Antineoplastic Agents Flashcards
Neoplasm
Uncontrolled and abnormal growth of tissue in animals or plants (aka tumor)
Targets of cancer chemotherapy
Cellular processes that are prevalent in rapidly-dividing cells
Leads to onset of side effects (hair loss, immune deficiencies, nausea)
What cancer chemotherapeutics must do in order to prevent remission
Must be able to kill every cancer cell
Unfortunately, most antineoplastic agents kill cells by first order kinetics (never actually kill every single cell)
Tumor cell properties
Uncontrolled cell proliferation
Decreased cellular differentiation
Capacity to invade surrounding tissue
Ability to establish growth at remote sites (metastasis)
How tumor cells bypass apoptosis
Reduce or remove tumor suppressor proteins (ex-p53)
Intrinsic apoptosis mechanism
Cyctochrome c is released from the mitochondria
Extrinsic apoptosis mechanism
TNF-family interacts with “death receptors”
Alkylating agents
Most effective against fast-growing tumors
Alkylate nucleic acids
Guanine alkylation
N-7 atom of guanine is particularly nucleophilic and prone to reaction with alkylating agents
N-7-alkylated guanine is unstable and decomposes
Nitrogen mustards
Contain nitrogen atom and one or more beta-halogens
Nitrogen attacks alkyl halide carbon atom, forming an aziridinium atom, a strong electrophile
Example: chlorambucil
Cyclophosphamide
Prodrug version of nitrogen mustard
Platinum agents
Certain cis-platinum complexes have antitumor activity
Inhibit DNA polymerase by forming intrastrand bis-alkylated adducts
Examples: cisplatin, carboplatin
N-alkyl-N-nitrosoureas
Decompose to isocyanates and diazohydroxides
Example: carmustine
Mitomycin C
Requires metabolic reduction of its quinone to a hydroquinone
Double alkylating agent: can crosslink DNA
Antimetabolites
Inhibit the biosynthesis of normal cellular metabolites
Most target the biosynthesis of nucleic acids
Examples: 5-fluorouracil, 6-mercaptopurine
5-fluorouracil
Metabolite, 5-fluoro-deoxyuracil monophosphate (5-fluoro-dUMP), inhibits thymidylate synthase
Blocks conversion of dUMP to dTMP
Lacks the proton required for the normal uracil to thymine mechanism
Thiol-containing purines
Inhibit ability to form purine metabolites
Examples: 6-mercaptopurine, thioguanine
Vidarabine and fludarabine
Commonly called adenine arabinosides
Competitive inhibitors of DNA polymerase
Folic acid antimetabolites
Inhibit DNA synthesis by irreversibly binding to dihydrofolate reductase
Examples: aminopterin, methotrexate
Antineoplastic antibiotics
Microbial origin
Diverse methods of targeting DNA: intercalation, alkylation, strand breakage through formation of radicals
Dactinomycin
Antineoplastic antibiotic
2 cyclic peptides attached to a 3-ring system
Intercalates into double-stranded DNA and inhibits topoisomerase II
Anthracyclines
Glycosylated tetracyclic anthraquinone core
Intercalates double-stranded DNA and inhibits topoisomerase II
Reduction of quinone can lead to formation of hydroxyl radicals and DNA strand scission
Camptothecins
Inhibitors of topoisomerase I, which normally produces short-term, single-strand breaks in DNA to add/release supercoiling
Can also intercalate (many-ringed systems)
Bleomycins
Chelators of copper (blue color)
Form a chelate with Fe (II) that can bind molecular O2, leading to formation of hydroxyl and superoxide radicals
Vinca alkaloids
Alkaloids: nitrogen-containing heterocycles from plants
Examples: vincristine, vinblastine
Cause mitotic arrest by promoting dissolution of microtubules
Paclitaxel
World’s top-selling antitumor drug (Taxol)
Inhibits mitosis by binding tubulin and preventing its depolymerization
Different tubulin binding site than vinca alkaloids
Mitomycins
3 features: quinone (redox activation), carbamate (electrophile), aziridine (electrophile)
Bisfunctional alkylating agents
Redox cycles can generate hydrogen peroxide near DNA
