Pharmacology: Antineoplastics II - 1
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Methotrexate is an analogue of what?
Methotrexate was the first drug to produce what effect in leukemia?
What phase of mitosis is methotrexate specific to?
What is the MOA of Methotrexate?
- Inhibits Dihydrofolate reductase
- Results in reduction of one carbon transfers (crucial for de novo synthesis of DNA)
If you overdose on Methotrexate, what can be given?
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
How are Folic acid and Methotrexate eliminated?
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
What is the MOA of Glucarpidase?
Cleaves glutamic acid, inactivating Methotrexate not in cancer cells and allowing for its metabolism and renal excretion
What are the toxicities associated with Methotrexate?
- Bone marrow toxicity
- Renal toxicity
- Liver toxicity
- Radiation recall
How can you improve methotrexate excretion?
Hydration and alkalinization of the urine
Does Methotrexate bind to serum albumin?
Is it safe to use alcohol during methotrexate use?
No, methotrexate is already very hard on the liver
What are the indications for methotrexate?
- oropharyngeal tumors
- acute childhood leukemia
- acute psoriasis (lower dose)
- rheumatoid arthritis (lower dose)
- corticosteroid-dependent asthma (lower dose)
- immunosupressive agent (moderate dose)
- abortifacient (moderate dose)
What type of methotrexate treatment is required for osteogenic sarcoma treatment?
- High IV dose
- Followed by leucovorin rescue
Pemetrexed is an analog of what?
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
What are the side effects of Pemetrexed (Almita)?
Would you use Pemetrexed (Almita) for leukemia?
How would you reduce toxicities due to Pemetrexed (Almita)?
Give Vitamin B12 or Folic acid
What is the MOA of pralatrexate (Folotyn)?
- Targets DHFR
- Also targets thymidilate synthetase and de novo purine synthesis
What are the indications for pralatrexate (Folotyn)?
Peipheral T-cell lymphoma
What are the side effects for pralatrexate (Folotyn)?
How can you reduce toxicities of pralatrexate (Folotyn)?
Give Folic acid and Vitamin B12
What are the pyrimidine analogs?
- 5 fluorouracil
By what route is 5-FU given?
IV or topical
After 5-FU is taken up by the cell, what happens?
Converted to FdUMP, which can be recognized by Thymidylate synthetase
What phase of DNA synthesis does 5-FU inhibit?
What is the effect of Leucovorin on 5-FU?
Leucovorin enhances the activity of 5-FU by stabilizing the FDUMP/thymidilate synthase complex
Why would you give 5-FU with Leucovorin?
Allow for lower doses and less toxicity from 5-FU
What are the side effects of 5-FU?
- Major: GI (N/V/D)
- Cerebellar ataxa
- Hand and foot syndrome
Does 5-FU cross the BBB?
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
capecitabine (Xeloda) is related in what way to what other drug?
Oral prodrug of 5 fluorouracil
How is capecitabine (Xeloda) metabolized?
- In the liver to:
- 1)5 deoxy-5 fluorocytidine
- 3)5 fluorouracil
What is the Mechanism of Action of capecitabine (Xeloda)?
Inhibits thymidylate synthetase.
What are the side effects of capecitabine (Xeloda)?
nausea, vomiting, severe diarrhea, but less myelosuppression
What are the Indications for capecitabine (Xeloda)?
- Metastatic breast cancer,
- Colorectal cancer
What type of molecule is cytarabine (cytosine arabinoside, ARA-C)?
Cytosine attached to an arabinose rather than deoxyribose
Cytarabine (cytosine arabinoside, ARA-C) is active or a prodrug?
- Must have 3 phosphates attached to the arabinose sugar for activity
What is the MOA for cytarabine (cytosine arabinoside, ARA-C)?
Inhibits DNA chain elongation and DNA polymerases
How can resistance to cytarabine (cytosine arabinoside, ARA-C) develop?
Through a deaminase reaction that changes an amino group to a ketone
What is the MOA of gemcitabine (Gemzar )
- Related to cytarabine
- Then it inhibits both DNA polymerase and
- ribonucleotide reductase
What are the Indications for gemcitabine (Gemzar)?
Solid tumors, non-small cell cancer of the lung, pancreatic cancer
What are the side effects gemcitabine (Gemzar )?
- rellatively well tolerated compared to other antimetabolites derivatives
- Mild vomiting and nausea
What are the purine analogs?
- 6 mercaptopurine
- 6 thioguanine
What is the action of HGPRT: hypoxanthine guanine phosphoribosyl transferase?
Transfers phosphoribosyl pyrophosphate (PRPP) on to purines
6 mercaptopurine is an analog of what other molecule?
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.
What phase does 6 mercaptopurine operate in?
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