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CTMD LOMO > Week 4 Borch > Flashcards

Week 4 Borch Flashcards

1
Q

Distinguish DNA damage from DNA mutation from genomic instability

A

Damage – change to structure
Mutation – change of base (ATCG)
Genomic Instability – Increased rates of mutation

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2
Q

Direct Repair

A

MGMT de-methylates oxygen on guanines

NOTE: without removing the base

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3
Q

Nucleotide Excision Repair

A

bulky adducts to bases, UV light causing pyrimidine dimers; causes a “bump” in DNA, recognized by enzymes, surrounding bases excised by endonucleases, then re-polymerized

Xermodoma Pigmentosum

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4
Q

Base Excision Repair

A

from x-rays, oxidation, alkylating agents, depurination (loss of base from backbone); DNA glycosylases remove bad base, other enzymes then remove the backbone, allowing polymerase to replace it

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5
Q

NonHomologous End Joining

A

overhanging nucleotides get cleaved, which can lead to loss of information

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6
Q

Homologous recombination

A

can have excessive crossing over without BLM helices

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7
Q

What is a microsatellite and why is it unstable? Give a classic example of a syndrome involving this.

A

Sequence of repeated bases, prone to slippage during DNA replication.
HNPCC (Lynch syndrome) – increased risk of colon and endometrial cancer due to MSI in mismatch repair genes

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8
Q

Differentiate Numerical and Structural Chromosomal Abnormalities

A

Numerical – relating to Number of chromosomes – aneuploidy

Structural – breakages, deletions, etc

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9
Q

Describe the connection between telomeres and aberrant bridge formations in a cell

A

Loss of shelterin on telomeres exposes them to be “repaired” and joined end to end. Then, during mitosis, the chromatids are pulled apart, but the aberrant bridge is broken in an unpredictable place, resulting in an imbalance of genetic information.

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10
Q

Define chromothripsis

A

Shattered chromosome, thought to be a single event

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11
Q

Differentiate Palliative, Adjuvant, and Neoadjuvant Therapies

A

Adjuvant – reducing recurrence risk
Neoadjuvant – before surgery to help make tumor more resectable AND to reduce recurrence risk
Palliative – to prolong life in quality or quantity

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12
Q

Chemotherapy and Radiation is designed to target aspects of tumor cells. Which other cells are often a part of the “collateral damage?” Why?

A

Targets rapidly dividing cells (ie tumor cells). Unfortunately, GI tract, hair follicle, and bone marrow cells are also rapidly dividing – hence the side effects.

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13
Q

Name the characteristic chromosomal abnormality

in CML

A

t(9;22) ie the Philadelphia Chromosome

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14
Q

Name the aberrant protein created in CML (and say what it does)

A

BCR-ABL, a tyrosine kinase that promotes cell growth and inhibits apoptosis (via JAK/STAT pathway)

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15
Q

How have we used this CML protein as a target for cancer therapy?

A

Imatinib mesylate (Gleevec), which competitively binds to the ATP pocket on the BCR-ABL – so it can’t phosphorylate things (ie it can’t be a kinase)

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16
Q

How and why does Rituximab work for Diffuse Large B cell lymphoma?

A

DLBCL is a B-cell neoplasm, Rituximab is an antibody that targets B-cell surface receptor CD20; causes body’s own phagocytes to think cancer cells are invaders and then to eat them

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17
Q

What is a big class of side effects for Rituximab?

A

Immunosuppression – since this drug causes the immune system to attack itself and a resulting paucity of B cells. Opportunistic infections and reactivated dormant viral infections (zoster, PML)

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18
Q

Dose Intensification Chemotherapy

A

give chemotherapy at the maximum tolerated dose

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19
Q

Dose Consolidation Chemotherapy

A

give chemotherapy at the shortest possible interval

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20
Q

Induction Chemotherapy

A

high initial dose intending to start a curative regimen

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21
Q

Consolidation Chemotherapy

A

repetition of the initial high dose in a pt who has achieved remission

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22
Q

Maintenance Chemotherapy

A

long term low dose in pt who has achieved remission with intent of prolonging cancer free survival

23
Q

Name four mechanisms of tumor drug resistance to Chemotherapy

A

Decreased drug uptake by cell
Increased drug extrusion by cell (ie MDR gene)
Increased DNA repair by cell
Mutation in target within cell

24
Q

Alkylating Agents

A

Mechanism of Action: Transfers alkyl groups that cause cross linking in DNA
Target phase in Cell Cycle: Not specific to any part of cell cycle (works against G0 cells)
Side Effects: Myelosuppression, GI, Reproductive, GU, Nephrotoxicity

25
Q

Anti tumor antibiotics

A

Mechanism of Action: DNA topoisomerase inhibitors (by binding to DNA), which prevents nucleic acid synthesis
Cell Cycle Target: Nonspecific (G0 active)
Side Effects: Hemo, GI, Repro, Cardiac, Pulm

26
Q

Antimetabolites

A

Mechanism of Action: Fake nucleotides/amino acids that compete with real ones to interfere with Cell cycle phase: DNA and protein synthesis
Specific to dividing cells (Not active on G0 cells)
Side effects: Hemo, GI - Hepatic

27
Q

Microtubule inhibitors

A

Mechanism of Action: Inhibit microtubule polymerization, thus arresting cell in mitosis
Cell Cycle Phase: Targets dividing cells (not G0)
Side Effects: Hemo, GI, Reproductive, CNS/PNS

