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Block F: Defence > W1P3 > Flashcards

W1P3 Flashcards

1
Q

What are platelets

A

Cell fragments that function as part of hemostasis

  • Initiate thrombus formation with overt vascular injury
  • Proposed role in wound repair, innate immune response, metastatic malignancy
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2
Q

What is the lifespan of platelets

What is the normal count?

A

Life span of 7-10 days
Normal count 150 x 109/L – 450 x 109/L
1/3 of platelets are always transiently sequestered in the spleen

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3
Q

Platelet production

- how is production regulated?

A

Bone marrow production of megakaryocytes stimulated by thrombopoietin

Megakaryocytes shed platelets from their cytoplasm – each produces 1000-3000 platelets

Thrombopoietin induces megakaryocyte maturation and differentiation
Produced in liver
- c-mpl receptors expressed on circulating platelet mass provide feedback loop
- Decreased platelet mass = decreased amount of c-mpl receptors = decreased clearance of TPO = resulting increase in megakaryocyte production

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4
Q

What is Primary Hemostasis

- What are the four steps?

A

Hemostasis is process by which bleeding is stopped at site of injury with normal blood flow elsewhere

Four steps

  1. Adhesion to injured site
  2. Activation and secretion
  3. Aggregation
  4. Interaction with coagulation factors
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5
Q

What are some strong vs weak physiologic stimuli of platelets?

A

strong: collagen, thrombin

Weak: ADP, epinephrine

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6
Q

How does endothelium usually maintain anticoagulant surface?

- What happens in injury?

A

via. production of NO and prostacyclin

INJURY: exposes the subendothelial matrix -> exposed collagen activated platelets

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7
Q

What are the two major platelet-collagen receptors?

A

GPIa/IIa (alpha 2, betal 1) - platelet adhesion
GPVI - platelet activation

inheritied loss of GPIa = mild bleeding diathesis BUT
congenital absence of GPVI = spontaneous bleeding episodes

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8
Q

What receptor does Thrombin use to activate platelets?

A

platelets express PAR: G proteins coupled Protease-Activated Receptors

PAR1 - high affinity, PAR4- low affinity receptor

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9
Q

P2Y12 receptor involvement in platelets?

- What is it inhibited by?

A

ADP binds to two G-protein coupled purinergic receptors – P2Y1 and P2Y12
When activated, P2Y12 induces platelet secretion and stable aggregation
Activated platelets secrete ADP which works in a paracrine/autocrine manner to recruit and stimulate more platelets enhancing aggregation
Activity of the P2Y12 receptor is inhibited by clopidogrel

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10
Q

Platelet Adhesion

A

Platelet surface receptor GPIb/IX/V complex binds exposed von Willebrand factor (vWF) in the subendothelial matrix

Von Willebrand factor (vWf) is a large multimeric protein secreted by endothelial cells and megakaryocytes

A. vWf adheres to subendothelial collagen conformational change allowing it to bind to GPIb-V-IX
B. Rolling process slows platelet transit and allows platelet signalling receptor, GPVI to bind collagen
C. Signalling cascade leads to activation of integrin α2β1 (GPIa/IIa)  platelet firmly adheres to vessel wall

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11
Q

Platelet Aggregation

A

GPIIb/IIIa complex (integrin alpha IIb beta 3) is most commonly expressed receptor on platelet surface

Stimulation of platelet induces conformational change in GPIIb/IIIa rendering it a high-affinity receptor for fibrinogen

GPIIb/IIIa binds vWF affixed to the subendothelial matrix cytosolic component of GPIIb/IIIa adheres to the platelet cytoskeleton and induces platelet spread and clot retraction

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12
Q

What are the two platelet granules

A

Dense granules:
Contain platelet agonists
-ADP, ATP, serotonin

Alpha granules:
Contents serve to enhance platelet adhesion
-Fibrinogen, vWF, fibronectin

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13
Q

Define sequestration

A

To hide or isolate

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14
Q

Relationship between platelet count and risk of bleeding?

