Lec 19 & 20 (Chemotherapy & Cancer)

Question 1

Chemotherapy

Answer 1

use of chemical agents against an invading organism or cancer cells

Question 2

Chemical Agents (4)

Answer 2

1. antibiotics: made by one organism, lethal to another
2. plant alkaloids
3. analogous of endogenous molecules essential for cell replication/vitality
4. monoclonal Ab: specific for target

Question 3

Beta-lactam Antibiotics

mechanism, resistance, gram -/+, impact

Answer 3

i. e. penicillins, cephalosporins
1. covalently bind an inhibit bacterial trasnspeptidase enzyme
- cross-links polymers of cell wall
- selective, no human homologue of enz.
2. resistance: bacterial expression of beta lactamase
- enzyme that cleaves beta lactam ring of antibiotic, increasing IC/ED50
3. typically on gram negative bacteria, have membrane pore that allows for drug influx
4. impaired cell wall synthesis: bacteriocidal (cell death)

Question 4

Folate Synthesis

equation, antibacterial action

Answer 4

• PABA (DHF synthetase) DHF (DHF reductase) THF
• dUMP/THF (thymidylate synthetase) dTMP/DHF
• dTMP required for nucleic acid synthesis
• sulfonamide antibiotics: inhibit DHF synthetase
• trimethoprim (+other): inhibit DHF reductase

Question 5

Protein Synthesis Antibiotics

Answer 5

• inhibit 50S and 30S ribosomal machinery for mRNA translation into protein
• block formation of initiation complex, peptide chain elongation, cause miscoding
  ex: tetracyclines, azithromycin

Question 6

Treatment Types (3)

Answer 6

• Definitive: based on test of bacterial culture/drug sensitive. documented.
• Empiric: based on clinical assessment of likely cause + effective drug.
• Prophylactic: pretreatment with empirically chosen agent to reduce infection risk.

Question 7

HIV: fusion/entry inhibitor

Answer 7

prevent entry of HIV material into Th cell

Question 8

HIV: reverse transcriptase inhibitor

Answer 8

inhibit enzyme that catalyzes formation of DNA from viral DNA

Question 9

HIV: integrase inhibitor

Answer 9

inhibits incorporation of proviral DNA into human host genome

Question 10

HIV: protease inhibitor

Answer 10

inhibition of viral protein that catalyzes breakdown of large viral protein to release viral structural proteins

Question 11

HCV drug target: interferons

Answer 11

• interferons (i.e. INFa-2a) activate macrophages and lymphocytes to enhance antiviral efficacy
• drug target/activate INFs. pegylated to extend t1/2 and combined with ribavirin to increase antiviral effect

Question 12

HCV drug target: proteases

Answer 12

• inhibit NS3/4a protease that catalyzes breakdown of large viral proteins and release them for replication
• protease inhibitors restore innate immune response in the liver to viral infection (eg telapravir)

Question 13

HCV drug target: nonstructural proteins

Answer 13

-inhibit NS5A protein replication complex, thus blocking its role in replication and assembly of viral proteins (eg ledipasir)

Question 14

HCV drug target: (non) nucleoside polymerases

Answer 14

• inhibit NS5B polymerase by binding one of several sites on the enzyme (RNA-dependent RNA polymerase) inhibiting its ability to generate viral DNA
• can be chain terminators or allosteric inhibitors

Question 15

Malarial Life Cycle

Answer 15

mosquito injects sporozoites into host, replicate in liver and released. target RBCs where schizont pathology can be seen

• infect RBCs and propagate, then cause RBCs to lyse
• leads to aggregation and adhesion of infected RBCs, tissue damage
• gametes taken back up into mosquito, continue cycle

Question 16

Malaria: Chloroquine

Answer 16

accumulates in parasite lysosomes (parasite in RBCs) and inhibits Hb digestion

• Hb digestion releases heme that can causes oxidative damage
• resistance due to a decreased intracellular concentration because of mutated lysosomal transporter, increasing drug efflux

Question 17

AZT (zidovudine)

Answer 17

nucleoside analog. originally studied for use in cancer, now used as reverse transcriptase inhibitor in HIV.

