Term
| Vinca Alkaloids bind where on the tubulin molecule? |
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Definition
| Beta-subit (site V) near the GTP binding site |
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Term
| Taxanes bind where on the tubulin molecule? |
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Definition
| Bind the beta-subunit (site T) |
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Term
| Epothilones bind where on the tubulin molecule? |
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Definition
| Bind the beta-subunit (site T) |
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Term
| The Vinca Alkaloids include: |
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Definition
- Vinblastine
- Vincristine
- Vinorelbine
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Term
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Definition
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Term
| Vinca Alkaloids: MOA, Drug Resistance |
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Definition
- Bind the beta subunit of the tubulin heterodimer near the GTP binding site
- Cause shortening (depolymerization) of microtubules -- low concentrations can stabilize microtubule polymers
- Cell cycle arrest in metaphase -- duplicated chromosomes cannot align properly at division plane
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Term
| Vinca Alkaloids: Drug Resistance |
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Definition
- Drug efflux via P-glycoprotein and the MDRP family
- Mutations in the beta subunit can decrease drug affinity
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Term
| Vinca Alkaloids: Toxicity |
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Definition
- Neurotoxic symptoms (tingling of extremities, numbness, reduced tendon reflex, motor weakness)
- Leukopenia (nadir 7-10 days)
- Inappropriate secretion of ADH (rare)
- Intrathecal administration FATAL
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Term
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Definition
- Binds beta subunit (site T)
- Stabilizes microtubules, resulting in polymerization
- Cancer cells arrest in mitosis (metaphase) and enter apoptosis
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Term
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Definition
- Binds beta subunit (site T)
- Stabilizes microtubules, resulting in polymerization
- Cancer cells arrest in mitosis (metaphase) and enter apoptosis
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Term
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Definition
- Drug efflux mechanisms similar to vinca alkaloids
- Increased anti-apoptosis factors (survivin and aurora kinase)
- Taxane resistance is p53 independent
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Term
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Definition
- Peripheral neuropathy and asthenia is more severe with paclitaxel
- Paclitaxel --> neutropenia nadir usually occurs 8-11 days after a dose and then reverses by 15-21 days
- Docetaxel --> more severe, but shorter duration neutropenia
- Low water solubility requires ethanol or castor oil vehicle administration --> hypersensitivity to vehicle
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Term
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Definition
- Binds near taxane site
- Promotes polymerization
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Term
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Definition
- Peripheral neuropathy limits treatment
- Myelosuppression
- Little cross-resistance with taxanes
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Term
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Definition
- Interferes with microtubule polymerization
- Blocks mitosis
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Term
| Eribulin Mesylate: Toxicity |
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Definition
- Neutropenia
- Peripheral neuropathy
- Asthenia
- QT interval prolongation
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Term
| The Camptothecins include: |
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Definition
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Term
| The Epipodophyllotoxins include: |
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Definition
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Term
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Definition
- Binds topoisomerase I
- Inhibits ligation of DNA strand
- Apoptosis triggered in S-G2 phase
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Term
| Camptothecins: Drug Resistance |
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Definition
- Drug efflux (P-glycoprotein)
- Mutations in topoisomerases
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Term
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Definition
- Neutropenia (topotecan > irinotecan)
- Severe diarrhea (irinotecan > topotecan)
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Term
| Mechanisms of Diarrhea caused by Irinotecan |
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Definition
- Increased unconjugated SN-38 to polymorphisms in UGT
- Irinotecan inhibits AChE enzyme --> results in increased amounts of ACh, which results in diarrhea
- Irinotecan affects rapidly turning over cells (such as epithelial cells) which could result in diarrhea
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Term
| The Anthracycline Antibiotics include: |
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Definition
- Daunorubicin
- Doxorubicin
- Epirubicin
- Idarubicin
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Term
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Definition
- DNA intercalation --> disrupts replication and transcription
- Binds topoisomerase II and inhibits ligation
- Drug-DNA interaction generates hydroxyl radicals and hydrogen peroxide which can directly damage (oxidize) DNA bases
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Term
| Anthracycline: Drug Resistance |
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Definition
- Efflux
- Topoisomerase II mutation
- Increased DNA repair
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Term
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Definition
- Myelosuppression
- Cardiotoxicity, through binding of ferrous iron (generates hydroxyl radicals from hydrogen peroxide) and lack of catalase in heart tissue to convert hydrogen peroxide to H2O and O2 --> results in cardiac myocyte damage and heart failure
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Term
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Definition
- Intercalates between guanine-cytosine base pair stacks
