Lecture 19 - Principles of Chemotherapy Flashcards
What are the mechanisms of selective targeting in chemotherapy?
- Unique targets - unique to pathogen or cancer cell not present in host (high theraputic index)
- Similar targets - similar but not identical to cells in the host
- Common targets - Targets shared with host but vary in importance between pathogen and host
What is a popular unique target for antibacterial drugs?
The biochemical pathway that leads to synthesis of the bacterial peptidoglycan cell wall (ex penicillin, vancomycin)
What is a popular unique target for treating fungal infections?
Ergosterol is essential for fungi cell membrane made up of glucan and chitin
Selective inhibition of similar targets - Vemurafenib
Preferably inhibits B-raf protein kinase mutated in skin cancer
Selective inhibition of similar targets - Nilotinib
selectively inhibits mutated BCR-Abl kinase
Selective inhibition of similar targets - Streptomycin
Inhibitor of bacterial protein synthesis, targets ribosomal RNA and proteins utilized in bacteria
Selective inhibition of similar targets - DHFR (dihydrofolate reductase) inhibitors
Blocks folate metabolism, DHFR protein sequeces cross species vary greatly
What causes chronic myeloid leukemia (CML)?
Translocation on chromosome 9 of the ABL1 proto-oncogene which encodes a cytoplasmic and nuclear protein tyrosine kinase to chromosome 22 –> can result in a hybrid Bcr-Abl protein which causes it to be constitutively active
What drug inhibits dihydropteroate synthase in bacteria?
Sulfonamides
What drugs inhibit DHFR in humans and bacteria?
Trimethoprim, Methotrexate, Pyrimethamine
What drugs inhibit the conversion of tetrehydrofolate to thymidine required for DNA synthesis in humans and bacteria?
S-fluorouracil and Flucytosine
Common target drugs - Maraviroc
An antiviral drug that inhibits human chemokine receptor CCR5 which is essential for entry of certain strains of HIV into cells, but is dispensible for human health
Common target drugs -
5-fluorouracil (5-FU)
An antimetabolite that inhibits thymidylate synthase (converts dUMP to dTMP) by causing DNA damage, induces the cell to activate its apoptotic pathway. Does not affect on-dividing cells
Antineoplastic drug classes - Inhibitors of DNA synthesis and integrity
- Antimetabolites
- Folate pathway inhibitors
- Topoisomerase inhibitors
Antineoplastic drug classes - DNA damagin agents
- Alkylating agents
- Antitumor antibiotics
- Platinum complexes
Antineoplastic drug classes - Inhibitors of microtubule function
- Vinca alkaloids
- Taxanes
Antibacterial drug classes - Inhibitors of cell wall synthesis
- Fosfomycin
- Cycloserine
- Vancomycin
- Penicillins
- Cephalosporins
- Monobactams
- Carbapenems
- Ethambutol
- Pyrazinamide
- Isoniazid
Antibacterial drug classes - Inhibitors of transcription and translation
- Rifampin
- Aminoglycosides
- Spectinomycin
- Tetracyclines
- Macrolides
- Chloramphenicol
- Linocosamides
- Streptogramins
- Oxazolidinones
- Pleuromutilines
Antibacterial drug classes -Inhibitors of DNA synthesis and integrity
- Sulfonamides
- Trimethoprim
- Quinolones
Unique antifungal agents - Flucytosine
An antimetaolite that inhibits fungal DNA synthesis
Unique antifungal agents - Griseofulvin
Inhibits fungal mitosis by disrupting mitotic spindles, arresting metaphase in cell division
Unique antifungal agents - Allylamines, benzylamines, imidazoles, triazadoles
Inhibit the ergosterol synthesis pathway in the endoplasmic reticulum
Unique antifungal agents - Echinocandins
Inhibits the synthesis of glucan formation for fungal cell walls
Unique antifungal agents - Polyenes (Amphotericin B)
Binds to ergosterol in the fungal membrane disrupting plasma membrane integrity (forms cation-selective pores in the membranes)
Mechanisms of genetic drug resistance - Reduced intracellular concentration of drug with antimicrobial examples
- Inactivate drug - Inactivation of beta-lactam antibiotics by beta-lactamase
- Prevent uptake of drug - Prevention of aminoglycoside entry by altered porins
- Promote efflux of drug - Efflux of multiple drugs by MDR membrane efflux pump
Mechanisms of genetic drug resistance - Reduced intracellular concentration of drug with antineoplastic examples
- Inactivate drug - Inactivation of antimetabolites by deaminase
- Prevent uptake of drug - Decreased methotrexate entry by decrease expression of reduced folate carrier
- Promote efflux of drug - Efflux of multiple drugs by p170 membrane efflux pump (MDR1)
Mechanisms of genetic drug resistance - Target based mechanisms with antibacterial examples
- Altered drug target - Expression of altered peptidoglycan that no longer binds vancomycin
- Bypass metaolic requirement for target - Inhibition of thymidylate synthase bypassed by exogenous thymidine
Mechanisms of genetic drug resistance - Target based mechanisms with antineoplastic examples
- Altered drug target - Expression of muant DHFR that no longer binds methotrexate
- Bypass metabolic requirement for target - Loss of estrogen receptor-dependent growth results in tamoxifen resistance
Mechanisms of genetic drug resistance - Sensitivity to apoptosis with antineoplastic drugs
Loss of active p53
What is the multidrug resistance protein 1 (MDR1)?
Aka P-glycoprotein 1, a member of the ABC (ATP-binding cassette) family of efflux transporters (drug compounds are actively transported back into the intestinal lumen and reduces some drug bioavalability)
How do cancer cells make the tumor less sensitive to chemotherapy or targeted treatments?
Cancer cells can use DNA methylation or histone modification to silence key tumor-suppressor genes or regulate genes involved in drug metabolism
- These epigenetic changes can upregulate expression of ABC transporters which actively pump out chemotherapy drugs from the cancer cell
What are the advantages of combination chemotherapy?
- Additive or synergistic effects
- Increased spectrum of activity
- Decreased drug resistance
What are the disadvantages of combination chemotherapy?
- Possible antagonistic effects
- Increased risk of drug interactions
- May have increased toxicity
- Increased cost
What type of combination chemotherapy is the result of DHFR inhibitors and sulfonamides and why is it more effective?
Sequential blockade
- sulfonamide decreases the intracellular concentration of dihydrofolate –> increases the effctiveness of the DHFR inhibitor –> competes with DHF for binding to the enzyme
- Resistance to drug combination develops much slower
