Cancer Pharm: Antimetabolites Flashcards
What is the MOA of Methotrexate?
- Inhibits synthesis of THF
- Interferes w/ formation of DNA, RNA, and key cellular proteins
Which enzyme is responsible for activating and increasing the selectivity of the antifolates: methotrexate, pemetrexed, and pralatrexate?
Folyl polyglutamate synthase (FPGS) catalyzes formation of intracellular metabolites which are selectively retained in cancer cells
What are 4 mechanisms by which resistance to Methotrexate may develop?↓
- ↓ drug transport via the reduced folate carrier or folate receptor protein
- ↓ formation of cytotoxic methotrexate polyglutamines
- ↑ levels of the target enzyme DHFR thru gene amplification, etc.
- Altered DHFR protein with reduced affinity for methotrexate
What are 4 drug-drug interactions that you must be aware of when giving Methotrexate?
Aspirin, NSAIDs, penicillin, and cephalosporinsallinhibititsrenal excretion—> ↑toxicity
Which drug is sometimes used in combo with high-dose methotrexate therapy to rescue normal cells from undue toxicity?
Reduced folate leucovorin; reverses action of methotrexate
Which antifolate drug has activity during the S-phase?
Pemetrexed
What is the MOA of the antifolate, Pemetrexed?
- Inhibition of thymidylate synthase (TS)
- Targets and inhibits DHFR and enzymes involved in de novo purine nucleotide biosynthesis
What are some AE’s associated with the antifolate, Pemetrexed; which is unique to this drug?
- Hand-foot syndrome* = painful erythema and swelling of hands and feet
- Myelosuppression
- Skin rash + Mucositis
- Diarrhea + Fatigue
Vitamin supplementation with what can significantly reduce toxicities associated with Pemetrexed and Pralatrexate?
Folic acid and Vitamin B12
What are the 3 MOA’s of the antifolate, Pralatrexate?
- Inhibits DHFR
- Inhibits enzymes involved in de novo purine nucleotide biosynthesis
- Inhibits thymidylate synthase (TS)
The antifolate, Pralatrexate has been approved for the tx of what?
Relapsed or refractory peripheral T-cell lymphoma
What are the 3 active metabolites of 5-FU and what is the MOA of each?
- FdUMP —> inhibition of DNA synthesis thru “thymineless death”
- FUTP –> incorporated in RNA; interferes w/ RNA processing and mRNA translation
- FdUTP –> incorporated into DNA resulting in inhibition of DNA synthesis
What are 4 AE’s of the antimetabolite, 5-FU; which is unique?
- GI toxicity (diarrhea/mucositis) = unique
- Myelosuppression
- Skin toxicity (hand-foot syndrome) = unique
- Neurotoxicity
5-FU is the most widely used drug in the tx of which cancer?
Colorectal cancer
What is special about the antimetaboite, Capecitabine?
A prodrug that is metabolized to 5-FU by thymidine phosphorylase (which has higher expression in some solid tumors - breast and colorectal)
2 main AE’s of the antimetabolite, Capecitabine?
Main = diarrhea, hand-foot syndrome
Capecitabine used in conjunction with what drug is the first-line tx for metastatic colorectal cancer?
Capecitabine + oxaliplatin = XELOX regimen
What are the 2 components of the antimetabolite, TAS-102 and how does each work?
- Trifluridine = metabolized to monophosphate form (inhibits TS) or metabolized to triphosphate form (inhibits DNA synthesis and function)
- Tipiracil = a TP inhibitor, the key enzyme that degrades trifluridine
TAS-102 is useful in which type of colorectal cancer?
- Wild-type and mutant RAS colorectal cancer
- Used in progressive, refractory colorectal cancer
Which phase of the cell cycle is Cytarabine specific for?
S phase
The antimetabolite, Cytarabine is converted into what; describe the 3 MOA of this metabolite.
- Converted to ara-CMP —> ara-CTP
- Inhibits DNA polymerase-α and β (blocks DNA synthesis and repair)
- Incorporated into DNA –> interferes w/ chain elongation and causes defective ligation of new DNA fragments
- Incorporated into RNA
What are 4 AE’s of Cytarabine?