A

Minimal at 50 x 10^9/L
spontaneous bleeding at <20 x 10^9/L
severe, fatal: <5 x 10^9/L

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15
Q

Thrombocytopenia causes

A

Decreased platelet production
Increased destruction or consumption (immune-mediated and non-immune-mediated)
Increased splenic sequestration of platelets with normal platelet survival
Pseudothrombocytopenia

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16
Q

Pseudothrombocytopenia

A

In vitro agglutination of platelets
15-30% of all isolated thrombocytopenia

Associated with use of EDTA as anticoagulant in tube
- Confirm by ordering smear of CBC showing thrombocytopenia with automated counting

*Can be avoided by using citrate/heparin as anticoagulant

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17
Q

What are the DDx for isolated thrombocytopenia?

A

Primary immune thrombocytopenia (ITP)
Inherited thrombocytopenia
Marrow failure/myelodysplastic syndrome/malignancy
Splenic sequestration

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18
Q

ITP

A

Primary immune thrombocytopenia

-otherwise healthy looking kid (NORMAL CBC/smear) , minimal history/recurrence, apart from petechie

Immune-mediated destruction of otherwise normal platelets

  • Triggered by viral infection, other immune phenomenon
  • most commonly age 2-5 y/o
  • Natural history is self-resolution within 6 months (75-80%)
  • Most presentations include mild bruising, petechiae

IgG directed against platelet membrane antigens, most commonly GPIIb/IIIa ie integrin αIIbβ3

  • Increased clearance by splenic macrophages
  • Production inhibited
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19
Q

Management of ITP

A

Management options include observation or active therapy with corticosteroids, IVIg, or anti-D (if Rh-positive)

Treatment options include
IVIg (80% effective, increase within 24h, peak within 2-7d)
Short-course corticosteroids (70-80% effective, increase within 48h)
Other:
IV anti-D (“blackbox” warning)
Tranexamic acid may be used as adjunct (not if hematuria)
Platelet transfusion contraindicated except for acute life-threatening bleed or if urgent surgery required

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20
Q

Menorrhagia

- CBC finding

A

is a condition marked by abnormally heavy, prolonged, and irregular uterine bleeding. Women with this condition usually bleed more than 80 ml, or 3 ounces, during a menstrual cycle. The bleeding is also unexpected and frequent.

otherwise healthy looking, no pain, normal physical exam

CBC finding: HIGH Mean Platelet Volume (MPV)

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21
Q

What is used to measure platelet activation and aggregation in vitro?

A 
Platelet agonists
(ensure pts not on meds that interfere with platelets) 
Common agonists are: 
ADP
collagen 
Epi
Ristocetin
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22
Q

Bernard- Soulier Syndrome

  • characteristic symptoms?
  • lab findings include?
A

Autosomal recessive platelet disorder
Deficiency of GPIb receptor for vWF, which leads to impaired platelet adhesion
RARE, affects males and females equally

Symptoms include spontaneous/excessive mucocutaneous bleeding; varying bleeding severity throughout life. Can be diagnosed in adulthood (can be mistaken for chronic ITP)

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23
Q

Lab findings and Management for Bernard-Soulier Syndrome?

A

Laboratory findings include
Macrothrombocytopenia, normal coagulation studies (PT, aPTT)
No aggregation with ristocetin, that is uncorrected by addition of plasma (vWD would correct)

Management includes
Avoidance of anti-platelet therapies
Transfusion for bleeding, or pre-procedural

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24
Q

What are Bone Marrow Cancers

  • general lab findings
  • progression of disease?
A

Myeloid malignancies – cancers derived from the hematopoietic stem or progenitor cell

  • Affect predominately the bone marrow
  • Effects are seen primarily in the blood

Lab Findings:
a. Cytopenias – decrease in one or more cell lines
Anemia, thrombocytopenia, leukopenia, neutropenia – etc
b. Pancytopenia – decrease in all cell lines
c. May also see elevation in one or more line
Erythrocytosis, thrombocytosis,leukocytosis, neutrophilia – etc

May be very aggressive or more indolent cancers

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25
Q

Define Leukemia

A

By definition a leukemia is a myeloid or lymphoid cancer that involves the bone marrow as its primary site.
May be acute or chronic

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26
Q

Acute Leukemia

A

Rapid proliferation of abnormal clone that overtakes bone marrow and prevents normal hematopoiesis

Severe anemia, thrombocytopenia, and neutropenia

Patients are symptomatic at the outset

  • Rapidly progressive
  • Death within weeks to months

Cells show impaired differentiation

  • Immature appearance
  • Little functionality
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27
Q

Chronic Leukemias

A

Differentiation is more or less intact.

