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Flashcards in Cancer I Deck (37):
1

Carcinoma = ______ tissue. Examples?

 

Sarcoma = _________ tissue. Examples?

Carcinoma = epithelial tissue. Breast, colon, and lung 

 

Sarcoma = mesenchymal tissue. Bone, cartilage, muscle, fat, vascular, and hematopoietic

2

1. Estimated cancer deaths per year?

2. Estimated new cancer cases per year?

3. Highest types of new cancer cases for men?

4. Highest types of new cancer cases for women?

5. Lowest 5 year survival rates?

1. Deaths = 600,000

2. New = 1.7 million

3. Men = prostate and lung/bronchus

4. Women = breast and lung/bronchus

5. Lowest = pancreas, followed by lung/bronchus

3

Tumor progression:

1. Cancer arises through a series of ____ changes.

2. 2 types of changes?

3. Induced by carcinogens, ___ ___, or integration of ____ DNA

Tumor progression:

1. Cancer arises through genetic changes

2. Heritable (change in DNA sequence) or epigenetic (change in pattern of expression w/o change in DNA)

2. Induced by carcinogens, ionizing radiation, or integration of viral DNA

4

Two hit model of tumor progression:

1. Wild type at birth -->? 

2. Heterozygous at birth --> ?

3. Which of these is sporadic and which has inherited suceptibility?

Two hit model of tumor progression:

1. Wild type --> mutation --> heterozygous --> LOH (loss of heterozygosity) --> homozygous = malignant

2. Heterozygous --> LOH --> homozygous = malignant

3. Sporadic = wild type; inherited suceptibility = heterozy.

5

Properties of normal cells:

1. Lifespan?

2. Exhibit _____ inhibition. What is this?

3. Normal cells depend on ___ ___ for growth and division.

4. Normal cells are ____-dependent.

Properties of normal cells:

1. Limited lifespan; finite - telomeres

2. contact inhibition: only one layer, once there is no more room in the layer they stop replicating

3. Normal cells depend on growth factors

4. Normal cells are anchorage-dependent

6

Properties of cancerous cells:

1. Abnormally persistant ______ and overcome programmed limits to _____

2. They avoid ____. From this they can become invasive and _____.

3. Cancer cells can undergo endless divisions = _____ due to preserved ____

Properties of cancerous cells:

1. Persistant proliferation and overcome limits to proliferation

2. Avoid apoptosis and can metastasize

3. immortality due to preserved telomeres

7

Cell cycle problems:

1. What causes a sustained proliferative signal?

2. What causes evasion of growth suppression?

3. What causes avoidance of immune destruction?

Cell cycle problems:

1. Sustained proliferative signal = EGFR inhibitors

2. Evasion of growth suppression = CDK inhibitors

3. Avoidance of immune system = immune activating anti-CTLA4 mAb

8

Cell cycle problems:

1. What causes immortality?

2. What causes tumor-promoting inflammation?

3. What activates invasion and metastasis?

Cell cycle problems:

1. Immortality = telomerase inhibitors

2. Inflammation = selective anti-inflammatory drugs***

3. Invasion = inhibitors of HGF/c-Met

9

Cell cycle problems:

1. What induces angiogenesis?

2. What causes genome instability and mutation?

3. What causes resistance of cell death?

4. What causes deregulation of cellular energetics?

Cell cycle problems:

1. Angiogenesis = inhibitors of VEGF signaling

2. Genome instability = PARP inhibitors

3. Resistance of cell death = Proapoptotic BH3 mimetics

4. Deregulation of energetics = aerobic glycolysis inhibitors

10

Drug actions:

1. What is the role of 6-mercaptopurine and 6-thioguanine?

2. Functions of methotrexate?

3. What is the function of PALA?

4. Function of hydroxyurea?

Drug actions:

1. 6 = inhibit purine ring synthesis and neucleotide interconversion

2. Methotrexate = inhibits DHF reduction, blocks TMP (tumor membrane protein) and purine synthesis

3. PALA = inhibits pyrimidine biosynthesis

4. Hydroxyurea = inhibits ribonucleotide reductase

11

Drug actions:

1. What is the role of camptothecins, etoposide, teniposide, daunorubicin, and doxorubicin?

2. What is the function of protein tyrosine kinase inhibitors, bortezomib, and antibodies?

3. Function of L-asparaginase?

Drug actions:

1. Block topoisomerase function

2. Block activity in general

3. L-asparaginase - deaminates asparagine and inhibits protein synthesis

12

Drug actions:

1. Function of 5 flourouracil?

2. Function of gemecitabine, cytarabine, fludarabine, and chlorodeoxyadenosine?

Drug actions:

1. 5-fluorouracil = inhibits TMP synthesis

2. Inhibits DNA synthesis

13

Drug actions:

1. Function of platinum analogs, alkylating agents, mitomycin, cisplatin, temozolomide?

2. Function of paclitaxel, vinca alkaloids, colchicine, and estramustine?

Drug actions:

1. forms adducts with DNA

2. Inhibits function of microtubules

14

Drug actions:

