Einstein/Shannon Chemotherapy Notes (does not include individual CT notes) Flashcards
static population
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
Expanding population
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
Renewing population
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
Average Doubling time for human cancer
Duplicate
50 days
Human growth fractions
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.
When is single agent chemotherapy curative?
log kill is very large (>99%) and with repetitive therapy
When is prolongation of survival or cure achieved?
cell population is reduced to between 10-1,000 cells (not clinically detectible)
Also seen 10-10^4 (10,000) reported
Cell cycle specific agents more effective against?
tumors with high proliferative rate and high growth rate
Not effective against the slower growing tumors
Cell cycle NON specific agents
Kill in all phases
ALKYLATING agents
Goldie-Coldman Theory
(Duplicate)
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 $$$!!
Intrinsic resistance (relating to chemotherapy)
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
Acquired resistance
occurs in cells that were initially sensitive
Mechanisms of drug resistance (6)
- Defective transport
- Altered hormone receptor concentration
- Altered DNA repair
- Gene amplification
- Impaired activation
- 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
What is the mechanism of doxorubicin resistance in ovarian cancer cell lines?
Defective transport
Describe a mechanism for hormone resistant breast cancers
Altered hormone Receptor concentration / expression leads to altered binding affinity
What mechanism of resistance is Involved in the resistance to alkylating and platinum agents
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
How do cancer cells develop resistance to methotrexate? (What is the mechanism of resistance)
Gene amplification - Methotrexate resistant cells can have amplified dihydrofolate reductase gene expression
Mechanisms of Impaired activation for 5FU, MTX, doxorubicin, and cyclophosphamide
- 5-FU, low uridine kinase and phosphorylase
- MTX, low polyglutamation
- Doxorubicin low p450 enzymes
- Cyclophosphamide hepatic dysfunction
Mechanism of Multidrug Resistance
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
Modulators of resistance to chemotherapy (3)
- 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.
- Glutathione S-transferase inhibitors: deplete glutathione, making cells more susceptible to oxidative stress. Ex: Ethacrynic acid
- Lonidamine: inhibits aerobic glycolysis in cancer cells.
Buthionine Sulfoxime
- Tumor resistance to number of compounds are associated with over expression of glutathione and glutathione transferases
- Buthionine is a specific inhibitor of glutamyl system synthetase (rate limiting enzyme in glutathione production)
- Administration with concurrent melphalan ongoing
- Shown to decrease glutathione levels
Glutathione S transferase inhibitors
Ethacrynic acid (loop diuretic) which inhibits glutathione production and in preclinical studies sensitized cancer cell lines to chlorambucil, melphalan, BCU, mustard, and doxorubicin