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Flashcards in Hematology/oncology Deck (109):
1

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

2

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

3

TT= Thrombin time

Conversion of fibrinogen--> fibrin
- Prolonged by heparin

4

Ceruloplasmin

Carries Copper (decreased in Wilson's disease)
- alpha-2-globulin produced by liver, kidneys

5

Anaplasia

Loss of cell polarity, architecture
- variation in size, shape (pleomorphic)
- Giant multinucleated cells
- Nuclear hyperchromatism, pleomorphism
- Increased nuclear:cytoplasm ratio, abnL mitoses

6

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

7

Blood cell differential

Neutrophils (55%)
Lymphocytes (30%)
Monoctes (5%)
Eosinophils (3%)
Basophils (0-1%)

8

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

9

Macrophages

Precursor= monocyte (kidney-shaped nucleus)

Activated by IFN-gamma
Presents MHC II
Cell marker= CD14

Secretes TNF-alpha

10

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

11

Basophil

Mediates allergic reaction
Contain:
- Heparin
- histamine (vasodilator)
- Leukotrienes (LTD4)

12

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

13

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

14

Factor V Leiden mutation

Factor V resistant to inhibition by APC (activated protein C)
- most common cause of inherited hypercoagulability in whites

15

ESR

Erythrocyte sedimentation rate

Increased in: infections, autoimmune diseases, malignant neoplasia, GI disease, pregnancy (inflammation)

Decreased in:
- Polycythemia
- Sickle cell anemia
- CHF
- Microcytosis
- Hypofibrinogenemia

16

Acanthocyte

Spur cell

Seen in:
- Liver disease
- abetalipoproteinemia (cholesterol dysregulation states)

17

Basophilic stippling

Ribosomal RNA remnants in RBC

Seen in:
- Thalassemia
- Anemia of chronic disease
- Lead poisoning

18

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

19

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

20

TIBC

Total iron binding capacity= Transferrin (transport of iron in blood)
- increased when body needs more iron
- increased by OCPs, pregnancy

21

Ferritin

Storage form of iron (in macrophages in bone, liver)

22

Haptoglobin

Picks up hemoglobin after intravascular hemolysis--> brings to macrophages ("suicide protein")
- alpha-2-globulin produced by liver, kidneys

23

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

24

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)

25

Lead poisoning

Inhibits:
1. ferrochelatase--> protoporphyrin excess
2. ALA dehyratase--> delta-ALA excess
3. 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)

26

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)

27

Folate deficiency

Hypersegmented neutrophils
Megaloblastic anemia
- Increased Homocyteine

Symptoms:
- Sore tongue
- Pain on swallowing
- Angular stomatitis
- GI upset
- Hyperpigmentation

28

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

29

Plummer-Vinson syndrome

Triad:
- iron deficiency anemia
- Esophageal webs
- Atrophic glossitis

30

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

31

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)

32

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

33

HbC defect

Glutamic acid--> Lysine at beta-globin residue 6 (vs Glu--> val in SC)
- HbSC have milder disease than HbSS

34

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

35

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)

36

Warm agglutination

IgG
- Chronic anemia in SLE, CLL, certain drugs

37

Cold agglutination

IgM
- Acute anemia triggered by cold
- Seen in CLL, Mycoplasma pneumoniae, Infectious mono

38

Direct Coomb's

Test Patient RBCs
- Add anti-Ig antibody--> RBC agglutination= positive test

39

Indirect Coomb's test

Test patient plasma
- add normal RBCs to patient serum--> agglutination= anti-RBC surface Ig

40

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)

41

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

42

Bernard-Soulier syndrome

Decreased GpIb--> defect in platelet to vWF adhesion
Decreased platelet count, increased bleeding time

43

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

44

Idiopathic thrombocytopenic purpura

Anti-GpIIb/IIIa antibodies--> splenic macrophages consume platelets (bound to Abs)
--> purpura (no platlets!)

