Week 4 Borch Flashcards
Distinguish DNA damage from DNA mutation from genomic instability
Damage – change to structure
Mutation – change of base (ATCG)
Genomic Instability – Increased rates of mutation
Direct Repair
MGMT de-methylates oxygen on guanines
NOTE: without removing the base
Nucleotide Excision Repair
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
Base Excision Repair
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
NonHomologous End Joining
overhanging nucleotides get cleaved, which can lead to loss of information
Homologous recombination
can have excessive crossing over without BLM helices
What is a microsatellite and why is it unstable? Give a classic example of a syndrome involving this.
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
Differentiate Numerical and Structural Chromosomal Abnormalities
Numerical – relating to Number of chromosomes – aneuploidy
Structural – breakages, deletions, etc
Describe the connection between telomeres and aberrant bridge formations in a cell
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.
Define chromothripsis
Shattered chromosome, thought to be a single event
Differentiate Palliative, Adjuvant, and Neoadjuvant Therapies
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
Chemotherapy and Radiation is designed to target aspects of tumor cells. Which other cells are often a part of the “collateral damage?” Why?
Targets rapidly dividing cells (ie tumor cells). Unfortunately, GI tract, hair follicle, and bone marrow cells are also rapidly dividing – hence the side effects.
Name the characteristic chromosomal abnormality
in CML
t(9;22) ie the Philadelphia Chromosome
Name the aberrant protein created in CML (and say what it does)
BCR-ABL, a tyrosine kinase that promotes cell growth and inhibits apoptosis (via JAK/STAT pathway)
How have we used this CML protein as a target for cancer therapy?
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)
How and why does Rituximab work for Diffuse Large B cell lymphoma?
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
What is a big class of side effects for Rituximab?
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)
Dose Intensification Chemotherapy
give chemotherapy at the maximum tolerated dose
Dose Consolidation Chemotherapy
give chemotherapy at the shortest possible interval
Induction Chemotherapy
high initial dose intending to start a curative regimen
Consolidation Chemotherapy
repetition of the initial high dose in a pt who has achieved remission
Maintenance Chemotherapy
long term low dose in pt who has achieved remission with intent of prolonging cancer free survival
Name four mechanisms of tumor drug resistance to Chemotherapy
Decreased drug uptake by cell
Increased drug extrusion by cell (ie MDR gene)
Increased DNA repair by cell
Mutation in target within cell
Alkylating Agents
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
Anti tumor antibiotics
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
Antimetabolites
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
Microtubule inhibitors
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
Topoisomerase Inhibitors
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
Cyclophosphamide Side-Effects
hemorrhagic cystitis (CYclophosphamide causes CYstitis)
Cisplatin Side-Effects
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))
Doxorubicin Side-Effects
cardiotoxic (DoxoRUBicin causes RUBs)
Bleomycin Side-Effects
pulmonary fibrosis (BLEOmycin causes BLEBs)
6-MP Side-Effects
hepatotoxic (6 + 1 for mecaptopurine = 7, Hept, HEPatotoxic)
Vincristine Side-Effects
peripheral neuropathy (Vindicitive Christine pokes my hands and feet with pins and needles)
Name the 3 components of the microenvironment that communicate with tumor cells. What do they do?
Fibroblasts – produce ECM for tumor growth
Immune cells – protective or supportive for tumor growth
Vascular cells – angiogenesis for tumor blood supply
What is the role of Tumor Associated Macrophages?
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
Name some mechanisms that tumor cells use to evade immune destruction.
“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
VEGF
vascular leakiness, promotes endothelial growth
bFGF
promotes endothelial growth
CXCL12
Promotes recruitment of endothelial precursors
Angiopoetins
Balance angiogenic growth
Name the features of Tumor vasculature that are different from typical vasculature.
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
What is special about lymphatics in the tumor environment and why? What effect does this have?
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
How do tumors “turn on” the angiogenic switch?
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.
What are micrometastases and why are they signficant?
Tiny colonies, usually undetectable that are almost always present by the time the primary has been identified.
Give the molecular mechanisms for transformation from boring epithelial cell to invasive mesenchymal cell (ie EMT)
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
Name 3 mechanisms by which herbal supplements interact with drugs.
Cytochrome P450 upregulation
Phase II enzyme upregulation
ABC drug transporters
What is Tamoxifen?
A Selective Estrogen Receptor Modulator (SERM) for breast cancer chemoprevention
What are tamoxifen’s effects on:
osteoporosis?
endometrium?
lipid profile?
osteoporosis: favorable
endometrium: Not favorable
lipid profile: Possibly favorable
What has been proven in regards to ASA as a chemopreventative for CRC?
Secondary prevention: significant reduction in CRC in patients who had previously had a CRC
Differentiate “Driver” and “Passenger” mutations.
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
Name the two most common malignancies in the pediatric population.
Brain/CNS tumors
Leukemias
Name the most common non CNS, non leukemia malignancy in children.
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
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.
Sacromas (think of them as growth spurt cancers)
Rhabdomyosarcomas
Ostesarcoma, Ewing’s Sarcoma t(11;22)