- Myelosuppression
- Mucositis
- N/V
- Neurotoxicity (at high doses)
2 clinical uses for Cytarabine?
AML and NHL’s; only has activity against hematologic malignancies
The anti-metabolite Gemcitabine is phosphorylated to a diphosphate and triphosphate form, what is the MOA of each form?
- Diphosphate = inhibits ribonucleotide reductase; ↓ level of deoxyribonucleotide triphosphates needed for DNA synthesis
- Triphosphate = inhibits DNA polymerase-α and β (blocks DNA synthesis and repair)
What is the dose limiting toxicity of Gemcitabine and which AE is most common?
- Dose limiting = myelosuppression in form of neutropenia
- Nausea and vomiting (70% of patients) + flu-like syndrome
Although both deoxycytidine analogs, how does the clinical use of Cytarabine differ from Gemcitabine?
- Cytarabine only effective against hematologic malignancies
- Gemcitabine can be used for both solid and hematologic malignancies
Gemcitabine was initally approved for use in what type of cancer?
Advanced pancreatic cancer
Which enzyme is responsible for metabolizing the 6-thiopurines; which toxic effects may be seen with loss of this enzyem?
- Metabolized by thiopurine methyltransferase (TPMT)
- Loss of this enzyme can lead to: myelosuppression and GI toxicity (mucositis and diarrhea)
6-mercaptopurine (6-MP) is inactive in parent form and becomes active when metabolized to what?
Metabolized by HGPRT –> monophosphate nucleotide 6-thioinosinic acid
What is the MOA of the active metabolite of 6-MP, mono- and triphosphate nucleotide 6-thioinosinic acid?
- Monophosphate acts to inhibit several enzymes of de novo purine nucleotide synthesis
- Triphosphate form incorporated into both DNA and RNA
How is the active form of 6-mercaptopurine (6-MP) inactivated and what clinical implication does this have?
- Converted to inactive metabolite by xanthine oxidase
- Allopurinol (xanthine oxidase inhibitor) is commonly used in tx of acute leukemia for prevention of hyperuricemia
- If allopurinol is used w/ 6-MP, would result in ↑ levels of 6-MP and excessive toxicity
6-mercaptopurine is used in the tx of what?
Childhood acute leukemia
List the 5 MOA of 6-thioguanine?
- Inhibits several enzymes in de novo purine nucleotide synthesis
- Inhibition of purine nucleotide interconversion
- ↓ IC levels of guanine nucleotides –> inhibits glycoprotein synthesis
- Interferes w/ formation of DNA and RNA
- Incorporation of thiopurine nucleotides in DNA and RNA
6-thioguanine synergizes with what drug in the tx of adult acute leukemia?
Cytarabine
What is the MOA of the triphosphate and diphosphate form of Fludarabine (purine antagonist)?
- Triphosphate: inhibits DNA polymerase-α and β (interferes w/ DNA synthesis and repair)
- Diphosphate: inhibits ribonucleotide reductase leading to inhibition of production of deoxyribonucleotide triphosphates
- Also induces apoptosis in susceptible cells
What is an AE you must consider when using the purine antagonist, Fludarabine; how can this AE be managed?
- ↑ risk for opportunistic infections i.e., P. jiroveci pneumonia (PCP)
- PCP prophylaxis w/ TMP-SMX at least 3x/week during tx and for one week after
2 clinical uses for the purine antagonist, Fludarabine?
- Low-grade NHL’s
- Chronic lymphocytic leukemia
The purine antagonist, Cladribine, has a high specificity for what cells?
Lymphoid cells
What is the MOA of the purine antagonist, Cladribine, when in active triphosphate form?
- Incorporated into DNA, causing inhibition of synthesis and function
- Inhibition of DNA polymerase-α and β (interferes w/ synthesis and repair)
What AE must you keep in mind when using the purine antagonist, Cladribine?
- Main effect = myelosuppression
- ↓ in CD4 and CD8 T cells can last 1+ year
2 main clinical applications of the purine antagonist, Cladribine?
- Hairy cell leukemia
- Low-grade lymphoid malignancies: CLL and low-grade NHL’s
