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PHRM 864 > Lecture 1 - Concepts of Chemotherapy > Flashcards

Lecture 1 - Concepts of Chemotherapy Flashcards

1
Q

How is cancer defined, categorized and staged?

A

cancer: any malignant neoplasm
defined as “the plasias” and the “omas”
numerical staging system
characterized by: uncontrolled cellular growth (benign tumors), tissue invasion and metastasis (cancer)
cancer is unstable, atypical, and loses normal cellular function

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2
Q

Cancer is a disease of progression

A

cell with mutation –> hyperplasia –> dysplasia –> in situ cancer –> invasive cancer

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3
Q

Numerical staging system

A

0: in situ carcinoma, no sign of local invasion (not outside of tissue it was originally diagnosed in)
I: microscopic invasion of surrounding tissue
II: 4-9 surrounding lymph nodes are involved
III: 10 or more surrounding lymph nodes are involved
IV: distant metastases are detected
largely based on tumor size, location and number; primarily only solid tumors get staged
stages 3-4 usually means poorer outcomes, it does not always mean lethality

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4
Q

Specific clinical staging system - TNM staging system

A

primary tumor (T)
regional lymph nodes (N)
distant metastasis (M)

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5
Q

Primary tumor (T)

A

TX: primary tumor cannot be evaluated
T0: no evidence of primary tumor
Tis: carcinoma in situ - no spreading to neighboring tissue yet
T1, T2, T3, T4: size and/or extent of invasion of the primary tumor

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6
Q

Regional lymph nodes (N)

A

NX: regional lymph nodes cannot be evaluated
N0: no regional lymph node involvement
N1, N2, N3: degree of regional lymph node involvement (# + location of lymph nodes)

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7
Q

Distant metastasis (M)

A

MX: distant metastatis cannot be evaluated
M0: no distant metastasis
M1: distant metastasis is present

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8
Q

Summary staging

A

insitu
localized
regional
distant
unknown

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9
Q

In situ

A

abnormal cells are present only in the layer of cells in which they developed

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10
Q

Localized

A

cancer is limited to the organ in which it began, without evidence of spread

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11
Q

Regional

A

cancer has spread beyond the primary site to nearby lymph nodes or tissues and organs

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12
Q

Distant

A

cancer has spread from the primary site to distant tissues or organs or to distant lymph nodes

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13
Q

Unknown

A

there is not enough info to determine the stage

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14
Q

The “plasias”

A

hyperplasia
metaplasia
dysplasia
anaplasia

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15
Q

Hyperplasia

A

an increase in organ or tissue size due to an increase in the number of cells
can be physiologic, compensatory, or pathologic

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16
Q

Metaplasia

A

an adaptive, substitution of one type of adult tissue to another type of adult tissue

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17
Q

Dysplasia

A

an abnormal cellular proliferation in which there is loss of normal architecture; transforms cell into abnormal version of itself

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18
Q

Anaplasia

A

a loss of structural differentiation
cells dedifferentiate
occurs frequently in tumors

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19
Q

The “omas”

A

carcinoma
adenocarcinoma
sarcoma
lymphoma and leukemia
melanoma
blastoma
teratoma

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20
Q

Carcinoma

A

malignant neoplasm of squamous epithelial cell origin

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21
Q

Adenocarcinoma

A

malignant neoplasam derived from glandular tissue

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22
Q

Sarcoma

A

malignant neoplasm with origin in mesenchymal tissues or its derivatives e.g. bone, muscle, fat

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23
Q

Lymphoma and leukemia

A

malignant neoplasms of hematopoietic tissues (blood tissues)

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24
Q

Melanoma

A

a type of cancer of pigment producing cells (melanocytes) in the skin or the eye (uveal melanoma)

