Lec 19 & 20 (Chemotherapy & Cancer) Flashcards Preview

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Flashcards in Lec 19 & 20 (Chemotherapy & Cancer) Deck (35):


use of chemical agents against an invading organism or cancer cells


Chemical Agents (4)

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


Beta-lactam Antibiotics
(mechanism, resistance, gram -/+, impact)

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)


Folate Synthesis
(equation, antibacterial action)

-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


Protein Synthesis Antibiotics

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


Treatment Types (3)

-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.


HIV: fusion/entry inhibitor

prevent entry of HIV material into Th cell


HIV: reverse transcriptase inhibitor

inhibit enzyme that catalyzes formation of DNA from viral DNA


HIV: integrase inhibitor

inhibits incorporation of proviral DNA into human host genome


HIV: protease inhibitor

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


HCV drug target: interferons

-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


HCV drug target: proteases

-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)


HCV drug target: nonstructural proteins

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


HCV drug target: (non) nucleoside polymerases

-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


Malarial Life Cycle

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


Malaria: Chloroquine

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


AZT (zidovudine)

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


Cancer characterized by....

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


Cancer origins..

genetic predisposition and the environment


Target Based Screens

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.


Cytotoxic Cancer Chemotherapuetics

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


Alkylating Agents (anti-cancer agent)

-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)


Antimetabolites (anti-cancer agent)
[methotrexate, 5-FU]

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


Hormone Antagonists

drugs that modulate hormone expression
i.e. tamoxifen modulates estrogen in breast cancer


Interference w/ DNA Supercoiling & Topology

Topoisomerase II corrects any errors
i.e. Etopside: inhibits topoII, blocking cell cycle S phase--> G2


Mitosis Inhibitors

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

vinblastin: prevents MT polymerization


DNA Intercalating Agents

high affinity binding with DNA by intercalation, blocking replication and transcription
-cardiotoxicity concerns
ex: doxorubicin



kinase inhibitor of BCR-ABL
chronic myelogenous leukemia (CML)



EGFR kinase inhibitor
lung cancer



BRAF kinase inhibitor


Inhibition of Growth Promoters

-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)


Inhibition of Blood Vessel Formation

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


Ab Based Therapeutics (3)

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



targets ErbB2/HER2 in breast cancer (mAB therapy)



targets VEGF in NSCLC and glioblastoma
-angiogenesis inhibitor