1. What drugs inhibit purine ring biosynthesis and nucleotide interconversion?

2. What drugs block topoisomerase function?

3. What drug inhibits TMP synthesis?

Drug actions:

1. Purine/nucleotide = 6mercaptopurine and 6tioguanine

2. Topoisomerase = camptothecins, etoposide, teniposide, daunorubicin, and doxorubicin

3. TMP synthesis = 5-fluorouracil

15

Drug actions:

1. What drug inhibit pyrimidine synthesis?

2. What drugs inhibit DNA synthesis?

3. What drug deaminates asparagine and inhibits protein synthesis?

Drug actions:

1. Pyrimidine = PALA

2. DNA = gemcitabine, cytaabine, fudarabine, chlorodeoxyadenosine

3. L-asparaginase

16

Drug actions:

1. What drugs form adducts with DNA?

2. What drugs inhibit function of microtubules?

Drug actions:

1. Adducts = platinum analogs, alkylating agents, mitomycin, cisplatin, temozolomide

2. Microtubules = vinca alkaloids, paclitaxel, colchicine, estramustine

17

Drug actions:

1. What drug inhibits ribonucleotide reductase?

2. What blocks activity in general?

Drug actions:

1. Ribonucleotide = hydroxyurea

2. Activity = protein tyrosine kinase inhibitors and bortezomib antibodies

18

Cell cycle:

1. What phase is the principal determinant of cell cycle length?

2. What makes up interphase?

3. What is the growth fraction?**

 

Cell cycle:

1. Principle determinant of length = G1

2. Interphase = G1, S, and G2

3. Growth fraction = ratio of proliferating cells to G0 cells**

19

Drugs:

1. Cytotoxic drugs act by disrupting what 2 things?

2. Drugs have a tendency to affect normal tissues with high growth fractions: what are these tissues?

3. Growth fraction of solid tumors vs disseminated cancers response to cytotoxic drugs?

4. What are common cancers treated with cytotoxic drugs?

 

Drugs:

1. Cytotoxic drugs disrupt DNA synthesis or Mitosis

2. High growth fraction tissues: GI epithelium, bone marrow, hair follicles, and sperm forming cells

3. Solid - less responsive; disseminated - more responsive

4. Common cancers treated with cytotoxic drugs: leukemia and lymphoma

20

Drugs:

1. 4 cell cycle specific agent classes?

2. Cell cycle nonspecific agents?

3. Most frequently mutated gene in human cancer? Activated by?

Drugs:

1. Specific = Antimetabolites, bleomycin, podophyllin alkaloids, and vinca alkaloids

2. Nonspecific =  Antibiotics

3. P53 is the most frequently mutated gene activated by DNA damage

21

Apoptosis:

1. Tissue cell# = ?

2. Apoptosis is ______ regulated. Fragmented where?

3. How is apoptosis different from necrosis?

Apoptosis:

1. Tissue cell # = cell proliferation (oncogenes - tumor suppressor genes) - cell death (apoptosis - anti-apoptosis genes)

2. Genetically regulated; fragmented in between nucleosomes in the chromatin

3. Necrosis = cell membrane destroyed first and inflammation (no inflammation with apoptosis and nuclear membrane first)

22

Intrinsic apoptosis:

This is also known as the ___ pathway. Stimuli trigger the release of ______ ____ from the mitochondria as well as ___ and apoptosis _____ factor. Once released ____ ___ together with dATP, binds to ____ and this complex, along with ____ nucleotides, promotes procaspase __ autoactivation which in turn activates caspases __, __, __, __, and __

Intrinsic apoptosis:

This is also known as the mitochondrial pathway. Stimuli trigger the release of cytochrome C from the mitochondria as well as caspases, and apoptosis inducing factor. Once released cyto c together with dATP, binds to APAF-1, along with adenine nucleotides, promotes procaspase 9 autoactivation which in turn activates caspases 2368, and 10

23

Extrinsic apoptosis pathway:

This is also referred to as the ___ ___ - mediated apoptosis pathway. __/___ ligand, __/___ receptor ligation,  or TRAIL with __ or ___ transduce death signals to activate caspase ___, which activates the downstream caspases. This caspase also cleaves a ___-apoptotic Bcl-2 family member, ___, and this induces mitochondrial ___ __ release. Both caspase __ and __ activate caspase 3.

