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Methotrexate is an analogue of what?
Folic acid
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Methotrexate was the first drug to produce what effect in leukemia?
Temporary remission
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What phase of mitosis is methotrexate specific to?
S
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What is the MOA of Methotrexate?
- Inhibits Dihydrofolate reductase
- Results in reduction of one carbon transfers (crucial for de novo synthesis of DNA)
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If you overdose on Methotrexate, what can be given?
Leucovorin
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What is the MOA of Leucovorin?
- Contribute to the synthesis of thiamine in a normal cell by substituting for N5,N10 methylene DHF
- Saves normal cell
- Won’t get into the cancer cell
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How are Folic acid and Methotrexate eliminated?
Renally (only)
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How can methotrexate be safely given to patients with renal failure?
Glucarpidase can be given after Methotrexate has been taken in to the cancer cells
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What is the MOA of Glucarpidase?
Cleaves glutamic acid, inactivating Methotrexate not in cancer cells and allowing for its metabolism and renal excretion
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What are the toxicities associated with Methotrexate?
- Bone marrow toxicity
- GI
- Renal toxicity
- Liver toxicity
- Radiation recall
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How can you improve methotrexate excretion?
Hydration and alkalinization of the urine
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Does Methotrexate bind to serum albumin?
Yes
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Is it safe to use alcohol during methotrexate use?
No, methotrexate is already very hard on the liver
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What are the indications for methotrexate?
- oropharyngeal tumors
- choriocarcinoma
- acute childhood leukemia
- acute psoriasis (lower dose)
- rheumatoid arthritis (lower dose)
- corticosteroid-dependent asthma (lower dose)
- immunosupressive agent (moderate dose)
- abortifacient (moderate dose)
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What type of methotrexate treatment is required for osteogenic sarcoma treatment?
- High IV dose
- Followed by leucovorin rescue
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Pemetrexed is an analog of what?
Folic acid
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What is the MOA of Pemetrexed (Almita)
- Main target: Thymidylate synthase
- Also targets: DHF reductase, glycinamide ribonucleotide formyl transferase (GARFT) and
- aminoimidazole carboxamide formyl transferase (AICARFT)
- The later stop de novo purine synthesis
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What are the side effects of Pemetrexed (Almita)?
- myelosuppression
- rash
- mucositis
- diarrhea
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Would you use Pemetrexed (Almita) for leukemia?
Not specifically
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How would you reduce toxicities due to Pemetrexed (Almita)?
Give Vitamin B12 or Folic acid
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What is the MOA of pralatrexate (Folotyn)?
- Targets DHFR
- Also targets thymidilate synthetase and de novo purine synthesis
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What are the indications for pralatrexate (Folotyn)?
Peipheral T-cell lymphoma
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What are the side effects for pralatrexate (Folotyn)?
- myelosuppression
- rash
- mucositis
- diarrhea
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How can you reduce toxicities of pralatrexate (Folotyn)?
Give Folic acid and Vitamin B12
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What are the pyrimidine analogs?
- 5 fluorouracil
- capecitabine
- cytarabine
- gemcitabine
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By what route is 5-FU given?
IV or topical
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After 5-FU is taken up by the cell, what happens?
Converted to FdUMP, which can be recognized by Thymidylate synthetase
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What phase of DNA synthesis does 5-FU inhibit?
S phase
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What is the effect of Leucovorin on 5-FU?
Leucovorin enhances the activity of 5-FU by stabilizing the FDUMP/thymidilate synthase complex
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Why would you give 5-FU with Leucovorin?
Allow for lower doses and less toxicity from 5-FU
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What are the side effects of 5-FU?
- Major: GI (N/V/D)
- Melosupression
- Cerebellar ataxa
- Alopecia
- Teratogenic
- Hand and foot syndrome
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Does 5-FU cross the BBB?
Yes
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What are the indications for 5-FU?
- IV: Solid tumors, breast cancer, carcinomas of GI tract (can be given orally)
- Topically: skin keratosis or psoriasis
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capecitabine (Xeloda) is related in what way to what other drug?
Oral prodrug of 5 fluorouracil
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How is capecitabine (Xeloda) metabolized?
- In the liver to:
- 1)5 deoxy-5 fluorocytidine
- 2)5-deoxy-5-fluorouridine
- 3)5 fluorouracil
- 4)FdUMP
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What is the Mechanism of Action of capecitabine (Xeloda)?
Inhibits thymidylate synthetase.
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What are the side effects of capecitabine (Xeloda)?
nausea, vomiting, severe diarrhea, but less myelosuppression
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What are the Indications for capecitabine (Xeloda)?
- Metastatic breast cancer,
- Colorectal cancer
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What type of molecule is cytarabine (cytosine arabinoside, ARA-C)?
Cytosine attached to an arabinose rather than deoxyribose
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Cytarabine (cytosine arabinoside, ARA-C) is active or a prodrug?
- Prodrug
- Must have 3 phosphates attached to the arabinose sugar for activity
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What is the MOA for cytarabine (cytosine arabinoside, ARA-C)?
Inhibits DNA chain elongation and DNA polymerases
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How can resistance to cytarabine (cytosine arabinoside, ARA-C) develop?
Through a deaminase reaction that changes an amino group to a ketone
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What is the MOA of gemcitabine (Gemzar )
- Related to cytarabine
- Phosphorylated,
- Then it inhibits both DNA polymerase and
- ribonucleotide reductase
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What are the Indications for gemcitabine (Gemzar)?
Solid tumors, non-small cell cancer of the lung, pancreatic cancer
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What are the side effects gemcitabine (Gemzar )?
- rellatively well tolerated compared to other antimetabolites derivatives
- Myelosuppression
- Mild vomiting and nausea
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What are the purine analogs?
- 6 mercaptopurine
- 6 thioguanine
- fludarabine
- cladribine
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What is the action of HGPRT: hypoxanthine guanine phosphoribosyl transferase?
Transfers phosphoribosyl pyrophosphate (PRPP) on to purines
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6 mercaptopurine is an analog of what other molecule?
hypoxanthine analog
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What is the MOA of 6 mercaptopurine?
- Inhibits the conversion of IMP to AMP or GMP
- Competes with hypoxanthine at HGPRT
- Its derivative 6-TIMP competes with IMP for the formation of AMP and GMP
- Stops purine biosynthesis or purine synthesis for reutilization, inhibits purine biosynthesis, nucleotide interconversion, and biosynthesis of nucleic acids.
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What phase does 6 mercaptopurine operate in?
S phase
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