Chapter 17

Question 1

define tumor stem cell

Answer 1

tumor cells w/ an indefinite ability to proliferate.

loss of reproductive integrity of tumor stem cells is key to controlling a tumor

Question 2

describe the basic clonogenic assay - how does it work, what does it measure?

Answer 2

measurement of cell survival after drug (or RT) treatment.
see how many cells when put in culture can produce a clone. compare to untreated cells since many cells are non-clonogenic anyway. essentially it measures effectiveness of killing tumor stem cells.

Question 3

nonclonogenic assays evaluate what population of cells, name a few examples of non-clonogenic assays used to assess drug activity.

Answer 3

evaluates all tumor cells (not a selected pop of cells ie not just tumor stem cells only).
effects MAY correlate w/ effects on tumor stem cells.

ex: microscopic evaluation of cell damage, apoptotic assays, damage to cell membrane, separation of live from dead cells by ability to metabolize colored dyes, inhibition of cell growth under defined conditions, impairment of macromolecular synthesis, changes in proliferative parameters, formation of macronuclei, exchange of sister chromatids detected at mitosis, MTT assay

Question 4

list 2 assays used to quantitate stem cells after drug treatment

Answer 4

17.2
at least be aware of formation of metastatic lung colonies, formation of spleen colonies, growing colonies in petrie dish or on agar.

TD50 - # of cells that lead to growth of tumors in 50% of animals injected

Question 5

Non-clonogenic assays are better at predicting tumor cell (resistance or sensitivity) to drugs).

Answer 5

Resistance - resistance is usually accurate but sensitivity does not correlate. Should only be used in research setting!

Question 6

Draw 2 cell survival curves, one for drugs that are cell phase specific and one for drugs that are non-specific. Differentiate between rapidly and slowly proliferating tumor cells on each graph. Label axes.

Answer 6

17.1 B and A
For cell phase specific drugs - survival decreases exponentially at low drug doses but w /short survival. Plateau occurs bc once all cells in the drug sensitive phase of the cycle are killed even greater exposure will not result in extra cell kill bc other cells are not in a sensitive phase of the cycle. Mostly antimetabolites and vincas.

Question 7

What is adjuvant chemo?

Answer 7

giving chemo to patients that have no overt evidence of residual cancer after local treatment w/ surgery or RT. Based on high rate of relapse after these local procedures in past patients due to undetectable microscopic mets.

Question 8

Why is microscopic metastatic disesae potentially more curable than treating bulky disease w/ chemo?

Answer 8

1 - eradication of a smaller # of cells is more likely with a given dose of drug
2 - smaller tumors have better perfusion allowing better drug access
3 - bc they have better nutrition, the proliferation rate will be higher
4 - drug resistant cells are more likely to be present in larger tumors

Question 9

define neoadjuvant chemo. list pros and cons

Answer 9

chemotherapy started bf treatment of the primary tumor.

pros - may give an indication of responsiveness to drugs used. may kill circulating cells preventing seeding of mets by cells in circulation

cons - may increase metastasis to lungs (mech not fully understood but shown in animal models)

Question 10

What is the major limitation to clinical use of drugs to prevent metastasis formation?

Answer 10

many tumors will met, already have microscopic mets prior to detection and tx of the primary tumor. May prevent secondary mets (mets from mets) but unlikely to actually increase cure.

Question 11

define therapeutic index. draw an ideal curve including normal tissue effects from chemo and tumor response to a drug

Answer 11

17.7 p358

TI - relationship bt the probability of a biologic effect of a drug and the administered dose. If clinically useful, there must be a significant likelihood of tumor response at a lower dose than will likely cause toxicity. Often described as TI = TD-05/ED50 Where TD05-5% probability of toxicity in patients and ED50 = 50% of anti-tumor effect

Question 12

Administration of growth factors such as GCSF after chemo has been shown to help in what ways?

Answer 12

Accelerates the appearance of mature cells in the peripheral blood.
Decreases possibility of infection that can occur in absence of mature granulocytes.

Question 13

Explain 2 reasons why giving myelosuppressive drugs to patients w/ low peripheral blood counts can cause problems

Answer 13

Delays recovery, increases chance of infection and bleeding

Most notably - higher chance of depleting stem cell population bc they will proliferating rapdily

Question 14

Drug induced vomiting may occur bc stimulation of what 2 centers in the brain?
Name 2 neurotransmitters nb in producing signs of nausea and vomiting:
Name 1 vet drug that works to counteract those neurotransmitters:

Answer 14

CRTZ, vomiting center
Substance P - maropitant (NK-1 receptor antag)
Serotonin - dolasetron (5HT3 antag)

Question 15

Which group of chemo agents is most likely to cause a second malignancy in the future?

Answer 15

alkylators - acute leukemia

Question 16

describe synergy and additivity

Answer 16

Survival after drug A x Survival after drug B
Survival after drug AB given at same time
Interaction bt two agents that is greater would be predicted from the activity of either alone
Additivity range of effects that might be expected when 2+ cytotoxic agents are used in combo for treatment of cells or tumors where there is no specific interaction between them

Question 17

draw an isobologram and label the axes and different regions of the curve

Answer 17

p365 17.10

Question 18

name 2 drugs reported to inhibit MDR

Answer 18

Verapamil and cyclosporine

Question 19

how does dexraz work to inhibit cardiotoxicity and (supposedly) not decrease tumor efficacy?

Answer 19

chelates iron, heart is not affected bc high concentration of iron in the heart

Question 20

how does amifostine work (moa) and what is its affect on the patient

Answer 20

prodrug that is converted to sulfydryl containing in active form. localized selectively in normal tissues bc of increased activation on cell membranes of those tissues

Question 21

describe rational drug design and how it differs from previous screening of chemo agents

Answer 21

in rational drug design, a target is known such as BCR-ABL mutation in CML patients and drugs are designed to try to inhibit that problem specifically rather than DNA agents that attack all replicating DNA strands

Question 22

name a novel approach to targeting tumors w/ RAS mutations

Answer 22

inhibition of farnesyltransferase

ex: tipifarnip, lonafarnib

Question 23

what targets are affected by imatinib

Answer 23

BCR-ABL, c-KIT, PDGFR

Question 24

monoclonal abys against growth factor receptors have been developed. name two examples and the targets they inhibit

Answer 24

herceptin - HER2 in breast cancer aka trastuzumab

bevacizumab - against VEGFR

Question 25

what does flavopirodol do

Answer 25

first generation cyclin dependent kinase inhibitor

Question 26

liposomal forms of drugs can be used to deliver relatively high concentrations of drugs to tumors. these drugs are initially taken up by what cells in the body?

Answer 26

reticuloendothelial cells of the liver, spleen, lungs.
can see long times in circulation and cause slow prolonged drug release. internal delivery of drug to cells by fusion w/ cell membranes, selective localization of liposomes to tumor tissue

Question 27

name 3-4 ways that the use of chemo and RT together can improve outcome

Answer 27

RT is used for local control and chemo for mets (treating different parts of the tumor)
Use of each may kill cells that are resistant to the other
Inhibition by drugs of repopulation of surviving cells during RT
Use of drugs selective for hypoxic cells that are resistant to RT