Extrinsic apoptosis pathway:

This is also referred to as the death receptor - mediated apoptosis pathway. Fas/Fas ligand, TNF/TNF receptor ligation, or TRAIL with DR4 or DR5 transduce death signals to activate caspase 8, which activates the downstream caspases. This caspase also cleaves a proapoptotic Bcl-2 family member, BID, and this induces mitochondrial cyochrome c release. Both caspase 8 and 9 activate caspase 3

24

Bcl-2 family:

1. Which are pro-apoptotic?

2. Which are anti-apoptotic?

3. In tumor cells, Bcl-2 has been found to confer resistance in response to what drugs?

Bcl-2 family:

1. Pro-apoptotic: Bax, Bak, Diva, Bad, Bid, Bim

2. Anti: Bcl-2, Bcl-XL, Mcl-1

3. Resistance to vincristine, taxol, cisplatin, methotrexate, and cytosine arabinoside

25

Toxicity of chemotherapeutic drugs:

1. Toxicity to normal cells is ___ ____.

2. Bone marrow suppression causes?

3. GI injury leads to?

Toxicity of chemotherapeutic drugs:

1. Toxicity is dose limiting

2. BM suppression - infection, bleeding, and anemia

3. GI - stomatitis (inflammation, ulderation, infection) and diarrhea

26

Toxicity of chemotherapeutic drugs:

Hyperuricemia:

1. Major complication of ___ ___ ___. Due to?

2. Can cause?

3. Symptoms?

Toxicity of chemotherapeutic drugs:

Hyperuricemia:

1. Major complication of tumor lysis syndrome; due to massive release and breakdown of nucleic acid to uric acid

2. Can cause acute renal failure

3. Symptoms: N/V, diarrhea, and anorexia

27

Toxicity of chemotherapeutic drugs:

Other toxic side effects?

Toxicity of chemotherapeutic drugs:

a. N/V

b. Alopecia

c. Reproductive toxicity

d. Local injury

e. Carcinogenesis

28

Obstacles to successful chemotherapy:

1. Cure requires?

2. Kinetics? What does this imply?

3. Also, affects ___ cells. 

Obstacles to successful chemotherapy:

1. Cure requires 100% cell kill

2. First order kinetics: at any given dose, drug kills a constant percentage of malignant cells

3. Also, affects NORMAL cells

29

Obstacles to successful chemotherapy:

1. Role of host immunity?

2. Symptoms vs. cancer cells?

3. ______ of tumor cell population.

Obstacles to successful chemotherapy:

1. Host defenses dont participate because the drugs are immunosuppressive

2. Symptoms disappear before all cancer cells are killed

3. heterogeneity of tumor cell population

30

Obstacles to successful chemotherapy:

1. Late detection: ___ may have occurred already. ____ tumors are less responsive.

2. Limited drug access due to ___ and ___. Example

Obstacles to successful chemotherapy:

1. Late detection: metastasis may have already occurred. Large tumors less responsive

2. Limited drug access due to location (hard to cross BBB) and vascularization (core of large solid tumor with poor vascularization)

31

Melanoma:

___ % of melanomas carry a mutation in the ___ gene. ___ blocks this gene and ___% had partial to complete regression. Almost all patients who demonstrated positive response developed ___.

Melanoma

>50% carry a mutation in the BRAF gene. Vemurafenib blocks BRAF and 80% had regression. Most developed resistance

32

Mechanisms of drug resistance:

1. Reduced drug ___.

2. Increased drug ___.  Example?

3. _____ drug activation

4. ____ target molecular sensitivity

Mechanisms of drug resistance:

1. Reduced drug intake

2. Increased drug efflux. P-glycoprotein (pumps drug out of cell; multiple drug resistance)

3. Reduced drug activation

4. reduced target molecular sensitivity

33

Mechanisms of drug resistance:

1. Drugs do not cause drug resistance mutation but rather?

2. ____ number of targeted receptors

3. Modify the ___ to make the drug ineffective

 

Mechanisms of drug resistance:

1. Dont cause resistance but rather provide selection pressure favoring resistant mutants

2. increase the number of targeted receptors

3. Modify the target to make drug ineffective

34

Strategies to achieve maximal benefits of chemo:

What are the 4 strategies?

Strategies to achieve maximal benefits of chemo:

a. Intermittent chemo

b. combination chemo

c. Optimizing dosing schedule

d. regional drug delivery

35

Strategies to achieve maximal benefits of chemo:

Intermittent chemo:

1. What is the primary technique to have 100% kill with minimal normal tissue damage?

2. What is the caveat to intermittent chemo?

Strategies to achieve maximal benefits of chemo:

Intermittent chemo

1. Primary technique - intermittent chemotherapy

2. Caveat - normal cells must repopulate faster than cancer

36

Strategies to achieve maximal benefits of chemo:

Combo chemo:

1. Causes ____ cell kill. Using different drugs with different ___ and different cell cycle ____

2. ___ injury to ____ cells with combos that dont have overlapping ____

3. ____ of drug resistance

Strategies to achieve maximal benefits of chemo:

Combo chemo

1. Causes increased cell kill using drugs with different MOA and different cell cycle specificity

2. Reduced injury to normal cells with combos that dont have overlapping toxicities

3. Suppression of resistance

37

Strategies to achieve maximal benefits of chemo:

1. Optimising dosing schedules: what phase specific drugs need longer exposure to tumor cells?

2. Regional delivery: what types?

Strategies to achieve maximal benefits of chemo:

1. Optimal: S-phase-specific drugs need longer exposure

2. Delivery: intra-arterial, intrathecal, portal v, intra-cavity, or carmustine wafer implanted in brain after surgery