Leukemic cells resemble mature, normal white cells and may even function normally

Clone grows such that for most of the disease course, the growth of normal blood cells is not significantly impaired.
- Generally follow a more indolent course

Patients often present because of an abnormal CBC (usually elevated white count)

often asymptomatic for long periods; life expectancy measured in years.

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28
Q

Can you have leukemia if you have a perserved blood cell function and numbers?

A

Yes, this is what CHRONIC leukemia looks like

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29
Q

Myeloproliferative Neoplasms

A

Cancerous stem cell disorder of the marrow
Excessive production of one or more cell lines- disordered proliferation of cells
Relatively intact differentiation
May affect WBC, RBC or platelets
May also see proliferation of other cells such as fibroblasts – myelofibrosis – and other, rarer entities

with accumulation of one or more mature cell lines in the marrow and blood

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30
Q

Myelodysplastic Syndromes

A

Cancerous stem cell disorder with
Impaired differentiation

Results in cytopenias:
Increased growth of cells inside the marrow
Decreased cell numbers outside the marrow
Faulty cells die (apoptosis) before they get into circulation

May evolve to acute myeloid leukemia over time.

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31
Q

What is the Origin of Myeloid Cancers

A

All of these cancers occur as the result of genetic changes in the hematopoietic stem cell

Effects maturation and growth of all progenitor cells

Several changes likely necessary to achieve transformation
Changes may be at chromosomal or molecular level.

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32
Q

What cytogenetic changes are associated with development of Leukemia and related disorders

A

Changes at the level of the chromosome involving large amounts of DNA at a time

May result in deletion of whole genes, even whole chromosomes

Duplication of DNA may also occur

Translocations of DNA from one chromosome to another
May result in fusion genes

Molecular genetic changes:

a. Smaller changes at critical points in DNA
Insertions/deletions
Point mutations
Missense and nonsense mutations

b. Epigenetic changes
Modifications to DNA and chromosomes that alter transcription without changing the base sequence
Methylation of cytosine
histone acetylation

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33
Q

What are the 4 broad categories of Leukemias?

A

Acute lymphoblastic leukemia (ALL)
Acute myeloid leukemia (AML)
Chronic lymphocytic leukemia (CLL)
Chronic myeloid leukemia (CML)

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34
Q

The Blast Cell

- what amount signifies Acute leukemia?

A

Immature hematopoietic cell with minimal differentiation

Characterized by:
Somewhat larger size than most hematologic cells
Large nucleus
Very “lacy” or “open” nuclear material
- DNA is not condensed as in mature blood cells
May have a prominent nucleolus or nucleoli

By definition having a blast count > 20% in the bone marrow is an acute leukemia (myeloid or lymphoid)

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35
Q

CLL

  • Subtype?
  • Marker?
  • Clinical course?
A

Chronic Lymphoid Leukemia

  • A subtype of B cell lymphoma
    Cells are mature B lymphocytes that may circulate in blood or grow in lymphoid organs (spleen, nodes)
  • Atypical CD5 expression (CD5 is a T cell marker)
    Cells appear indistinguishable from small lymphocytic lymphoma (SLL) cells
    Clinical course is like an indolent lymphoma
    Natural history measured in years to decades in most (but not all) cases
    Responds to many of the same agents as B cell lymphomas
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36
Q

What is the Pathobiology of Acute Leukemia

A

Occurs in a single stem or progenitor cell - Evidence for this includes:

  • shared chromosomal abnormalities
  • rearrangement of Ig or TcR genes in ALL

Mutations appear to be common in mechanisms affecting transcription and gene modification
- e.g. 25% of all AML is initiated by a mutation in the gene DNA methytransferase-3

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37
Q

What are some clinical manifestations of Acute Leukemia?

A

Pancytopenia from marrow failure
- May or MAY NOT have leucocytosis with circulating blast cells

Constitutional Symptoms:
Fevers
Fatigue
Bone pain*
Malaise

Direct Tissue Infiltration by blast cells
Leukostasis syndromes
Tumour Lysis Syndrome
Coagulation Disturbances
Usually short duration of symptoms (weeks to months)

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38
Q

What is Pancytopenia

- Combo of what three CBC findings?

