Anticancer I Flashcards
What are the 7 classes of anticancer agents?
Alkylating agents Antimetabolite and nucleoside analogs Antitumor antibiotics Antimitotic agents Miscellaneous antineoplastics Hormonal therapy Combination therapy
What are the different alkylating agents?
Nitrogen mustards Phosphoamide mustards Nitrosoureas Platins Other alkylating agents
What is the main MOA of alkylating agents?
React with DNA, preferentially alkylating the N-7 position of guanine (most common)
Bifunctional alkylating agents product inter- or intra-strand crosslinks preventing DNA separation
What is the MOA of nitrogen mustards?
They activate the chloride
What are some nitrogen mustards?
Melphalan Cyclophosphamide Ifosfamide Chlorambucil Estramustine phosphate
What are some other alkylating anticancer agents?
Busulfan (Myleran)
Thiopeta
Procarbazine (Matulane)
Dacarbazine
What is the MOA of nitrosureas?
Urea NH is deprotonated and the negatively charged oxygen displaces chloride to give a cyclic oxazolidine, which fragments to give 2-chloroethylisocyanate and vinyl diazohydroxide, which decomposes to give electrophilic vinyl cation
What are some nitrosureas?
Carmustine (BiCNU)
Lomustine (CeeNU)
Streptozin (Zanosar)
What are some platins?
Cisplatin
Carboplatin
What is the MOA of antimetabolites?
They care closely related to cellular precursors and thus they prevent use or formation of normal cellular products.
What are the MOAs of pyrimidine-based antimetabolites?
Inhibition of kinases
Inhibition of enzymes involved in pyrimidine biosynthesis
Incorporation into RNA or DNA, causes misreading
Inhibition of DNA polymerase
What is the role of folate?
DNA synthesis
DNA repair
DNA methylation
Cofactor
What are the active forms of folate?
Tetrahydrofolate and dihydrofolate
What do dihydrofolate reductase (DHFR) inhibitors do?
They inhibit DHFR, which leads to:
Decreased levels of FH2 and FH4
Decreased conversion of dUMP into dTMP
Decreased DNA synthesis
What are some DHFR inhibitors?
Methotrexate
Pemetrexed (Alimta)
Pralatrexate (Folotyn)
What does pralatrexate do?
Inhibits enzymes used in purine and pyrimidine synthesis:
thymidylate synthase
dihydrofolate reductase
glycinamide ribonucleotide formyltransferase
What does folinic acid do?
Adjuvant used in cancer chemotherapy to “rescue” bone marrow and GI mucosa cells from methotrexate
What is 5-fluorouracil?
“Mechanism-based” prodrug that acts as a suicide substrate and directly inhibits the thymidylate synthase
What are the 3 main active metabolites of 5-fluorouracil?
Fluorodeoxyuridine monophosphate (FdUMP) Fluorodeoxyuridine triphosphate (FdUTP) Fluorouridine triphosphate (FUTP)
What is the MOA of 5-FU (specifically, it’s active metabolite FdUMP)?
Direct inhibition of TS via the formation of a ternary complex in the nucleotide-binding site. This blocks dUMP from accessing the binding site.
This leads to an increase in dUTP, which causes DNA damage
What are some other pyrimidine-based antimetabolites?
Cytarabine (ARA-C)
Gemcitabine
What are some purine-based antimetabolites?
6-mercaptopurine
6-thioguanine
Fludarabbine phoshpate (Fludara)
Cladribine
What is the MOA of 6-mercaptopurine?
Blocks the synthesis of PRA and PRPP
What are some antitumor antibiotics?
Bleomycins Anthracyclines Etoposide and teniposide Camptothecins Actinomycins Mitomycins
What are bleomycins?
Cytotoxic glycopeptides
What is the MOA of bleomycins?
Chelates metail ions (Fe, Cu) producing a pseudo enzyme that reacts with oxygen to produce free radicals, causing DNA strand breaks
What is required for bleomycin DNA strand breaking? How is this achieved?
Reactivation and reorganization of bleomycin
The key to reorganization is the linker and the flexibility of the bithiazole tail
What are some topoisomerase poisons?
