Pharm cancer I.

Question 1

How many new cases of cancer a year? How many deaths due to cancer a year? (in the US)

Answer 1

1,000,000 new cases, 500,000 deaths

Question 2

What is cancer characterized by?

Answer 2

abnormal cellular growth and reduced cell death

Question 3

What are targets of genetic damage (or mutations)

Answer 3

1. growth promoting protooncogenes 2. growth-inhibiting tumor suppressor genes 3. genes that regulate apoptosis or cell death 4. genes that repair damaged DNA

Question 4

What drives tumorigenesis?

Answer 4

sequential alterations (mutations) in 2-8 driver genes conferring selective growth advantage

Question 5

passenger gene mutation

Answer 5

mutations in tumors in additional genes by do not confer growth advantage

Question 6

driver genes

Answer 6

linked to cell fate determination, cell survival, and genome maintenance

Question 7

clonal evolution of tumors

Answer 7

all tumors are believed to arise from a single transformed clone —> get new subclones become more aggressive, metastatic and ability to evade host defense

Question 8

cancer stem cells

Answer 8

sub-population of cells with ability to self-renew and differentiate have cancer initiating potential

Question 9

What are examples of conventional chemotherapeutic agents?

Answer 9

alkylating agents, antimetabolites, natural products, miscellaneous agents, hormones and antagonists

Question 10

alkylating agents

Answer 10

nitrogen mustard, ethylenimines & methylmelamines, alkyl sulfonates, nitrosoureas, triazenes

Question 11

antimetabolites

Answer 11

purine and pyrimidine analogs

Question 12

natural products

Answer 12

vinca alkaloids, taxanes, epipodophylotoxins, camptothecins, antibiotics, enzymes, biological response modifiers

Question 13

anticancer agents: how do they work?

Answer 13

induce cell cycle arrest or cell death

Question 14

normal cell cycle

Answer 14

G1, S, G2, M (sometimes G0 - post mitotic cells exit the cell cycle and enter non-proliferative phase)

Question 15

What two proteins control cell cycle progression?

Answer 15

cyclines (regulatory proteins A, B, D, E) and cyclin-dependent kinases (Cdks) catalytic proteins 1,2,4,6

Question 16

How do cyclin and cdk function?

Answer 16

as heterodimers that phosphorylate target proteins - CDKs have no kinase activity unless associated witha cyclin

Question 17

What does the cyclin determine?

Answer 17

which proteins would get phosphorylated

Question 18

What cyclin-cdk complex functions for G1 phase?

Answer 18

cdk4-cyclin D, cdk6-cyclin D, and cdk2-cyclinE

Question 19

What cyclin-cdk complex functions for S phase?

Answer 19

cdk2-cyclin A

Question 20

What cyclin-cdk complex functions for G2/M phase?

Answer 20

cdk1-cyclin B and cdk1-cyclin A

Question 21

What do cyclinD-cdk4, cyclinD-cdk6, and cyclinE-cdk2 phosphorylate?

Answer 21

Rb

Question 22

Rb does what when hypophosphorylated and what when hyperphosphorylated?

Answer 22

hypo: bound to E2F; hyper: release of E2F (causes conformation change)

Question 23

E2F

Answer 23

activates the transcription of genes whose products control progression from G1 to S phase

Question 24

If DNA is damaged in a normal cell….

Answer 24

cell will arrest in G1 or G2

Question 25

If DNA is not properly replicated….

Answer 25

S phase will arrest

Question 26

If there is improper spindle formation….

Answer 26

M phase arrest

Question 27

What morphological changes happen in apoptosis?

Answer 27

cell shrinkage, shape change, cytoplasmic condensation, alterations in nuclear envelop and nuclear shrinkage, nuclear chromatin condensation and fragmentation, cell membrane blebbing, formation of apoptotic bodies, cell detachment, phagocytosis of apoptotic bodies

Question 28

What activates proteases in an apoptotic cell?

Answer 28

caspases and serine proteases

Question 29

proteolysis

Answer 29

cleavage of important proteins involved in cell structure and function

Question 30

DNA fragmentation is done by what?

Answer 30

nucleases

Question 31

What is released from mitochondria in apoptotic cells?

Answer 31

cytochrome C

Question 32

caspases

Answer 32

integral component of apoptotic machinery - exist has inactive pro-enzymes, activated in response to apoptotic insults, recognize specific cleavage sites within proteins

Question 33

What are the 2 apoptotic pathways?

Answer 33

death receptor-dependent pathway and mitochondrial pathway

Question 34

intrinsic resistance

Answer 34

1. dysregulation of one or both apoptotic pathways common in many types of cancer and occur due to: inactivation of apoptosis promoting genes/proteins (mutations, deletions, epigenetic mechanisms) 2. hyperactivity of survival or anti=apoptotic genes 3. host factors (poor absorption, rapid metabolism//excretion, delivery failure)

Question 35

acquire resistance

Answer 35

dysregulation of one or both apoptotic pathways during chemotherapy - durin the course of chemo, many cancer cells acquire the ability to rapidly and efficiently repair DNA damage

Question 36

p-gp

Answer 36

multidrug transport (MRP1-MRP6 = multidrug resistance associated protein)

Question 37

What are toxic effects of anticancer drugs?

Answer 37

bone marrow suppression, oral mucosal ulceration, intestinal denudation, alopecia, permanent amenorrhea, azoospermia)

Question 38

What toxic effect do alkylating agents have on the body?

Answer 38

reproductive system toxicity - most are also leukemogenic

Question 39

How can major organ damage by avoided with anticancer drugs?

Answer 39

strict adherence to treatment protocols

Question 40

Which drug causes hemorrhagic cystitis?

Answer 40

cyclophosphamide