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81 Cards in this Set

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Neoplasia
New Growth
Tumor
Mass (Lump) The use of the word tumor does not necessarily imply that you have a neoplasm (inflammatory and cystic tumors)
Two Types of Neoplasia
1. Benign 2. Malignant (Define benign or malignant neoplasia based on the effect the neoplasia has on the body)
Selection of Successful Tumor Cells
Progression to Cancer Requires?
Multiple genetic hits or mutations in one cell
Tumor Growth to Diagnosable Size
There is a long period of times from the initial insult to the diagnosable tumor. Tumor doubling time in humans is relatively slow.
Malignancy is characterized by?
Local invasion and distant metastasis
Common Metastasis occur through what?
Blood, Lymphatics, Perineural, Cavitary
Metastatic Progression Pathway
1. Clonal expansion, growth, and diversification 2. Mestastatic subclone adhesion to and invasion of the basement membrane 3. Passage through the extracellular matrix 4. Intravasation 5. Interaction with host lymph cells 6. Tumor cell embolus 7. Adhision to basement membrane in distant site 8. Extravasation 9. Metastatic deposit
What are the two types of staging?
1. Clinical: Location of the tumorin relation to treatment 2. Pathological: Microscopic characteristics of the tumor
Tumor Grading
The grade indicates the loss of differentiation (anaplasia) 1. Low Grade = well differentiated 2. High Grade = poorly differentiated
Nomenclature of Cancers
Eplithelial Origin: 1. Benign = "-oma" 2. Malignant = "-carcinoma" Mesenchymal Origin: 1. Benign = "-oma" 2. Malignant = "-sarcoma"
Tools for the diagnosis of Cancer
1. Signs and Symptoms 2. Imaging (CT, MRI, PET) 3. Clinical Lab Assays 4. Histologic Examination (Biopsy)
Predictors of Prognosis
1. Type of Tumor: Biological Expectation 2. Staging: Size/Invasion/Mestastasis 3. Grading: Degree of Anaplasia
What is the most important predictor of prognosis?
1. Type of tumor 2. Staging
What are the histologic and molecular evaluation markers of tumors?
1. Histologic Patterns (Differentiation) 2. Histologic evidence of invasion 3. Cellular Atypia 4. Mitosis (Proliferation Index, S phase fraction) 5. Specialed Products (Immunohistochemistry markers) 6. Genetic Markers of Monotypism 7. Cytogenetics 8. Multigene Molecular Analysis
What are the cytologic features of neoplasia?
1. Increased nuclear size 2. Irregular nuclear shape 3. Increased Mototic Index 4. Increased Nuclear/Cytoplasmic ratio 5. Increased nucleolar size or number
What is the anticancer response in relation to tumor biology?
1. target variability 2. uptake/efflux of drug 3. activation of druf 4. inactivation/catabolism of drug
What is the anticancer response/toxicity as host factors?
1. age 2. gender 3. nutritional status 4. systemic drug exposure (pharmacokinetics) 5. drug interactions 6. genetics
What are the pharmacokinetic variability host factors?
1. age 2. gender 3. concomitant disease or drugs 4. hepatic and renal function 5. genetic variability in enzymes of drug metabolism
Why is PK variability a concern for anticancer agents?
1. narrow therapeutic window 2. increased toxicity 3. lack of efficacy (drug is excreted before activation) 4.there is a 2 to 20 fold variability of AUC of anticancer agents in patients with NORMAL hepatic and renal function
What determines the dose intensity of anticancer agents?
1. Amount of drug administered per unit time 2. Related to clinical activity of anticancer agents 3. Influences by: Protocol dose intensity (study design); Prescribed dose intensity (patient tolerance); administered dose intensity (patient compliance); Systemic dose intensity (ADME); and Cellular dose intensity (uptake, anabolism, catabolism)
What are pharmacokinetics?
The study of the disposition of drugs in animals and humans. Includes the processes of absorption, distribution, metabolism, and elimination. (what the body does to the drug)
What are pharmacodynamics?
The biologic effect of a drug in an in vivo system (What the drug does to the body)
What is absorption?
The rate at which a drug leaves its site of administration and the extent to which this occurs. Includes multiple routes (oral, dermal, IV, pulmonary).
What determines bioavailability?
The fraction of drug that reaches systemic circulation unchanged. Inclued multiple routes.
What are the factor influencing oral absorption and bioavailability?
1. GI motility 2. Gastric/intestinal pH 3. Stability of drug 4. Food 5. Concomitant drugs 6. Transport proteins 7. First pass effect
What is distribution?
The process by which a drug distributes into interstitial and intracellular fluids.
What is drug metabolism?
