Einstein/Shannon Chemotherapy Notes (does not include individual CT notes)

Question 1

static population

Answer 1

well differentiated cells that rarely undergo division e.g striated muscle, neurons, oocytes, nephrons

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Static population: well differentiated cells that rarely undergo division e.g striated muscle, neurons, oocytes
Expanding population: normally quiescent but can grow under stress e.g. liver, vascular endothelium
Renewing population: continually replicating e.g. bone marrow, GI epithelium

Question 2

Expanding population

Answer 2

normally quiescent but can grow under stress e.g. liver, vascular endothelium, bile duct epithelium,

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Static population: well differentiated cells that rarely undergo division e.g striated muscle, neurons, oocytes
Expanding population: normally quiescent but can grow under stress e.g. liver, vascular endothelium
Renewing population: continually replicating e.g. bone marrow, GI epithelium

Question 3

Renewing population

Answer 3

continually replicating e.g. bone marrow, GI epithelium, skin, spermatocyes

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Static population: well differentiated cells that rarely undergo division e.g striated muscle, neurons, oocytes
Expanding population: normally quiescent but can grow under stress e.g. liver, vascular endothelium
Renewing population: continually replicating e.g. bone marrow, GI epithelium

Question 4

Average Doubling time for human cancer

Duplicate

Answer 4

50 days

Question 5

Human growth fractions

Answer 5

variable, 25 - 95%

Internet:
Growth fraction of tumor refers to the percentage of cells engaged in proliferation versus G0 phases at any given point in time. Tumor burden refers to the number of cancer cells present in the tumor.

Question 6

When is single agent chemotherapy curative?

Answer 6

log kill is very large (>99%) and with repetitive therapy

Question 7

When is prolongation of survival or cure achieved?

Answer 7

cell population is reduced to between 10-1,000 cells (not clinically detectible)

Also seen 10-10^4 (10,000) reported

Question 8

Cell cycle specific agents more effective against?

Answer 8

tumors with high proliferative rate and high growth rate

Not effective against the slower growing tumors

Question 9

Cell cycle NON specific agents

Answer 9

Kill in all phases
ALKYLATING agents

Question 10

Goldie-Coldman Theory

(Duplicate)

Answer 10

Mutation towards resistance occurs spontaneously at a rate of 1 mutation per 1 million cell divisions or higher.

Thus the likelihood of spontaneous mutation increases as the mass increases. Drug exposure further increases mutations

Remember: Goldie makes Millions $$$!!

Question 11

Intrinsic resistance (relating to chemotherapy)

Answer 11

Card says this (?): cells with intrinsic resistance may arise from duct cells or cells lining excretory ducts

observed when cells are first exposed
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Intrinsic resistance - the innate resistance that exists before a patient is exposed to certain drugs, which usually causes reduced efficacy of the drug treatment.

Intrinsic resistance can be caused by:
1) pre-existing (inherent) genetic mutations in tumors that result in decreased responsiveness of cancer cells
2) heterogeneity of tumors in which pre-existed insensitive subpopulations (cancer stem cells) will be selected upon drug treatment
3) activation of intrinsic pathways used as defense against environmental toxins

Question 12

Acquired resistance

Answer 12

occurs in cells that were initially sensitive

Question 13

Mechanisms of drug resistance (6)

Answer 13

1. Defective transport
2. Altered hormone receptor concentration
3. Altered DNA repair
4. Gene amplification
5. Impaired activation
6. Multidrug resistance

Chi lists:
1. decreased drug uptake
2. increased efflux
3. Impaired activation
4. increased metabolism to inactive metabolite
5. Alteration in target
6. Improved DNA repair or tolerance to damage

Question 14

What is the mechanism of doxorubicin resistance in ovarian cancer cell lines?

Answer 14

Defective transport

Question 15

Describe a mechanism for hormone resistant breast cancers

Answer 15

Altered hormone Receptor concentration / expression leads to altered binding affinity

Question 16

What mechanism of resistance is Involved in the resistance to alkylating and platinum agents

Answer 16

Altered DNA repair

1) Downregulation of CTR1 transporter (reduced intracellular accumulation of platinum) (THIS vs NER most common, not sure)
2) Elevated levels cellular glutathione (GSH)
3) Nuclear excision repair (NER) pathway which repairs platinum-DNA adducts through ERCC1 protein
4) DNA MMR - loss of function of MMR contributes to developing DNA damage tolerance

Question 17

How do cancer cells develop resistance to methotrexate? (What is the mechanism of resistance)

Answer 17

Gene amplification - Methotrexate resistant cells can have amplified dihydrofolate reductase gene expression

Question 18

Mechanisms of Impaired activation for 5FU, MTX, doxorubicin, and cyclophosphamide

Answer 18

1. 5-FU, low uridine kinase and phosphorylase
2. MTX, low polyglutamation
3. Doxorubicin low p450 enzymes
4. Cyclophosphamide hepatic dysfunction

Question 19

Mechanism of Multidrug Resistance

Answer 19

MDR1 gene with P170 glycoprotein associated with increased drug efflux

May be implicated in paclitaxel and vinca alkaloids (these are both tubulin agents, active in M phase- to remember MDR1)

Significance
MDR1 has at least three major areas where its activity impacts clinical outcomes and toxicity. First, MDR1 confers resistance to cancer chemotherapeutic agents and is a major cause of treatment failures. Because MDR1 transports a wide range of chemotherapy drugs, such as the anthracyclines, vinca alkaloids, taxanes, etoposide, mitoxantrone, bisantrene, and the histone deacetylase inhibitor depsipeptide

Question 20

Modulators of resistance to chemotherapy (3)

Answer 20

1. Buthionine sulfoxime: irreversibly inhibits gamma-glutamylcysteine synthetase, thereby depleting cells of glutathione, a metabolite that plays a critical role in protecting cells against oxidative stress, and resulting in free radical-induced apoptosis. Elevated glutathione levels are associated with tumor cell resistance to alkylating agents and platinum compounds.
2. Glutathione S-transferase inhibitors: deplete glutathione, making cells more susceptible to oxidative stress. Ex: Ethacrynic acid
3. Lonidamine: inhibits aerobic glycolysis in cancer cells.

Question 21

Buthionine Sulfoxime

Answer 21

1. Tumor resistance to number of compounds are associated with over expression of glutathione and glutathione transferases
2. Buthionine is a specific inhibitor of glutamyl system synthetase (rate limiting enzyme in glutathione production)
3. Administration with concurrent melphalan ongoing
4. Shown to decrease glutathione levels

Question 22

Glutathione S transferase inhibitors

Answer 22

Ethacrynic acid (loop diuretic) which inhibits glutathione production and in preclinical studies sensitized cancer cell lines to chlorambucil, melphalan, BCU, mustard, and doxorubicin