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IHO 4 > Antineoplastics VI > Flashcards

Antineoplastics VI Flashcards

1
Q

Angiogenesis inhibitors

A

–Most work by interfering w/actions of substances that promote angiogenesis (esp. VEGF and mToR).

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2
Q

mTOR inhibitors

A

–Reduce cell growth and proliferation, prevent angiogenesis and increase the cytotoxicity of drugs that damage DNA

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3
Q

Which tissues secrete subtances that promote or inhibit angiogenesis?

A

All tissues (including tumors)

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4
Q

When must a cancer cell develop a blood supply in order to grow?

A

1-2mm. Blocking angiogenesis limits size of tumor growth

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5
Q

Rebound angiogenesis

A
  • -rapid growth of cancer when an angiogenesis inhibitor is stopped
  • -observed in patients with gliomas, where there is rapid, aggressive regrowth of the tumours after BEVACIXIMAB treatment is stopped
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6
Q

VEGF and VEGF-R drugs

A
  • Bevacizumab

- Pazopanib, sorafenib, sunitinib

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7
Q

mTOR inhibitor drugs

A

-Everolimus, temsiroliumus

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8
Q

Types of anti-angiogenics

A

Interferon-alpha.
VEGF and VEGF-R
mTOR inhibitors

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9
Q

mTOR function

A
  • is a serine/threonine kinase that plays a role in the control of cell growth and proliferation
  • senses changes in availability of growth factors and/or energy sources, and induces synthesis of proteins necessary for angiogenesis, cell growth/survival and nutrient uptake
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10
Q

Proteins regulated by mTOR

A
  • Cell cycle regulators (cylin D1)
  • Amino acid and glucose transporters
  • Proangiogenic factors
  • Enzymes required for DNA repair
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11
Q

VEGF-R

A

Tyrosine kinase receptor that activates mTOR to promote angiogenesis

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12
Q

mTOR and cancer cells

A

Increased mTOR activity in cancer cells–>secretion of VEGF and PDGF–>angiogenesis due to increased mTOR activity in vascular cells–> decreasing activity of VEGF/VEGF-R and mTOR can result in synergistic cell kill

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13
Q

Bevacizumab

A
  • -humanized monoclonal antibodydirected againstvascular endothelial growth factor (VEGF)
  • -approved (in combination with5-FU) for first-line treatment of metastatic colorectal cancer, lung cancer, breast cancer (controversial
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14
Q

Bevacizumab side effects

A
  • -Can cause GI perforation, wound dehiscence, hemoptysis (can be fatal). May worsen coronary or peripheral artery disease (preventing sprouting of new vessels)
  • -Also causes side effects common to antibodies
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15
Q

STIs of VEGF-R

A
  • -Receptors for VEGF and PDGF are receptor tyrosine kinases.
  • -Less specific than Imatinib (block multiple kinases
  • -1st line treatment for renal cell carcinoma
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16
Q

Sorafenib

A

Raf.

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17
Q

Pazopanib, sunitinib

A

c-KIT.

18
Q

STIs of VEGF-R (Pazopanib, sorafinib, sunitinib) pharmacokinetics

A
  • -Same PKs as forSTIs that block Bcr-Abl and HER2:
  • -oral administration; good bioavailability
  • -highly plasma protein bound
  • -metabolized in the liver (CYP 3A4), and excreted in the feces (hepatobiliary excretion)
19
Q

STIs of VEGF-R (Pazopanib, sorafinib, sunitinib) generla side effects

A

Same general toxicities as forSTIs that block Bcr-Abl and HER2:

  • -relativelyminor side effects: nausea, vomiting, fatigue, myalgia, diarrhea, skin rashes and acne, drug interactions
  • -can causecongestive heart failureand decreased left ventricular ejection fraction (causing shortness of breath, palpitations, fatigue) and/ormyocardial infarction
  • -teratogenic
20
Q

Pazopanib side effect (specific)

A

Severe (fatal) hepatotoxicity, hemorrhage, QT prolongation and torsades de points, GI perforation and hypertension

21
Q

Sorafenib side effects (specific)