25
Blastoma
malignancies in precursor cells, often called blasts, which are more common in children (nephroblastoma, medulloblastoma, and retinoblastoma) from developing cells
26
Teratoma
a germ cell neoplasm made of several different differentiated cell/tissue types from reproductive cells
27
Leukemia is a cancer of
the white blood cells of hematopoietic origin comes from multipotential hematopoietic stem cell (hemocytoblast) - myeloid leukemias and lymphocytic leukemias --> lymphomas
28
What are the "hallmarks" of cancer?
avoiding immune destruction enabling replicative immortality activating invasion & metastasis inducing or accessing vasculature genome instability & mutation resisting cell death sustaining proliferative signaling
29
Become familiar with tumor nomenclature
neoplasm: meaning a new growth, may be benign or malignant tumor: a nonspecific term meaning lump or swelling
30
Tumor grading
description of a tumor well-differentiated: if the cells of the tumor and the organization of the tumor's tissue resemble those of normal cells and tissue, these grow at a slower rate than tumors that are undifferentiated or poorly differentiated, which have abnormal looking cell/lack normal tissue structures GX: grade can't be assessed G1: well differentiated G2: moderately differentiated G3: poorly differentiated G4: undifferentiated
31
Some infections can cause cancer
RSV causes cancer - it integrates into the genome
32
Differentiate oncogenes vs. tumor suppressors
oncogene: gene capable of causing cancer proto-oncogene: any gene in a healthy cell capable of promoting tumor growth tumor suppressor: slow down cell division or tell cells to die at the right time tumor suppressors prevent cancer, oncogenes promote cancer
33
v-Src is an
oncogene
34
Kras is a
oncogene
35
RB1 is a
tumor suppressor
36
P16 and P53 are a
tumor suppressor P53 is the guardian of the genome
37
BRCA1 and BRCA2 are
tumor suppressors they encode for proteins involved in DNA repair
38
Most tumor suppressors need to be
homozygous deletion/mutation heterozygous mutations can be inherited and families show increased susceptibility to cancers "loss of heterozygosity"
39
2-hit hypothesis
hereditary retinoblastoma has a single deletion already
40
How will genome sequencing change personalized cancer treatment?
most cancers have a variety of gene mutations screen pt to find specific type of mutation, can then target that specific mutation
41
Targeting oncogenic mutations
EGFR mutation - tyrosine kinase which acts as oncogene, promotes growth
42
Tumor suppressor mutations
loss of function mutations can predict susceptibility to chemotherapies "synthetic lethality" - when you lose a tumor suppressor, there's still other pathways being utilized; ex. BRCA and PARP
43
BRCA mutations in breast cancer increase susceptibility to
PARP inhibitors normal cell: PARP1 and BRCA lead to repair cells with BRCA mutation: PARP1 is still able to lead to repair cells with drug-induced PARP1 inhibition: cancer drug inhibits PARP1, BRCA can still repair the DNA cells with BRCA mutation and PARP1 inhibition: cancer drug targets and inhibits PARP1, BRCA mutation leads to no repair and cell death
44
PARP inhibitor
olaparib: primarily for cancers with BRCA1/2 mutations; traps PARP to DNA --> unable to uncouple from DNA
45
CDK4/6 inhibitors
ribociclib, palbociclib, abemaciclib directly inhibit kinase, prevent phosphorylation of Rb1 and prevent cells from dividing quickly
46
Palbociclib
Cdk4/6 kinase inhibitor not a targeted therapy because they target all replicating cells approved for cancers arising dur to BRCA1/2 mutations
47
Importance of cell cycle in chemotherapy
chemo to target DOGMA central DOGMA of biology: DNA transcribed to RNA, RNA translated to protein cell cycle driven by cyclins paired with cyclin-dependent kinases R point is the critical time point when cells decide whether or not to enter the cell cycle controlled by cyclin D
48
Cell cycle checkpoints
G1 phase: mitogenic signaling S: DNA replication G2: sister chromatid separation M: mitosis, chromosome segregation G0: rest phase
49
Understand how chemotherapies target cancer growth and cancer survival
loss of checkpoint control results in increased cell death with chemotherapy
50
Kinetics of cancer cell proliferation (rate of tumor growth, growth fraction, doubling time) and kinetics of cancer cell killing by chemotherapy
when tumor cells have lost G1/S checkpoint control, the cells do not halt in G1 and attempt to replicate damaged DNA, this triggers apoptosis or the damaged DNA is replicated and lethal genetic damages are acquired, resulting in necrosis
51
Drugs that do not require cycling cells
DNA alkylating agents - effective against cancer cells resting in G0 and cells progressing through the cell cycle
52
Drugs that are more effective against cycling cells at many phases of the cell cycle (non-specific)
alkylating agents and DNA intercalation agents - most effective when the tumor cells are progressing through the cell cycle; not dependent upon the cell being in a specific phase of the cell cycle
53
Phase specific drugs
most effective against tumor cells in a specific phase of the cell cycle # of cells killed by the agent will be limited to the # of cells present in the apporpriate phase of the cell cycle; higher drug doses may not result in greater tumor cell killing increased cell kill requires prolonged exposure - repeated administration or continuous infusion
54
Major mechanisms of drug resistance in cancer chemotherapy
chemo kills a constant fraction, not # of tumor cells it will select for cells resistant to drug, undergo cycles of chemo to kill more fraction of tumor cells give as dose-intensive and early as possible and at shorter intervals (longer intervals lead to more time for growth of the tumors)
55
Drug resistance - altered drug metabolism
1. increased transport of drugs out of the cell through efflux pumps - PgP and MRP 2. reduced transport into cell - loss of drug importer, decreased membrane permeability 3. decreased activation of prodrug 4. increased detoxification of drug molecule
56
Drug resistance - changes in drug target or function
1. increased expression of drug target through gene amplification or expression - upregulation of a drug target makes it harder to inhibit 2. emergence of mutant, structurally altered target - mutants that are active but don't bind the drug 3. emergence of cells bearing alteration in genes whose products are functionally redundant with the drug target - cell can reqire pathways to bypass need for drug target
57
Drug resistance - physiological changes that promote resistance
refuge of cancer cells in drug-protected anatomical sites - metastasis to brain where drugs don't cross BBB massive stromalization - pancreatic carcinomas develop highly desmoplastic stroma that impedes drug transport changes in cell state such as EMT - slows cell cycle, increases drug effluc pumps and increases anti-apoptotic proteins
58
Most common dose-limiting toxicities resulting from cancer chemotherapy
hematopoietic - WBC (granulocytes) - infections, platelets - hemostasis, RBC - anemia gastrointestinal, N/V, loss of appetite
59
Principles of combination chemotherapy
use combo of drugs with distinct mechanism of action to help to prevent resistance also more effective to target different site in the cycle CHOP: cyclophoshamide, doxorubicin, vincristine, prednisone advantages: no additive toxicity for drugs with non-overlapping toxicities and increased cell killing

PHRM 864 (20 decks)

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