A

A condition in which there is a lower-than-normal number of red and white blood cells and platelets in the blood

  1. Neutropenia/Impaired immunity:
    - infections, sepsis
    - Usually bacterial
    - Fungal infections if pronlonged neutropenia
  2. Anemia:
    - fatigue, pallor
    - Cardiac ischemia in extreme cases
  3. Thrombocytopenia
    - bleeding, bruising
    - disseminated intravascular coagulation
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39
Q

Leukostasis

A

Accumulation of blasts in microcirculation with impaired perfusion

  • lungs: hypoxemia, pulmonary infiltrates
  • CNS: altered mental status, stroke

Risk Features

  • WBC&raquo_space; 50 x 109/L (not frequent)
  • AML > ALL
  • Monocytic/monoblastic features
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40
Q

Infiltration by blast cells

  • Is common sign of ____
  • What does this involve?
A

Acute Leukemias

Involves:
- Enlargement of liver, spleen, lymph nodes
- Gum hypertrophy
- Bone pain
Other organs: CNS, skin, testis, any organ…

41
Q

Laboratory features of Acute Leukemia

A

Pancytopenia
- WBC my be low or elevated (blasts)

Coagulation abnormalities

Electrolytes and renal disturbances
- auto tumour lysis syndrome (hyperuricemia, high K, PO4, creat)

Increased liver function tests

42
Q

Bone Marrow Studies in Acute Leukemia

A

Usually necessary for diagnosis

Cell morphology must show > 20% immature cells (blasts) to make the diagnosis

Confirmation of blast characteristics
- Large nuclei with open chromatin and promenent nucleoli are classic features of blasts

Myeloid/Lymphoid by morphology
Cytochemistry or Flow cytometry

Cytogenetics can be done on malignant cells

Molecular testing for specific gene defects becoming more routine and bring important information to treatment decisions

43
Q

Acute Promyelocytic Leukemia (APL)

A

A subtype of AML
Different treatment and prognosis:

Presents as AML

  • Pancytopenia
  • Coagulation disturbances
  • Frequent
  • Severe
  • Lethal
  • Characteristic morphology

t(15;17) in most cases
Rare variants

About 5-10% of AML
Different treatment
***Curable

44
Q

Clinical features of Acute Lymphoblastic Leukemia (ALL)

A

B lineage vs T lineage

80% are pre B ALL, 20% are T ALL
Pre B-ALL is primarily a disease of children
75% of cases occur in children under the age of 6
Most common malignancy among children
Peak incidence in children is approximately 2 to 3 years of age
Increased risk among children with Downs syndrome
About 20% of acute leukemias in adults

45
Q

AML rate in adults vs kids?

A

AML represents 80% of acute leukemia in adults, but only 20% of acute leukemia in children

46
Q

Morphological Features of Acute Myeloid Leukemia (AML)

A

Morphology

  • Usually larger than lymphoblasts, up to the size of a monocyte
  • Moderate to abundant cytoplasm with or without granules
  • May contain Auer rods
  • Sometimes convoluted nucleus with diffuse chromatin and one or more nucleoli

Cells usually stain positive for Sudan black or myeloperoxidase

47
Q

Classification of AML is based on?

A

Degree of differentiation of the blast (defined morphologically and by surface markers)

AML M0, M1 and M2 – poorly differentiated and may or may not contain granules

M0 and M1 may be difficult to distinguish from ALL
AML M4 is similar with a mixture of monocytic and granulocytic features
AML M5 cells resemble monocytes

48
Q

Developing targeted therapy in AML

A

Specific mutations in certain genes appear to be critical in driving the disease
Inhibiting function of mutated genes may alter biology and improve outcomes
- Easy to inhibit overexpressed or overactive processes
- Less clear what to do in cases of gene loss or loss of function

Small molecules, antibodies
Targets currently in development include
- ***FLT-3 – a protein tyrosine kinase overactive in about 30% of AML: inhibitor shown to improve AML outcomes

more common in patients over 60, however must consider whether treatment is worth it past that age

49
Q

What is the molecular lesion in APL?