A

Increased risk of hemorrhage, hypertension

22
Q

Sunitinib side effects (specific)

A

Skin discoloration, hand-foot syndrome

23
Q

mTOR inhibitor drugs

A

Everolimus, temsirolimus

24
Q

mTOR inhibitor drugs MOA

A
  1. Reducing cell growth and proliferation (decreased cell cycle progression, reduced bioenergetics)
  2. Prevention of angiogenesis
  3. Synergy with drugs that damage DNA
25
Q

mTOR inhibitor drugs pharmacokinetics

A
  • -oral administration; must be taken consistently (either with or without food) in order to minimize variability in drug concentration
  • -metabolized by CYP 3A4(drug interactions)
  • -substrate forP-glycoprotein
26
Q

mTOR inhibitor drug side effects

A
  • hypersensitivity– increased risk of lymphomas, –particularly of the skin and infection
  • angioedema
  • kidney arterial and venous —-thrombosis
  • delays in wound healing
  • hyperlipidemia
  • nephrotoxicity and proteinuria
  • male infertility
27
Q

immunomodulatory drug names

A

Lenalidomide, pomalidomide, thalidomide

28
Q

Thalidomide uses

A
  • Hansen’s disease

- Multiple myeloma

29
Q

Thalidomide side effects

A
  • -relatively few side effects in adult males and non-pregnant females, other than nausea, rashes, constipation andperipheral neuropathy
  • -increased risk ofdeep vein thrombosis, particularly inmultiple myelomapatients (most patients are placed on WARFARIN when THALIDOMIDE treatment is initiated)
  • -Significant teratogenic effects (esp. arond 3-4 weeks postconception).
30
Q

Thalidomide MOA

A
  • -In Hansen’s disease: suppresses immune and inflammatory reactions (as soon as treatment stopped, symptoms reappear).
  • Antieoplastic: alters ratios of various types of immune cells and changes that expression of molecular markers on their surfaces
  • -sedating and improves well being–restores appetite and decreases wasting
31
Q

Thalidomide pharmacokinetics

A

Oral

Renal excretion of metabolites

32
Q

Treatment strategies

A

Antineoplastic agents are almost always given in combination.Correct selection of drugs in a regimen can result in decreased development of resistance, synergistic effects and decreased toxic effects.

33
Q

Pulse therapy

A
  • -intermittent treatment with very high doses of a drug, followed by drug-free periods
  • -allow hematologic and immunologic recovery between treatment cycles

Example:METHOTREXATEfor the treatment ofchoriocarcinoma

34
Q

Rescue therapy

A

–following administration of toxic doses of a chemotherapeutic agent, normal cells can be rescued by giving “antidotes” that only they can use

Example:LEUCOVORINfollowing high dose METHOTREXATEtreatment

35
Q

Principles of drug selection

A
  • Active when used alone
  • Different mechanisms of action and/or different chemical classes (CCNS vs. CCS or active in different stages of cell cycle)
  • Enables use of more specific strategies
36
Q

Results of appropriate drug selection

A
  • -Synergistic effects (ex. cytarabine +6-thioguanine)
  • -decreased development of resistance
  • -broader cell kill in cancers that have heterogeneous tumor cell production
37
Q

Recruitment

A
  • -use aCCNS drugto achieve a significant log kill
  • -cause cancer cells in G0to be recruited back into the cell cycle
  • -administer aCCS drugto kill dividing cells
38
Q

Synchrony

A
  • -usingCCS drugsto synchronize cells into simultaneous cell division, so that they are more sensitive to other drugs or radiation
  • -timing the delivery of drugs so that the action of one drug doesn’t interfere with the actions of another
39
Q

Synchrony examples

A
  • -HYDROXYUREAfollowed by radiation
  • -VINCA ALKALOIDS(M phase) followed by anotherCCSdrug likeETOPOSIDE(S phase)
  • -METHOTREXATEfollowed byL-ASPARAGINASEfor the treatment of acute lymphocytic leukemia
40
Q

Recruitment examples

A

CMFin breast cancer

DAUNORUBICIN+CYTARABINEin AML

IHO 4 (4 decks)

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