28
Q

Topoisomerase Inhibitors

A

Mechanism of Action: Just like antitumor antibiotics, but they bind isomerases instead of DNA grooves
Cell Cycle Target: Cell cycle specific (not G0)
Side Effects: Heme, GI, Repro, CNS, secondary cancers

29
Q

Cyclophosphamide Side-Effects

A

hemorrhagic cystitis (CYclophosphamide causes CYstitis)

30
Q

Cisplatin Side-Effects

A

nephrotoxic, ototoxic (CisPLATin = PLATinum bling-bling = listen to rap music = ear death; cisPlatin = I have to P (pee) (but I can’t because I took cisplatin))

31
Q

Doxorubicin Side-Effects

A

cardiotoxic (DoxoRUBicin causes RUBs)

32
Q

Bleomycin Side-Effects

A

pulmonary fibrosis (BLEOmycin causes BLEBs)

33
Q

6-MP Side-Effects

A

hepatotoxic (6 + 1 for mecaptopurine = 7, Hept, HEPatotoxic)

34
Q

Vincristine Side-Effects

A

peripheral neuropathy (Vindicitive Christine pokes my hands and feet with pins and needles)

35
Q

Name the 3 components of the microenvironment that communicate with tumor cells. What do they do?

A

Fibroblasts – produce ECM for tumor growth
Immune cells – protective or supportive for tumor growth
Vascular cells – angiogenesis for tumor blood supply

36
Q

What is the role of Tumor Associated Macrophages?

A 
Promote Continuous Inflammation
Matrix remodeling
Angiogenesis
Assisting with metastasis
All of this depends on where they are within the tumor
More of them = Poor prognostic sign
37
Q

Name some mechanisms that tumor cells use to evade immune destruction.

A 
“immunoediting” ie. Evolving over time
Downregulating alert signals
Immunsuppressive factors
Killing attackers – ie Fas L
Re-programming surrounding myeloid cells to down regulate immune response
38
Q

VEGF

A

vascular leakiness, promotes endothelial growth

39
Q

bFGF

A

promotes endothelial growth

40
Q

CXCL12

A

Promotes recruitment of endothelial precursors

41
Q

Angiopoetins

A

Balance angiogenic growth

42
Q

Name the features of Tumor vasculature that are different from typical vasculature.

A

3-fold increase in capillary diameter
Chaotic organization of capillaries and cellular components
Contraction of myofibroblasts (as in wound healing) surrounding vasculature
Luminal gaps with increased permeability and leakiness

43
Q

What is special about lymphatics in the tumor environment and why? What effect does this have?

A

Excessive capillary leakage causes increased hydrostatic pressure in the tumor, which closes off lymphatics (like a valve). This increased hydrostatic pressure decreases gradient that allows small molecules to permeate the tumor, ie decreasing small molecule therapy effectiveness

44
Q

How do tumors “turn on” the angiogenic switch?

A

Encapsulated tumor leaks out signals to bring macrophages to come and chew up the capsule with MMPs to allow vasculature to invade thru the basement membrane.

45
Q

What are micrometastases and why are they signficant?

A

Tiny colonies, usually undetectable that are almost always present by the time the primary has been identified.

46
Q

Give the molecular mechanisms for transformation from boring epithelial cell to invasive mesenchymal cell (ie EMT)

A

Loss of cell-cell contact mechanisms (E to N cadherins)
Change of interactions between cell and matrix (integrins)
Assumption of a migratory cytoskeleton
Expression of proteinases to chew thru basement membrane

47
Q

Name 3 mechanisms by which herbal supplements interact with drugs.

A

Cytochrome P450 upregulation
Phase II enzyme upregulation
ABC drug transporters

48
Q

What is Tamoxifen?

A

A Selective Estrogen Receptor Modulator (SERM) for breast cancer chemoprevention

49
Q

What are tamoxifen’s effects on:
osteoporosis?
endometrium?
lipid profile?

A

osteoporosis: favorable
endometrium: Not favorable
lipid profile: Possibly favorable

50
Q

What has been proven in regards to ASA as a chemopreventative for CRC?

A

Secondary prevention: significant reduction in CRC in patients who had previously had a CRC

51
Q

Differentiate “Driver” and “Passenger” mutations.

A

Drivers – confer selective advantage to clone (these will be repeated “themes” over several tumors)
Passengers – genes and mutations that get “carried along” in the clone because of the Driver mutation

52
Q

Name the two most common malignancies in the pediatric population.

A

Brain/CNS tumors

Leukemias

53
Q

Name the most common non CNS, non leukemia malignancy in children.

A

Neuroblastoma (ok, if you said Wilm’s Tumor/Nephroblastoma, I’ll accept that)
NEUROBLASTOMA:
Typically an abdominal mass (adrenal mass) in a 2-3 y/o child.
Resected ideal. Neoadjuvant therapy if nonresectable.
MYCN
Age is most important prognostic factor

54
Q

For adolescents, what tumor type is uniquely abundant in this age group? What is the most common subtype? Name the other two less common ones.

A

Sacromas (think of them as growth spurt cancers)
Rhabdomyosarcomas
Ostesarcoma, Ewing’s Sarcoma t(11;22)

CTMD LOMO (14 decks)

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