Podcast
Questions and Answers
Capecitabine is favored over 5-FU, especially in treating gastric cancers, due to what primary advantage?
Capecitabine is favored over 5-FU, especially in treating gastric cancers, due to what primary advantage?
- Increased efficacy against rapidly dividing cancer cells.
- Lower cost of production compared to 5-FU.
- Direct targeting of cancer cells, reducing systemic toxicity.
- Its ability to be administered orally, enhancing patient convenience. (correct)
Raltitrexed, a specific thymidylate synthase (TS) inhibitor, is transported into cells via what mechanism?
Raltitrexed, a specific thymidylate synthase (TS) inhibitor, is transported into cells via what mechanism?
- Folate transporters, utilizing the cell's folate uptake pathways. (correct)
- Active transport using a specific ATP-dependent pump.
- Direct injection into the tumor cells bypassing normal transport mechanisms.
- Passive diffusion across the cell membrane.
How does Raltitrexed inhibit thymidylate synthase (TS)?
How does Raltitrexed inhibit thymidylate synthase (TS)?
- By competing with N5N10-methylene THF, a cofactor necessary for TS activity. (correct)
- By preventing the synthesis of TS within the cell, reducing enzyme levels.
- By altering the genetic code to produce a non-functional form of TS.
- By irreversibly binding to the active site of TS, causing permanent inactivation.
The primary effect of thymidylate synthase (TS) inhibitors like Raltitrexed on DNA synthesis is:
The primary effect of thymidylate synthase (TS) inhibitors like Raltitrexed on DNA synthesis is:
Why is Raltitrexed considered S phase specific?
Why is Raltitrexed considered S phase specific?
What is the role of deoxythymidine phosphorylase in the mechanism of action of capecitabine?
What is the role of deoxythymidine phosphorylase in the mechanism of action of capecitabine?
What is the initial metabolic step in the activation of cytarabine (araC)?
What is the initial metabolic step in the activation of cytarabine (araC)?
Both cytarabine and gemcitabine are categorized as what?
Both cytarabine and gemcitabine are categorized as what?
Cytarabine (araC) is commonly used in the treatment of acute myeloid leukemia (AML) in combination with what other type of drug?
Cytarabine (araC) is commonly used in the treatment of acute myeloid leukemia (AML) in combination with what other type of drug?
What is the primary mechanism by which dFdCDP (the diphosphate form of Gemcitabine) exerts its anti-cancer effect?
What is the primary mechanism by which dFdCDP (the diphosphate form of Gemcitabine) exerts its anti-cancer effect?
Which of the following mechanisms is NOT a recognized mode of clinical resistance to Cytarabine (araC)?
Which of the following mechanisms is NOT a recognized mode of clinical resistance to Cytarabine (araC)?
Why is Fludarabine used in non-myeloablative allogeneic transplants?
Why is Fludarabine used in non-myeloablative allogeneic transplants?
Gemcitabine's activity in treating solid tumors, such as pancreatic, lung, and breast cancers, is attributed to which key mechanism of action?
Gemcitabine's activity in treating solid tumors, such as pancreatic, lung, and breast cancers, is attributed to which key mechanism of action?
Which phase of the cell cycle is Cytarabine (araC) most specific for?
Which phase of the cell cycle is Cytarabine (araC) most specific for?
Fludarabine inhibits different enzymes, however its mechanism of action as a purine analog is BEST described as what?
Fludarabine inhibits different enzymes, however its mechanism of action as a purine analog is BEST described as what?
A patient undergoing chemotherapy with Cytarabine (araC) develops increasing levels of drug resistance. Which of the following mechanisms would MOST directly lead to decreased levels of the active araCTP metabolite inside the cell?
A patient undergoing chemotherapy with Cytarabine (araC) develops increasing levels of drug resistance. Which of the following mechanisms would MOST directly lead to decreased levels of the active araCTP metabolite inside the cell?
A researcher is investigating novel approaches to overcome resistance to thiopurines. Targeting which enzyme would MOST likely enhance the efficacy of 6-mercaptopurine (6-MP) by preventing its inactivation?
A researcher is investigating novel approaches to overcome resistance to thiopurines. Targeting which enzyme would MOST likely enhance the efficacy of 6-mercaptopurine (6-MP) by preventing its inactivation?
Which of the following statements BEST describes the use of thiopurines in the treatment of acute lymphoblastic leukemia?
Which of the following statements BEST describes the use of thiopurines in the treatment of acute lymphoblastic leukemia?
Why is the duration of exposure more critical than peak concentrations in the context of antifolate drugs like methotrexate?
Why is the duration of exposure more critical than peak concentrations in the context of antifolate drugs like methotrexate?