The process by which a drug undergoes biotransformation to a usually inactive (but sometimes active) metabolite.
What is drug excretion?
The process by which a drug and/or its metabolites are removed from the body.
What is the therapeutic index?
Conceptual description of the ratio of the toxic dose to the therapeutic dose of a drug, describing the dose range over which a drug is therapeutic but not unacceptably toxic.
What is the coefficient of variation?
The ratio of the standard deviation to the mean, multiplied by 100%. A high coefficient of variation means high interindividual variability.
What is bioavailability?
The fraction of an administered dose that reaches systemic circulation.
What is the first pass effect?
The decrease in bioavailability of an oral drug owing to enteric metabolism, hepatic metabolism and excretion before the drug reaches the systemic circulation.
What is the area under the curve (AUC)?
The area under the curve in a graph of plasma concentration against time -- a measure of drug exposure. (AUC = dose/clearance)
What is polymorphism?
The presence of two or more alleles with a frequency of at least 1% in the general population at the same gene locus.
What are prodrugs?
Pharmacologically inactive derivatives of active drugs that must undergo metabolic conversion to the active agent.
What are pharmacogenetics (pharmacogenomics)?
The study of genetically determined variations in drug response.
What are the sources of ADME pharmacokinetic variability in cancer?
1. Absorption (previous surgery, radiation, or chemotherapy) 2. Distribution (amount of body fat) 3. Metabolism (hepatic dysfunction) 4. Excretion (hepatic, renal dysfunction)
What are pleural effusions?
An abnormal collection of fluid between the thin layers of tissue (pleura) lining the lunch and wall of the chest cavity.
What is the glomerular filtration rate?
A measure of renal function that equals the quantity of glomuerular filtrate formed per unit of time in all nephrons of both kidneys.
What is the best method of reducing interindividual variability?
Dose individualization
What is bilirubin?
A breakdown product of heme that circulates in the plasma, is taken up by the liver and conjugated so that it is water soluble, and is then excreted in the bile. Routinely measured as a blood test to assess liver function.
What are population pharmacokinetics?
The study of the variability in plasma drug concentrations between individuals who receive standard dosage regimens and who represent the target population.
What is the Calvert equation for carboplatin dosing?
Total dose = toarget AUC x (GFR+25)
What is volume of distribution (Vd)?
The apparent size of a compartment able to account for the total amount of drug in the body. Patterns of distribution may reflect disease states, physicochemical properties of drug.
What are the factors affecting Vd?
1. Lipophilicity 2. Hydrophobicity 3. Bind to plasma proteins or tissues. Examples (etoposide, teniposide, paclitaxel, docetaxel)
What is systemic clearance?
The intrinsic ability of the body to remove a drug from plasma or blood (volume/time)
What does the Skipper-Schabel model of cancer chemotherapy state?
If one dose of drug (d) improved survival by a certain time interval (t), then additional doses (z) would improve survival time by z*t. Therefore chemotherapy would always kill a constant fraction of cells-----first order kinetics.
What does the Gompertzian model state?
That unimpeded growth eventually leads to a plateau phase of slow growth and functionally stable cell population size.
What did Norton and Simon add/conclude from the gompertzian model?
Cell kill is proportional to to growth activity and that some drugs are cell cycle dependant. The rate of response to the drug is higher when growth of the cancer is higher.
What are the primary targets for chemotherapy?
DNA and microtubules.
What mutations do cancers relie on most?
Oncogene activation. (although there is numerous tumor suppressor loss)
What are validated targets?
True validation requires proof of efficacy in human clinical trials. The number of truly validated cancer chemotherapy targets is relatively small.
What are the ways chemotherapeutic drugs kill tumor cells?
1. Apoptosis 2. Senescence 3. Autophagy 4. Necrosis
What is the CHOP regimen?
1. Cyclophosphamide 2. Doxorubicin 3. Vincristine 4. Prednisone
What are the resistance mechanism?
1. defective activation 2. increased inactivation 3. altered nucleotide poos 4. altered DNA repair 5. altered target 6. decreased target 7. gene amplification 8. decreased accumulation 9. increased efflux.
What are the types of drug resistance?
1. Pharmacokinetic resistance (low concentration of drug in the tumor) 2. Kinetic resistance (small fraction of cells in a susceptibnle state) 3.Genetic resistance (biochemical resistance of the tumor cells to the drug) As sensitive cells are killed, resistant cells constitute a greater proportion of the total tumor cells.
What are the cell cycle properties of alkylating agents?
They are non-cell cylce specific, are especially toxic to proliferating cells. The appropriate drug must be chosen for the growth rate of the tumor. Dose and schedule is more critical of cell cycle-specific drugs however, scheduling needs to be considered for combination therapy and mechanism of action.