- Amino acid side chains insert along the minor groove of DNA forming a very stable drug-DNA interaction
- Transcription and replication blocked (RNA polymerase more sensitive)
- Also causes single strand breaks through generation of free radicals and possibly topoisomerase II inhibition
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Term
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Definition
- Bone marrow suppression
- Musocal damage
- Hyperpigmentation of skin (X-ray)
- Extravasation concern
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Term
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Definition
- DNA binding
- Forms complex with ferrous Fe
- Free radical generation from conversion of ferrous iron to ferric iron which can break glycosidic and phosphodiester bonds
- Cycle arrest in G2 phase
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Term
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Definition
- Some myelosuppression
- Pulmonary fibrosis --> may depend on hydrolase which is low in skin andlungs
- Cutaneous effects (hyperpigmentation, hyperkeratosis, erythema)
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Term
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Definition
- Requires metabolism for activation of akylation activity of adenine and guanine bases
- Free radical damage can cause strand breaks
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Term
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Definition
- Myelosuppression
- Pulmonary fibrosis
- Hemolytic uremic syndrome
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Term
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Definition
- Binds topoisomerase II
- Prevents ligation of the double strand cut
- The cycle stops in S or G2 phase and the tumor cell enters apoptosis
- Free radical generation may also be important
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Term
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Definition
- Binds topoisomerase II
- Prevents ligation of the double strand cut
- The cycle stops in S or G2 phase and the tumor cell enters apoptosis
- Free radical generation may also be important
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Term
| Epipodophyllotoxins: Drug Resistance |
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Definition
- Expression of drug efflux pumps (P-glycoproteins)
- Decreased drug binding to topoisomerase
- Mutation of p53 tumor suppressor gene
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Term
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Definition
- Myelosuppression dose limiting
- GI disturbances
- Alopecia
- Risk of toxicity is higher with low serum albumin, such as in hepatic diseases (albumin capacity is saturated so more free drug available)
- Associated with development of leukemia --> Mixed-Lineage Leukemia gene rearrangement
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Term
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Definition
- Myelosuppression dose limiting
- GI disturbances
- Alopecia
- Risk of toxicity is higher with low serum albumin, such as in hepatic diseases (albumin capacity is saturated so more free drug available)
- Associated with development of leukemia --> Mixed-Lineage Leukemia gene rearrangement
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Term
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Definition
- Inhibits ribonucleotide reductase --> blocks formation of deoxyribonucleotides needed for DNA synthesis
- Also enhances antimetabolite incorporation (such as cytarabine, fludarabine, and cladribine)
- Cell arrest near G1-S interface
- Increases expression of fetal hemoglobin
- Increases sensitivity to irradiation
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Term
| Hydroxyurea: Drug Resistance |
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Definition
| Increased production or mutation of hRRM2 subunit of the ribonucleotide reductase enzyme |
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Term
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Definition
- Leukopenia
- Megaloblastic anemia (MCV, RDW)
- Thrombocytopenia
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Term
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Definition
- Enter cell by diffusion or through a copper transporter
- Crosslinking with two adjacent N7 on guanines of the same strand (intrastrand crosslinking)
- Adjacent A-G crosslinking also occurs
- Interstrand crosslinking occurs with much less frequency
- Drug-DNA adducts interfere with replication and transcription
- Can trigger apoptosis
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Term
| Platinum Complexes: Drug Resistance |
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Definition
- Intracellular nucleophiles (ie glutathione)
- Enhanced DNA repair (nucleotide excision)
- Copper efflux transporter
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Term
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Definition
- Nephrotoxicity dose limiting -- Amifostine can react with and neutralize cisplatin
- Ototoxicity
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Term
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Definition
| Peripheral neuropathy dose-limiting |
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Term
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Definition
- Less ototoxicity, neurotoxicity, and nephrotoxicity --> conversion to reactive (cytotoxic) intermediate is much slower than cisplatin and oxaliplatin
- Major concern is bone marrow suppression
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Term
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Definition
- Anti-proliferative effect
- Blocks adhesion with stromal bone marrow cells
- Inhibits angiogenesis
- Enhances natural killer production
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Term
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Definition
- Periperhal sensory neuropathy
- Severe birth defects
- Venous thromboembolism in multiple myeloma patients
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Term
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Definition
- Inhibits proteasome pathway
- Degradation of target (IkB) protein blocked
- Gene transcription inhibited of cell survival genes in tumor cells
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Term
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Definition
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Term
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Definition
- Inhibits histone deacetylases --> favors transcription of genes that regulate cell division, cause cell differentiation, and apoptosis
- Increases lysine acetylation
- Activates gene transcription
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