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What is the route of administration for 6 mercaptopurine?
Oral
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What are the side effects of 6 mercaptopurine?
myelosuppression, GI
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What are the indications of 6 mercaptopurine?
Acute lymphocytic leukemia (ALL) or CML
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What DDIs does 6 mercaptopurine have?
- Metabolized by xanthine oxidase
- Allopurinol inhibits xanthine oxidase and will increase mercaptopurine toxicity
- 6 MP also metabolized by 6-thiopurine methyltransferase (TPMT) a genetic deficiency in this enzyme will cause toxicities
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Azathioprine (Imuran) is active or a prodrug?
Prodrug
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Azathioprine (Imuran) is metabolized to what?
6-mercaptopurine
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What is Azathioprine (Imuran) used for?
As an immunosuppressant and for treating rheumatoid arthritis
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6-thioguanine is an analog of what?
Guanine (with a sulfur on it)
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What is the route of administration for 6-thioguanine?
Oral
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What enzyme activates 6-thioguanine?
HGPRT
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What is the MOA of 6-thioguanine?
- Ribose phosphate added
- Ribonucleotide reductase changes it to the deoxy form
- Incorporated into DNA
- Inhibits DNA polymerase
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What phase of the cell cycle is 6-thioguanine active in?
S phase
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What is the MOA of 6 Thioguanine?
- Damages DNA after incorporation
- Inhibits synthesis of AMP and GMP
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Does 6-thioguanine have a DDI with allopurinol?
No, it is not degraded by xanthine oxidase
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In general what type of disease are Purine antimetabolites used to treat?
Leukemia
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Most purine analogs cause what adverse reaction that will need to be treated?
Tumor lysis syndrome
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fludarabine (Fludara) is an Analog of what?
Adenosine
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How is Fludarabine (Fludara) administered?
IV
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By what Mechanism of action does Fludarabine (Fludara) operate?
- Converted to 2-fluoro-ara-ATP
- Inhibits DNA polymerase and ribonucleotide reductase
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What are the Side effects for Fludarabine (Fludara)?
- Bone marrow depression
- Nausea
- Vomiting
- Rare neurological effects
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What are the Indications for Fludarabine (Fludara)?
B-cell chronic lymphocytic leukemia (CLL)
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Fludarabine (Fludara) has a Florine group for what reason?
To inhibit deaminase deactivation
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Cladribine (Leustatin) is an analog of what?
Deoxyadenosine (with an additional chlorine)
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What needs to occur to activate Cladribine (Leustatin)?
Phosphorylation
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What is the Mechanism of action for Cladribine (Leustatin)?
- Incorporated into DNA
- Inhibits DNA synthesis and repair
- Induces DNA strand breaks.
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Is Cladribine (Leustatin)resistant to deaminase, why or why not?
- Yes, resistant to adenosine deaminase specifically
- Due to Chlorine group
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Why does Cladribine (Leustatin) have an extended half life?
Cl group reduces adenosine deaminase deactivation
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What phase does Cladribine inhibit?
S phase
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Is Cladribine (Leustatin) active against quiescent or dividing cells?
Both
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What type of tumor does Cladribine (Leustatin) have no activity against?
Solid tumors
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What is the indication for Cladribine (Leustatin)?
Hairy cell leukemia
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What are the side effects of Cladribine (Leustatin)?
- Myelosuppression, nephrotoxicity and neurotoxicity
- Tumor lysis syndrome
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What type of cancer is Cladribine (Leustatin) mainly used to treat?
Leukemias
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Hydroxyurea (Hydrea) is what type of drug?
Ribonucleotide Reductase Inhibitor
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What is the MOA of Hydroxyurea (Hydrea)?
- Inhibits ribonucleotide reductase = Rate limiting step of DNA synthesis
- Prevents formation of deoxy riboses
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What are the indicatons for Hydroxyurea (Hydrea)?
- Chronic myelogenous leukemia
- Solid tumors
- Sickle cell anemia
- Psoriasis
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What are the side effects Hydroxyurea (Hydrea)?
- Bone marrow depression (leukopenia)
- Stomatitis and GI ulceration
- Skin (hyperpigmentation and hyperkeratosis)
- Radiation sensitizer
- Radiation recall
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What are the Vinca alkaloids?
- vinblastine (Velban)
- vincristine (Oncovin)
- vinorelbine (Navelbine)
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What are the Vinca alkaloids derived from?
Periwinkle plants
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What is the mechanism of action for Vinca alkaloids?
- Disruption of microtubules for mitosis by:
- Aggregation of the free tubulin dimers so that they cannot form a polymer of microtubules
- Inhibits the mitosis phase of the cell cycle
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What is a common side effect of all Vinca alkaloids?
All are severe vesicants
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What are the side effects of vincristine?
Severe Neurotoxicity, mild bone marrow, alopecia
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What are the side effects of vinorelbine?
Bone marrow, neurotoxicity, alopecia (toxicities are in between other vinca alkaloids)
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What are the side effects of vinblastine:
Severe Bone marrow, mild neurotoxicity, alopecia
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Which vincristine analog is commonly combined with Cisplatin?
Vinblastine
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How are the vinca alkaloids administered?
IV
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Which vincristine analog would you not want to combine with Cisplatin?
Vincristine
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What are the indications for Vinca alkaloids?
Different for each one (don’t need to know them all)
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What are the Taxanes?
- Paclitaxel (Taxol)
- Nanoparticle albumin-bound paclitaxel (Abraxane)
- Docetaxel (Taxotere)
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Where are the Taxanes derived from?
Pacific Yew Tree bark
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What are the benefits of Nanoparticle albumin-bound paclitaxel (Abraxane) over normal paclitaxel?
- Increases selectivity for tumor cells
- Decreases hypersensitivity reactions
- Causes a little less myelosupression
- May be more efficacious
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