What are the concerns for toxicities associated with alkylating agents?
1. Normal tissues generally recover more rapidly than tumor cells 2. Supportive treatment is important (antibiotics, vitamins) 3. Antitumor agents produce characteristic toxicity to carious body tissues that are related to tissue growth rate (nausea, vomiting, hair loss) 4. Close monitoring of leukocyte counts is important (nadir----make sure count is not too low)
What are the non-therapeutic toxicities associated with alkylating agents?
1. nausea/vomiting 2. toxicity to rapidly dividing tissues 3. tumor lysis syndrome (patient shock) 4. secondary cancer
What is the mechanism of action of the nitrosureas?
Chemical decomposition yiedls species that alkylate and carbamoylate cellular macromolecules.
What is the clinical pharmacology of the nitrosureas?
They are highyly lipophillic drugs that enter the brain with 50% bound to plasma protein. Most of the parent and metabolites are secreted in urine.
What are some of the clinical uses for nitrosureas?
Brain cancer, Hodgkin's and NH lymphoma, multiple myeloma,etc
What is the mechanism of action of the nitrosureas?
Chemical decomposition yiedls species that alkylate and carbamoylate cellular macromolecules.
What is the clinical pharmacology of the nitrosureas?
They are highyly lipophillic drugs that enter the brain with 50% bound to plasma protein. Most of the parent and metabolites are secreted in urine.
What are some of the clinical uses for nitrosureas?
Brain cancer, Hodgkin's and NH lymphoma, multiple myeloma,etc
What is the mechanism of action for the platinum drugs?
1. enters cell by passice diffusion 2. aquated moieties react with N-7 of guanine and other nucleophiles 3. Intrastrand (rapidly) and interstrand (slowly) crosslinks in DNA 4. DNA-protein crosslinks 5. Cell cycle nonspecific, but may be most active in G1
What are the properties of antimetabolites?
1. mimic normal cellular precursors or cofactors 2. intergere with celular metabolic processes 3. tumor cells have differences in metabolism that these target 4. ultimate target is interference with DNA synthesis, but also interfere with other cellular processes 5. biochemical pathways relating to nucleotide and nucleic acid synthesis have proved to be most vulnerable.
What are the pharmacological considerations of antimetabolites?
1. systemic and cellular pharmacodynamics are key 2. systemic effects dictate bolus v. steady state infusion 3. cellular uptake rates and activation v. degradation pathways determine intracellular drug levels 4. drug concentration and time of exposure together form an intergral dose relationship (AUC)
What are the mechanisms of action of actinomycin D?
1. DNA binding (GC pairs) in minor groove to interacalate DNA 2. Inhibits RNA synthesis 3. Inhibits protein synthesis
What are some properties of actinomycin D?
1. accumulates by passive diffusion 2. response is dependent on accumulation and retention of drug 3. membrane effects affect uptake (temp, composition) 4. uptake is different among tumor types 5. does not cross the blood-brain barrier
What are the resistance mechanisms associated with actinomycin D?
1. reduced uptake associated with decreased membrane permeability 2. increased efflux (MDR phenotype)
What are some properties of mytomycin C?
1. daily low-dose schedules resulted in severe cumulative myelosuppression 2. intermittent bolus injections resulted in more manageable hematologic toxicity 3. active against breast, pancreatic, gallbladder, colorectal, cervical, prostate, and superficial bladder cancers.
What is the mechanism of action of the anthracyclines?
1. inhibition of topoisomerase II 2. high affinity binding to DNA through intercalation with consequent blockade of the synthesis of DNA, RNA 3. binding to cellular membranes to alter fluidity and ion transport. 4. generation of semiquinone free radicals and oxygen free radicals through an enzyme-mediated reductive process.
Name the natural product anticancer agents
1. vinca alkaloids 2. taxanes 3. epipodophyllotoxins 4. camptothecins
What are the properties of vinca alkaloids?
1. taken into cells by an ATP dependent transport system 2. bind to tubulin and causes microtubule dissolution
What is the mechanism of action of the taxanes?
1. most effective as an inhibitor of cell replication where it acts in the G2 to M transition 2. binds specifically and reversibly to tubulin subunits, preferentially the beta subunit 3. polumerized tubulin into stable microtubules.
What constitutes taxol resistance?
1. alterations in alpha and beta subunits of tubulin 2. p-glycoproteins transport system associated with MDR
What are the epipodophyllotoxins?
etoposide and teniposide. The epipodophyllotoxins are topoisomerase II inhibitors.
What toxicities are caused by epipodophyllotoxins?
neutropenia, thrombocytopenia, alopecia, hypersensitivity, and mucositis