-5% of adult hemoglobin
