Lecture 12: Antineoplastic drugs

Question 1

hyperplasia

Answer 1

increased capacity for proliferation

Question 2

6 hallmarks of cancer

Answer 2

1. sell-sufficiency in growth signals
2. insensitivity to growth inhibitory signals
3. evasion of programmed cell death (apoptosis)
4. limitless replication potential
5. sustained angiogenesis
6. tissue invasion and metastasis

Question 3

What type of disease is cancer?

Answer 3

Genetic disease
all cancer caused by abnormalities in DNA sequence composition

Question 4

Gompertzian Growth

Answer 4

tumor grow faster early and slower later
effect of early intervention great than latter intervention
small tumor more responsive

Question 5

Advantage of intermittent dosing

Answer 5

can allow for recovery of normal tissue between drug cycles

Question 6

Nitrogen mustards

Answer 6

cause alkylation of DNA
form DNA crosslink by sequential N7-guanine alkylation
generate DNA adducts

Question 7

Clastogen

Answer 7

any agent that induce sugar-phosphate backbone cleavage

Question 8

Cyclophosphamide

Answer 8

Most useful alkylating agent
PRODRUG
activated by hepatic cytochrome P450
cytotoxic products: phosphoramide mustard and acrolein

Question 9

Nitrosoureas

Answer 9

highly lipid-soluble, can cross BBB
useful in brain tumors
alkylating agent

Question 10

Platinum complexes (Cisplatin)

Answer 10

NOT an alkylating agent
cause DNA crosslinking
1, 2 intrastrand adducts
cause severe distortion of DNA helix
covalent bonds to N7 positions of purine bases

Question 11

Methotrexate

Answer 11

folic acid analogues
competitive inhibitor of dihydrofolate reductase
inhibit dTMP synthesis
normal cells can be rescued from toxicity by administering leucovorin

Question 12

Leucovorin (folinic acid)

Answer 12

folic acid analogues
less metabolically active folic acid coenzyme
preferred uptake into normal cells

Question 13

5-FU

Answer 13

pyrimidine analogues
5-FU converts into F-dUMP (active)
irreversible inhibitor of thymidylate synthetase
block DNA synthesis
major use in acute lymphoblastic leukemia (ALL), colon cancer

Question 14

6-mercaptopurine, 6-thioguanine

Answer 14

purine analogues
counterfeit incorporation
interfere with purine biosynthesis

Question 15

Anthracyclines (Daunorubicin, Doxorubicin)

Answer 15

antibiotics
one of the most useful class
inhibit topoisomerase II
DNA intercalation
produce ROS

Question 16

Etoposide, Teniposide

Answer 16

derivatives of podophyllotoxin
no effect on microtubular structure at normal dose

stabilize “cleavable complex”
inhibit topoisomerase II
block cells in late S-G2 phase (prevent initiation of mitosis)

Question 17

Topoisomerase II action

Answer 17

helps to segregate DNA before mitosis
drugs inhibit religation of the cleavable complex

Question 18

Vincristine, Vinblastine (vinca alkaloids)

Answer 18

spindle poisons
depolymerization of microtubules
mitotic arrest at metaphase

Question 19

Paclitaxel

Answer 19

significant activity in ovarian and advanced breast cancer
mitotic spindle poison
cause stabilization of microtubules and formation of abnormal bundles of microtubules

Question 20

Tamoxifen

Answer 20

antiestrogen
competitive antagonist at the estrogen receptor
extremely useful in breast cancer

Question 21

Traztuzumab (Herceptin)

Answer 21

humanized monoclonal antibody
targets HER2
inhibit proliferation of tumor that overexpress HER2
dont attach to other protein, few side effects

Question 22

Bevacizumab (Avastin)

Answer 22

humanized monoclonal antibody
attach to circulating VEGF, prevents activation of VEGF receptors
used with 5-FU to treat metastatic colorectal cancer

Question 23

Imatinib mesylate (Gleevec)

Answer 23

RTK inhibitor
used in chronic myelogenous leukemia

Question 24

Acquired resistance

Answer 24

most common reason for drug resistance
initially sensitive tumor cell
selects for resistant cells in a tumor

Question 25

New way to view MOA by antineoplastic drugs

Answer 25

no longer considered to kill cells
instead trigger DNA damage response in cell

Question 26

p53

Answer 26

over 50% of tumor contains p53 mutation
“guardian of the genome”
increase p53 activity can sensitize tumor to apoptotic signal