A

Translocation between

  • Retinoic acid receptor gene (chromosome 17)
  • PML gene (chromosome 15)

Resultant PML-RARa gene drives disease (normally would have stimulated promyelocytic maturation)

Translocation can be detected rapidly with FISH or RT-PCR

50
Q

Treatment of APL

A

Early recognition of APL

Early correction of coagulation abnormalities

Early institution of All-trans Retinoic Acid (ATRA)

  • Specific treatment of APL
  • Ligand for the PML-RAR protein

Addition of arsenic trioxide +/- chemotherapy now considered largely curative in nearly all cases of disease

51
Q

Morphology of ALL?

A

Blasts are usually small with a high nuclear to cytoplasmic ratio
The bone marrow aspirate is usually hypercellular and infiltrated with blasts.
To make the diagnosis of ALL, 20% or more of nucleated cells in the bone marrow must be blasts.

52
Q

Cytogenetics in ALL

A

Prognostically important in B-ALL, less so in T-ALL

can help determine if the prognosis is favourable or poor.

53
Q

Prognosis of ALL

A

Children – Excellent – between 60-90% cure with chemotherapy

Infants < 1 year are the exception with poor outcomes

Adults – Fair – Only about 40% cure

Pediatric regimens appear to be more effective although more toxic to adults
Adults treated on pediatric regimens may do better

54
Q

Principles of Acute Leukemia Treatment

A

Initial chemotherapy is directed at remission induction
Decreasing blast count in marrow to < 5%
Restoration of normal hematopoesis

Usually ~ 4 week period of treatment

  • Heavy transfusion needs
  • High risk of infection

Usually several more cycles of treatment needed to achieve long-term disease control
- Many, but not all patients will ultimately relapse

55
Q

What is Car-T

  • What is it used to treat?
  • What cells does it involve?
A

Immunotherapy – Adoptive Chimeric AntiGEN RECEptor T cells (Car-T)

Best established for diseases of B cells expressing CD19
(ALL, CLL, NHL)

  1. T cell collection from pt
  2. T cell transfection: CAR cell membrane insertion
  3. T Cell Adoptive Transfer
  4. Patient monitoring
56
Q

Immunotherapy for ACUTE leukemias

A 
blinatumumab
Bi-specific, T cell Engager Antibody
*Anti CD19/CD3
Brings T cells into proximity to target cells (tumour cells)
Enhanced immunologic response
57
Q

Clinical progression of Myeloproliferative Disorders

A

Usually patients are asymptomatic for long periods of time

After several years may develop to more aggressive disease that mimics acute leukemia

In some cases (essential thrombocytosis, polycythemia vera) there is also a tendency for thrombosis to occur

58
Q

What are the four major subtypes of Myeloproliferative Neoplasms

A
  1. Chronic Myeloid Leukemia – mainly white blood cells affected
  2. Essential Thrombocytosis – mainly platelets affected
  3. Polycythemia vera – mainly rbc cells affected
  4. Myelofibrosis – mainly accumulation of bone marrow fibroblasts
59
Q

Chronic Myeloid Leukemia

  • fall under which type?
  • Which chromosome is involved
  • accumulation of which cell type?
  • differentiation?
A
  • The prototype of the myeloproliferative disorders

Transforming event occurs in the hematopoetic stem cell

t(9;22) – Philadelphia chromosome
bcr-abl fusion gene

Results in accumulation of uncontrolled granulocytes
Platelets and rbc affected to a lesser extent

Differentiation is largely intact in the early stages

60
Q

What are the three phases of CML?

A

Chronic Myeloid Leukemia

1. Chronic Phase
Generally asymptomatic
	Sometimes vague symptoms (fatigue, night sweats, weight loss)
may have enlarged spleen
Lasts for 4-7 years
  1. Accelerated Phase
    Increasing numbers of immature (blast cells)
    Rising or falling platelets, enlarging spleen
    Evidence of new genetic changes in marrow studies
  2. Blast Phse
    Acute illness occurring when blasts > 20%
    Rapid collapse of bone marrow with pancytopenia
    Very similar to AML, but often with higher resistance to chemotherapy
    Death usually within 6 months if untreated
61
Q

What is the treatment for CML?