Methotrexate (MTX) is converted to polyglutamates inside cells. What is the primary purpose of this conversion?
Methotrexate (MTX) is converted to polyglutamates inside cells. What is the primary purpose of this conversion?
Leucovorin is used as a rescue agent in high-dose methotrexate therapy. What is the mechanism by which leucovorin protects normal cells from MTX toxicity?
Leucovorin is used as a rescue agent in high-dose methotrexate therapy. What is the mechanism by which leucovorin protects normal cells from MTX toxicity?
In osteosarcoma treatment, leucovorin rescue is considered 'selective'. What is the primary reason for this selectivity?
In osteosarcoma treatment, leucovorin rescue is considered 'selective'. What is the primary reason for this selectivity?
Which of the following mechanisms of resistance to methotrexate (MTX) involves alterations in intracellular drug metabolism?
Which of the following mechanisms of resistance to methotrexate (MTX) involves alterations in intracellular drug metabolism?
How does increased thymidine uptake contribute to methotrexate resistance?
How does increased thymidine uptake contribute to methotrexate resistance?
Fluorouracil (5-FU) is a pyrimidine analogue antimetabolite. Which of the following is the primary mechanism by which 5-FU inhibits DNA synthesis?
Fluorouracil (5-FU) is a pyrimidine analogue antimetabolite. Which of the following is the primary mechanism by which 5-FU inhibits DNA synthesis?
Why is 5-Fluorouracil (5-FU) combined with leucovorin in the treatment of colorectal cancer?
Why is 5-Fluorouracil (5-FU) combined with leucovorin in the treatment of colorectal cancer?
5-Fluorouracil (5-FU) is described as a 'cell cycle specific' drug. During which phase of the cell cycle is 5-FU most effective?
5-Fluorouracil (5-FU) is described as a 'cell cycle specific' drug. During which phase of the cell cycle is 5-FU most effective?
Which of the following is a common toxicity associated with both methotrexate and 5-fluorouracil?
Which of the following is a common toxicity associated with both methotrexate and 5-fluorouracil?
How does the action of FdUMP ultimately lead to inhibition of DNA synthesis?
How does the action of FdUMP ultimately lead to inhibition of DNA synthesis?
Which of the following resistance mechanisms is most likely to affect the efficacy of both methotrexate (MTX) and 5-Fluorouracil (5-FU)?
Which of the following resistance mechanisms is most likely to affect the efficacy of both methotrexate (MTX) and 5-Fluorouracil (5-FU)?
5-Fluorouracil is metabolized to several active metabolites, including FdUMP, FUTP and FdUTP. Which of these metabolites primarily affects RNA function?
5-Fluorouracil is metabolized to several active metabolites, including FdUMP, FUTP and FdUTP. Which of these metabolites primarily affects RNA function?
If a patient develops resistance to 5-Fluorouracil (5-FU) due to increased levels of thymidylate synthase (TYMS), which of the following strategies might be effective in overcoming this resistance?
If a patient develops resistance to 5-Fluorouracil (5-FU) due to increased levels of thymidylate synthase (TYMS), which of the following strategies might be effective in overcoming this resistance?
Considering the mechanism of action of 5-Fluorouracil (5-FU), which type of tumor would likely show a better response to 5-FU treatment?
Considering the mechanism of action of 5-Fluorouracil (5-FU), which type of tumor would likely show a better response to 5-FU treatment?
Flashcards
Capecitabine
Capecitabine
An oral prodrug that replaces 5-FU for treating gastric cancers.
Deoxythymidine phosphorylase
Deoxythymidine phosphorylase
An enzyme that activates capecitabine into its active form.
Raltitrexed
Raltitrexed
A rationally designed thymidylate synthase inhibitor used in cancer treatment.
Thymidylate synthase (TS)
Thymidylate synthase (TS)
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S phase specificity
S phase specificity
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Cytarabine
Cytarabine
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Gemcitabine
Gemcitabine
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Prodrugs
Prodrugs
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araC
araC
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Cytidine deaminase
Cytidine deaminase
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dCK
dCK
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S-phase specific
S-phase specific
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Fludarabine
Fludarabine
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Purine Analogues
Purine Analogues
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Thiopurines
Thiopurines
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Myelosuppression
Myelosuppression
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Ribonucleotide reductase
Ribonucleotide reductase
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Duration of exposure
Duration of exposure
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Methotrexate (MTX)
Methotrexate (MTX)
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Leucovorin
Leucovorin
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This drug can be a prodrug
This drug can be a prodrug
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Polyglutamation
Polyglutamation
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Resistance to MTX
Resistance to MTX
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Folate transporters
Folate transporters
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5-Fluorouracil side effects
5-Fluorouracil side effects
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Fluorouracil
Fluorouracil
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Pyrimidine analogues
Pyrimidine analogues
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Suicide substrate
Suicide substrate
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Study Notes
Antimetabolite Chemotherapy
- Antimetabolites mimic natural metabolites, disrupting biosynthetic pathways and critical steps in nucleic acid synthesis.