Amsacrine
Etoposide
Doxorubicin
Mitoxantrone
What are the functions of DNA topoisomerase?
DNA replication
DNA recombination
Chromosome condensation/decondensation
Segregation of sister chromatids
What do topoisomerase II poisons do?
Cause single and double strand DNA breaks
Increase in topoisomerase II levels - renders cell hypersensitive (more enzyme, more DNA breaks)
Stabilize topoisomerase II-DNA covalent complexes
What does topoisomerase II catalytic inhibitors do (…not do)?
Do not cause DNA strand breaks
Do not stabilize topoisomerase II-DNA cleavable complexes (and may destabilize them)
What is the MOA of anthracyclines?
intercalation followed by inhibition of topoisomerase II leading to DNA strand breakage and apoptosis
Additional mechanism: generation of free radicals
What are the 5 clinically useful anthracyclines?
Doxorubicin Daunorubicin Epirubicin Idarubicin Valrubicin
What limits the use of doxorubicin?
Cardiotoxicity; doxorubicin is a quinone and can be reduced to a semiquinone. The semiquinone reacts with oxygen to reform the quinone (redox cycling)
Doxorubicin also forms a strong complex with Fe3+, which can be reduced to Fe2+, which can form free radicals
What limits the use of etoposide?
Myelosuppression
What is the MOA of camptothecins?
Inhibitor of topoisomerase I (prevents realignment and resealing); leads to double stranded DNA breaks and cell death
What is increases the water solubility of campothecins to create topotecan and Irinotecan?
Addition of basic amine side chains
What’s the difference between topoisomerase I and II?
Top. I: single strand break
Top. II: double strand break
What are some antimitotic compounds?
Vinca alkaloids
Taxanes
Epothilones
IXA
What are the two conjoined groups of vinca alkaloids?
Catharanthine moiety (indole, azonine, piperidine ring systms) Vindoline moiety (dihydroindole, cyclohexane, pyrrolidine, piperidine)
What is the MOA of vinca alkaloids?
Disrupt formation of mitotic spindles, inhibiting microtubule assembly
What are some vinca alkaloids?
Vinblastine
Vincristine
Vinorelbine
What is the MOA of taxenes?
They bind to tubular at a different site than vinca alkaloids
This stabilizes microtubules and prevent depolymerization, blocking mitosis
What are some taxanes?
Paclitaxel (Taxol)
Docetaxel (Taxotere)
What does vinblastine bind to the microtubule? What does paclitaxel bind?
Vinblastine binds to the plus end
Paclitexel binds on the interior surface
What are epothilones?
They are macrocyclic lactones that have a MOA similar to taxanes but offer several advantages (don’t require Cremophor EL for water solubility)
What is IXA used for?
Taxane-resistant breast cancer
What growth factors do we often target with several drugs and monoclonal antibodies to control overgrowth of cells/tissues?
Epidermal GF Platelet-derived GF Nerve GF Vascular endothelial GF Stem cell F
What is the MOA of protein tyrosine kinase inhibitors
Kinase inhibitors mimic ATP to inhibit tyrosine kinases
What is the first protein tyrosine kinase inhibitor on the market?
Imatinib (Gleevec) for chronic myelogenous leukemia
What are other protein tyrosine kinase inhibitors?
Nilotinib
Dasatinib
Bosutinib
Ponatinib
How do type I kinase inhibitors bind?
They bind to the active conformation of the kinase with the aspartate residue and the DFG motif pointing into the ATP-binding pocket
How do the type II kinase inhibitors bind?
They bind and stabilize the inactive conformation of the kinase with the flipped aspartate residue facing outward of the binding pocket
What are the limitations of kinase inhibitors?
Cardiotoxicity (CHF, decreased ejection fraction, ischemia, infarction)
What are some anticancer monoclonal antibodies?
Bevacizumab Cetuximab Ipilimumab Nivolumab Ofatumumab Paitumumab Rituximab
What is the MOA of Bortezomib?
Inhibits proteosomes
What is the MOA of dactinomycin?
Binds to DNA by intercalation, inhibiting DNA function