A

Imatinib: abl-kinase inhibitors are mainstay of therapy*

Block the action of the fusion protein allowing restoration of normal hematopoiesis
Prevent progression to more severe disease and restore normal hematopoiesis
Not curative and must be taken indefinitely

62
Q

What are the Myelodysplastic Syndrome (MDS)

A

The MDSs are characterized by the development of cytopenias, most commonly anemia. Patients may require considerable support with transfusion and other agents to maintain blood counts. In addition to the expected problems from low blood counts:

Low white blood cells – frequent infections
Low platelets – frequent and serious bleeding
Low red blood cells – marked anemia and even ischemia

Transfusion-dependent anemia

May also have low platelets and/or white blood cells

Genetic disease with an enhanced risk of transformation to acute myeloid leukemia.

Highly variable prognosis
life expectancy a few months to several years

63
Q

What are the causes of MDS

A

Primary or de novo
Usually occurs above age 60
No clear provoking cause
Some association with toxins such as benzene, rubber and solvents

Therapy-related MDS
Secondary to chemotherapy, radiotherapy
Usually occurs 3 – 7 years after exposure
Worse prognosis with faster transformation to AML

MDS may occur secondary to other hematologic disorders
Aplastic anemia
Myelproliferative neoplasms
Paroxysmal nocturnal hemoglobinuria

64
Q

TReatment options for pts with MDS

A

Myelodysplastic Syndrome

low risk: RBC and platelet transfusions
high risk: immunosuppresions, chemotherapy, stem cell transplants

65
Q

Which type of disease is driven by bcr-abl kinase?

A

Myeloproliferative Disease:
Increased cell number but intact differentiation
May affect one ore more cell lines
CML – protoype disease driven by bcr-abl kinase

66
Q

Which type of disease has risk of transforming to AML

A

Myelodysplastic disease:

Low and high risk disease – may transform to AML
Impaired Differentiation
Increased bone marrow cells with decreased circulating cells

67
Q

Which type of leukemia is most common in adults?

A

Acute Myeloid Leukemia

  • Most common in adults
  • Variable prognosis depending on cytogenetics
68
Q

Which Leukemia has good prognosis with All-trans-Retinoic Acid treatment?

A

Acute Promyelocytic Leukemia (M3)

  • PML-RARa gene from translocation of chromosomes 15 and 17
  • Good prognosis with All-trans-Retinoic Acid
69
Q

Which Leukemia is most common in children?

A

Acute Lymphoblastic Leukemia

  • Most common in children
  • Excellent response to multiagent chemotherapy if in childhood, prognosis worse in adults
70
Q

What are some cancers of the blood

A
  • Leukemia
    • Lymphoma
    • Multiple myeloma
71
Q

Which cancer is most common for ages 0-14?

A

Leukemia!

72
Q

Define Cancer

Define the “ideal” Cancer treatment

A

Cancer: altered regulation of cell proliferation and differentiation

“Ideal” cancer treatment: eradicate cancer cells without harming normal cells

73
Q

What are the 4 types of Chemotherapeutic drugs?

A

DNA Alkaylation: Covalently binding DNA
Anti-metabolites: blocking DNA replication
Microtubules: Messing up the process of cell division
Topoisomerase Inhibitors: blocking DNA replication phase

These^ are all NON specific, so they will target ALL rapidly proliferating cells. Yet they are still useful, and still used.

74
Q

What are examples of DNA alkylation drugs?

A

Cyclophosphamide
Dacarbazine

  • non specific drugs
75
Q

What are examples of Anti-metabolite drugs?

A

Methotrexate
R-Fluorouracil
Cytarabine

76
Q

Examples of Microtubule drugs

A

Vincritine
Vinblastine
Taxols

77
Q

Example of Topoisomerase inhibitor drugs

A

Daunorubicin

DNA damage: Bleomycin

78
Q

Dacarbazine

  • type
  • mechanism
A

DNA alkylating agent

  • Methylates guanine at the o-6 and N-7 positions
79
Q

What cells does the toxicity of alkylating agents affect?

What does Resistance to alkylating agents look like?

