Chapter 17 Flashcards
define tumor stem cell
tumor cells w/ an indefinite ability to proliferate.
loss of reproductive integrity of tumor stem cells is key to controlling a tumor
describe the basic clonogenic assay - how does it work, what does it measure?
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.
nonclonogenic assays evaluate what population of cells, name a few examples of non-clonogenic assays used to assess drug activity.
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
list 2 assays used to quantitate stem cells after drug treatment
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
Non-clonogenic assays are better at predicting tumor cell (resistance or sensitivity) to drugs).
Resistance - resistance is usually accurate but sensitivity does not correlate. Should only be used in research setting!
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.
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.
What is adjuvant chemo?
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.
Why is microscopic metastatic disesae potentially more curable than treating bulky disease w/ chemo?
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
define neoadjuvant chemo. list pros and cons
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)
What is the major limitation to clinical use of drugs to prevent metastasis formation?
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.
define therapeutic index. draw an ideal curve including normal tissue effects from chemo and tumor response to a drug
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
Administration of growth factors such as GCSF after chemo has been shown to help in what ways?
Accelerates the appearance of mature cells in the peripheral blood.
Decreases possibility of infection that can occur in absence of mature granulocytes.
Explain 2 reasons why giving myelosuppressive drugs to patients w/ low peripheral blood counts can cause problems
Delays recovery, increases chance of infection and bleeding
Most notably - higher chance of depleting stem cell population bc they will proliferating rapdily
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:
CRTZ, vomiting center
Substance P - maropitant (NK-1 receptor antag)
Serotonin - dolasetron (5HT3 antag)
Which group of chemo agents is most likely to cause a second malignancy in the future?
alkylators - acute leukemia
describe synergy and additivity
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
draw an isobologram and label the axes and different regions of the curve
p365 17.10
name 2 drugs reported to inhibit MDR
Verapamil and cyclosporine
how does dexraz work to inhibit cardiotoxicity and (supposedly) not decrease tumor efficacy?
chelates iron, heart is not affected bc high concentration of iron in the heart
how does amifostine work (moa) and what is its affect on the patient
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
describe rational drug design and how it differs from previous screening of chemo agents
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
name a novel approach to targeting tumors w/ RAS mutations
inhibition of farnesyltransferase
ex: tipifarnip, lonafarnib
what targets are affected by imatinib
BCR-ABL, c-KIT, PDGFR
monoclonal abys against growth factor receptors have been developed. name two examples and the targets they inhibit
herceptin - HER2 in breast cancer aka trastuzumab
bevacizumab - against VEGFR
what does flavopirodol do
first generation cyclin dependent kinase inhibitor
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?
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
name 3-4 ways that the use of chemo and RT together can improve outcome
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