Labs: increased megakaryocytes

45

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

46

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

47

Prothrombin gene mutation

3' untranslated region mutation--> increased production--> increased plasma levels, clots

48

Antithrombin deficiency

Inherited deficiency--> thromboses
- Put patient on heparin to treat thrombosis--> abnormally LOW increase in PTT (would expect longer for clot to form)

49

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

50

Cryoprecipitate

Contains:
- Fibrinogen
- Factor VIII
- Factor XIII
- vWF
- Fibronectin

Use:
- Treat coagulation factor deficiency of fibrinogen, factor VIII (hemophilia A)

51

Fresh frozen plasma

Increased coagulation factor levels

Use:
- Treat DIC, cirrhosis, Warfarin overdose

52

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)

53

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

54

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

55

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

56

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

57

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

58

Follicular lymphoma

Adults

Genetics: t(14;18): heavy chain Ig (chrom14) and bcl-2 (inhibits apoptosis, chrom 18)

Difficult to cure; indolent course

59

Adult T-cell lymphoma

HTLV-1

Cutaneous lesions, hypercalcemia, opportunistic infections
- Japan, West Africa, Carribbean

Aggressive

60

Mycosis fungoides/Sezary syndrome

Adults: cutaneous patches/nodules

CD4+
indolent course

61

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

62

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)

63

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

64

Waldenstrom's macroglobulinemia

M-spike= IgM
--> hyperviscosity
NO lytic bone lesions

65

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

66

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)

67

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

68

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

69

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

70

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

71

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

72

Essential thrombocytosis

Specific expansion of megakaryocytes
Symptoms:
- Hemorrhagic, thrombotic symptoms (easy bruisin, microangiopathic occlusion)
- Thrombocytosis
- Megakaryocyte hyperplasia

73

Myelofibrosis

Fibrotic obliteration of bone marrow
- Teardrop cells
- Fatigue, spleno/hepatomegaly (extramedullary hematopoeisis)
- Anemia
- Early satiety
- Dry tap due to marrow fibrosis

74

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

75

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)

76

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

77

Lepidrudin, bivalrudin, argatroban

Derivative of hirudin (anticoagulant in leeches)
- Inhibits thrombin
- Alternative to heparin for anticoagulating patients with HIT

78

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

79

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

80

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

81

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)

82

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

83

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

84

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)

85

5-FU

Pyrimidine analog bioactivated to 5F-dUMP--> complexes with folic acid--> inhibits thymidylate synthase (FU thymidylate synthase!)

Tox:
- Myelosuppression; rescue with thymidine
- Photosensitivity

86

Cytarabine (arabinofuranosyl cytidine), capecitabine, gemcitabine

Pyramidine analog--> inhibits DNA polymerase

Tox: myelosuppression, megaloblastic anemia

87

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

88

Dactinomycin

Intercalates DNA (antitumor antibiotic)

Tox: myelosuppression

89

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)

90

Bleomycin

Antitumor antibiotic: free radical formation--> breaks in DNA strands

Tox: Pulmonary fibrosis, skin changes

91

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)

92

Carmustine
Lomustine
Semustine
Streptozocin

Nitrosureas
Require bioactivation (non-enzymatic hydroxylation) to cross BBB--> CNS

Tox: CNS (dizziness, ataxia)

93

Trastuzumab (Herceptin)

Monoclonal antibody against HER-2 (c-erbB2)= tyrosine kinase

Tox: cardiotoxic

94

Vincristine, Vinblastine

Alkaloids
Bind tubulin in M phase--> mitotic spindle can't FORM

Vincristine= neurotoxic (areflexia, peripheral neuritis, paralytic ileus)
Vinblastine= myelosuppression (blasts bone)

95

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

96

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)

97

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

98

Hydroxyurea

Inhibits ribonucleotide reductase--> decreased DNA synthesis

Use: melanoma, CML, sickle cell disease (increase HbF)

Tox: bone marrow, GI upset

99

Irinotecan, topotecan

Topoisomerase I inhibitors (block ss breaks to relieve supercoiling

100

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)

101

Busulfan

Alkylates DNA

Tox: pulmonary fibrosis, hyperpigmentation

102

Trastuzumab (Herceptin)

Monoclonal antibody against HER-2 (c-erbB2)

103

Irinotecan, topotecan

Topoisomerase I inhibitors (block ss breaks to relieve supercoiling

104

Imatinib (Gleevec)

bcr-abl tyrosine kinase inhibitor

TOx: fluid retention

105

Rituximab

Monoclonal ab against CD20 (B-cell neoplasms)

Use: non-Hodgkin's lymphoma, RA (with MTX)

106

Vemurafenib

Small molecule inhibitor of B-Raf kinase with V600E mutation

Use: metastatic melanoma

107

Bevacizumab

Monoclonal Ab against VEGF--> prevents angiogenesis

108

Osler-Weber Rendu= Hereditary hemorrhagic telangiectasia

Inherited disorder of blood vessels
- Telangiectasia of skin and mucosa
- Recurrent epistaxis
- GI bleeds
- Skin discolorations
- AV malformations

109

Hemoglobin A2

2 alpha, 2 delta chains
- Comprises 2-5% of adult hemoglobin