A

To rapidly proliferating cells

  • Hematopoietic system
  • GI tract
  • Gonads
Resistance to alkylating agents
- Increased inactivation
        Nucleophilic "trapping agents'
- Increased DNA repair
- Decreased activation
80
Q

Methotrexate

A

Anti metabolite drug, non specific cancer treatment

  • it is a folic acid analogue; competively binds to dihydrofolate reductase and inhibits cell division pathway (methyl transfers)
81
Q

5 - Fluorouracil

A

DNA base modification

type of anti-metabolite drug, non specific cancer treatment

82
Q

Cytarabine

A

Type of anti-metabolite, non specific cancer drug

Modification to the sugar: it competitively inhibits DNA polymerases. it’s incorporation into the DNA produces strand break and triggers apoptosis

83
Q

Vinca Alkaloids

A

from a plant, transformed to Vincristine/Vinblastine

  • Bind to tubulin, terminate assembly, cause depolymerization of microtubules and mitotic arrest

a Microtubule* type of non specific cancer drug

84
Q

Taxols

A

promote microtubule assembly and inhibit disassembly

a microtubule type of non specific cancer drug

85
Q

Daunorubicin (Doxorubicin)

  • Used to treat?
  • TYPE
  • Mechanism
A

AML
ALL
CML

Topoisomerase inhibitors, non specific cancer drug

mechanism: Intercalates in DNA and inhibits topoisomerase II: causes DNA strand breaks

86
Q

Bleomycin

A

topoisomerase inhibitor type non specific cancer drug

Binds to DNA and iron, forms free radicals (ROS), leading to DNA single and double strand breaks and chromosomal aberrations.

87
Q

Prednisone

A

A type of SPECIFIC target cancer drug
Steroid hormone receptor is the target

this is a type of glucocorticoid

can alter gene expression

88
Q

Imatinib

- What is it used to treat

A

this is a SPECIFIC cancer drug

Cancer specific Tyrosine Kinase Inhibitor (Fused BCR-Abl) fromed by translocation

Used to treat CML, chronic myeloid leukemia and ALL, acute lymphocytic Leukemia

89
Q

Rituximab

  • mechanism
  • used to treat?
A

Specific cancer drug: modifies the immune response,
it is Anti CD20

mechanism: destroys both NORMAL and MALIGNANT B cells

Treats:
B cell non Hodgkins Lymphoma that is CD20+

Chronic Lymphocytic Leukemia CLL

90
Q

What are drugs that block T cell priming?

A

Ipilimumab: block CTLA-4

Premrolizumab, Nivolumab: block PD-1/PD-L1

treats: Hodgkin Lymphoma plus other cancers

91
Q

Brentuximba Vedotin

What is it?
What does it target?
What does it treat?

A

what is it: : an antibody-drug conjugate

Targets tumor cells expressing CD30 (HL). Conjugated via a protease-cleavable linker to a potent anti-microtubule agent

treats: specific lymphomas

92
Q

Venetoclax

  • Target
  • Treats?
A

Targets BCL2, increasing apoptosis

Treats: B cell malignancies

93
Q

CAR T cell therapy

- steps

A
  1. remove blood to get T cells
  2. Make CAR T cells in the lab, proliferate
  3. Infuse CAR T cells into patients
  4. CAR T cells bind to cancer cells and kill them
94
Q

Principles of Classical Cancer chemotherapy

A
  1. High dose- maximize cell kill with tolerable toxicity
  2. Intermittent
  3. Drug Combinations
95
Q

Drug combinations - delay resistance

What are the four principles

A
  1. Efficacy
  2. Toxicity
  3. Optimum scheduling
  4. Mechanism of interaction
96
Q

What is the drug approach to Acute Lymphoblastic Leukemia?

A

Vincristine
Prednisone
Doxorubicin/Daunorubicin

97
Q

What is the drug approach to Chronic Myelogenous Leukemia

A

Philadelphia chromosome^

drug: Imatinib*

98
Q

Sample approach to Hodgkin Lymphoma

A

Think ABVD

Doxorubicin (Adriamycin)
Bleomycin
Vinblastine
Dacarbazine

Brentuximal vedotin
Nivolumab or Pembrolizumab

99
Q

Sample drug approaches to Non-Hodgkin Lymphoma

A 
Think CDVP
 Cyclophosphamide 
Doxorubicin 
Vincristine 
Prednisone

*Rituximab

Block F: Defence (9 decks)

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