- They are cell cycle-specific, most effective during the S-phase (maximal cytotoxic effects).
- Toxicity affects rapidly dividing cells, including gastrointestinal mucosa, bone marrow, and hair follicles.
- Antimetabolites differ from alkylating agents, avoiding carcinogenic issues associated with prolonged exposure linked to alkylating agents. Continuous infusion is more crucial than peak concentration for optimal effect.
Folate Cycle and Methotrexate (MTX)
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Folate is crucial for DNA synthesis (thymidine).
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MTX, a folate analog, inhibits dihydrofolate reductase (DHFR), blocking tetrahydrofolic acid (THF), a crucial cofactor in DNA synthesis, and depleting dTMP.
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Inside cells, folates and MTX are converted into polyglutamates, enhancing potency by affecting processes in the cell.
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MTX is a widely used antimetabolite in cancer chemotherapy, often used in combinations with other chemotherapy for various cancers, including breast cancer and childhood leukemia.
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Problems include oral and gastrointestinal ulceration, myelosuppression, and pulmonary infiltrates and fibrosis.
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Leucovorin can be used to rescue normal cells from MTX's toxicity (rescue therapy), important in cases like osteosarcoma.
Mechanisms of Resistance to MTX
- Reduced uptake through folate transporters, increased MTX efflux via ATP-binding cassette (ABC) transporters are significant mechanisms.
- Alterations in target enzymes, such as reductions in polyglutamation or alterations in folate transport, affecting the effectiveness of MTX.
- Increased thymidine uptake via the salvage pathway can also contribute to resistance.
Pyrimidine Analogues
- Antimetabolites mimicking pyrimidine structure for cancer treatment.
- Fluouracil (5-FU) inhibits thymidylate synthase (TS), a crucial enzyme in DNA synthesis, causing the loss of dTMP.
- 5-FU is often used in colorectal cancers and, in combination with other drugs like leucovorin, in other cancers.
- Capecitabine, a prodrug of 5-FU, enhances oral administration compared to the intravenous 5-FU.
Cytidine Analogues
- Cytarabine (araC) and Gemcitabine (dFdC) are cytidine analogs used in treating cancers.
- Similar mechanisms of action involve incorporation into DNA, disrupting DNA synthesis, affecting DNA polymerase or affecting active enzymes, resulting in cell death.
- Patient differences in sensitivity can occur, influencing treatment responses.
Clinical Resistance to AraC
- Reduced uptake via nucleoside transporters.
- Increased activity of cytidine deaminase.
- Decreased activity of dCK (deoxycytidine kinase).
- Changes in DNA polymerase activity may also contribute.
Cytarabine (araC)
- Used for Acute Myeloid Leukemia (AML).
- Long intravenous infusions (5-10 days).
- Rapid deamination and clearance.
- Myelosuppression (bone marrow toxicity) is a common effect.
Gemcitabine (dFdC)
- Similar pathway activation to cytarabine (Incorporating dFdCTP into DNA).
- Inhibition of DNA polymerization
- Irreversible inhibition of ribonucleotide reductase.
- Active in various solid tumors (pancreas, lung, breast).
- Myelosuppression is a possible side effect (bone marrow toxicity)
Purine Analogues (Fludarabine)
- Fludarabine is a purine analog used mainly in chronic lymphocytic leukemia (CLL).
- Inhibits various DNA and RNA enzymes.
- Effective against actively and passively dividing cells.
- Prolonged immunosuppression is also a potential side effect.
Pharmacogenomics of TPMT
- Genetic variations in TPMT (thiopurine methyltransferase) affect its activity, altering drug metabolism and leading to potential toxicities like myelosuppression.
- Increased susceptibility to toxicities due to metabolites from TPMT inhibition (drug accumulation).
- Genetic testing of TPMT can direct tailored treatment that accounts for individual variations affecting the drug's effectiveness and safety.
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Description
This lesson explores antimetabolite chemotherapy, focusing on drugs that mimic natural metabolites to disrupt DNA synthesis. It highlights Methotrexate (MTX), a folate analog, and its mechanism of action in inhibiting dihydrofolate reductase (DHFR), thereby blocking tetrahydrofolic acid (THF) and depleting dTMP.