Question 18

Cancer characterized by….

Answer 18

clonal overproliferation of abnormal cells, disrupting normal organ architecture
-DNA damage
-evasion of replication control
-metastasis
-resistance of cell death
[somatic mutations in oncogenes and tumor suppressor genes (p53)]

Question 19

Cancer origins..

Answer 19

genetic predisposition and the environment

Question 20

Target Based Screens

Answer 20

in vitro enzymatic assays used to identify inhibitors (i.e. of kinases) that are then developed into testing in animal modules. have to know specific oncogene.

Question 21

Cytotoxic Cancer Chemotherapuetics

Answer 21

contain anticancer properties, will halt cell cycle progression or cause DNA damage

• limited due to poor selectivity of S phase agents
• also attacks rapidly dividing cells such as hair, GI lining and bone marrow
• can lead to nausea (GI) and bone marrow failure

Question 22

Alkylating Agents (anti-cancer agent)

Answer 22

-contain amine groups that react with N7 guanine in DNA backbone
-lead to DNA-DNA cross linking, and damage, prevents cell cycle progression
-extensive damage leads to p53 dependent
cell death, p53 mutations confer resistance
(ex: sulfur and nitrogen mustards, cyclophosphamide)

Question 23

Antimetabolites (anti-cancer agent)

[methotrexate, 5-FU]

Answer 23

interfere with key enzyme in DNA replication process in S phase

[Methotrexate] competitively inhibits DHFR

• leads to depletion of deoxythymidine monophosphate (nucleotide, dTMP)
• inhibits S-phase progression, and RNA synthesis in G2
• resistance through reduced folate transporter that increases efflux

[5-Fluorouracil] block thymidine synthase, preventing dUMP->dTMP and blocking DNA replication

• irreversible inhibitor
• blocks cells in S phase

Question 24

Hormone Antagonists

Answer 24

drugs that modulate hormone expression

i.e. tamoxifen modulates estrogen in breast cancer

Question 25

Interference w/ DNA Supercoiling & Topology

Answer 25

Topoisomerase II corrects any errors

i.e. Etopside: inhibits topoII, blocking cell cycle S phase–> G2

Question 26

Mitosis Inhibitors

Answer 26

taxol (natural): binds to microtubules, prevents depolarization leading to defective chromosome segregation, stopping cells in M phase

vinblastin: prevents MT polymerization

Question 27

DNA Intercalating Agents

Answer 27

high affinity binding with DNA by intercalation, blocking replication and transcription

• cardiotoxicity concerns
  ex: doxorubicin

Question 28

Imatinib/Gleevec

Answer 28

kinase inhibitor of BCR-ABL

chronic myelogenous leukemia (CML)

Question 29

Erlotinib

Answer 29

EGFR kinase inhibitor

lung cancer

Question 30

Vemurafinib

Answer 30

BRAF kinase inhibitor

melanoma

Question 31

Inhibition of Growth Promoters

Answer 31

• block tumor receptors for growth promoting hormones (i.e. tamoxifen and estrogen receptors)
• can also used monoclonal Abs that target the receptor for growth promoting proteins (Herceptin and Her2 in breast cancer)

Question 32

Inhibition of Blood Vessel Formation

Answer 32

-antiangiogenic agents, block vessel growth in solid tumors that is required for their growth and survival (i.e. Avastin, blocks VEGF-R)

Question 33

Ab Based Therapeutics (3)

Answer 33

1. receptor function modulators (eg Cetuximab, EGFR mAB)
2. immune system modulators: activate cytotoxic agents, clearing tumor cells
3. antibody-drug conjugates: deliver toxic “payload” to tumor cells expressing a specific antigen

Question 34

Trastuzumab

Answer 34

targets ErbB2/HER2 in breast cancer (mAB therapy)

Question 35

Bevacizumab

Answer 35

targets VEGF in NSCLC and glioblastoma

-angiogenesis inhibitor