Antineoplastic therapy - Antimetabolites Flashcards
Name the folic acid analogs
Methotrexate
Trimetrexate
Pemetrexed
Pralatrexate (T cell lymphoma)
Name the pyrimidine analogs
5-Fluorouracil Floxuridine Capecitabine 5-Azacitidine Cytarabine
Name the purine analogs
Mercaptopurine Fludarabine Cladribine Thioguanine Pentostatin Clofarabine Nelarabine
Describe antimetabolites as a whole group
All are structural analogs of naturally occurring bases or intermediates
They inhibit enzymes or substitute for naturally occurring purines/pyrimidines
They have cytotoxic effects during S phase and impaired nucleotide synthesis in G1
What causes resistance in antimetabolites?
Gene amplification of enzymes that are inhibited
Production of target enzymes with less affinity for the drug
Which drug produced the first (temporary) remission of Leukemia?
Methotrexate
Which drug produced the first cure of a solid tumor?
Methotrexate
Besides cancer, what else is Methotrexate used for?
Immunosuppressant in rheumatoid arthritis, lupus, and transplants
It inhibits cell-mediated immune reactions, so you use low doses in the things listed above
What is the MOA of Methotrexate?
It is an analog for folic acid so it competes for dihydrofolate reductase, which is an enzyme that converts dihydrofolate to tetrahydrofolate
This reaction is responsible for the transfer of carbon groups in synthesis of THYMIDINE, CYSTEINE, and METHIONINE
Describe the pharmacokinetics of Methotrexate
It is actively transported into the cell (cancer cells more than normal cells!)
MTX is reduced in the cells to trap them (polyglutamate synthetase adds glutamyl residues)
Pralatrexate and pemetrexed the residues are added faster to lock into the cell
Does Methotrexate have a rescue
Yes - Leucovorin rescue
Leucovorin is converted into N5N10-methylene-FH4 in normal cells (ie bone marrow, kidney) to reduce the side effects
How is Methotrexate administered?
Oral, IV
Indications for Methotrexate
ALL in children (limited value in adults)
Choriocarcinoma, breast, head and neck, bladder, trophoblastic tumor in women, osteosarcoma, CNS lymphomas
Adverse effects of Methotrexate?
GI and oral epithelial ulceration (sores in mouth)
Bone marrow suppression
Nausea, vomiting, diarrhea, hepatotoxicity, alopecia
Teratogenic!!! It’s been used with Misoprostol as abortifacient
Must monitor renal function bc it is actively secreted into the proximal tubule
MULTIPLE BLACK BOX WARNINGS: Hepatic disease, pregnancy, pulmonary disease, infections (bc suppresses immune system)
Describe the MOA of Pemetrexed
Converted to poly-glutamated form, rapidly transported, inhibits BOTH thymidylate synthase and dihydrofolate reductase
Indications for Pemetrexed
It has activity against mesothelioma, non-small cell lung cancer
It’s better than methotrexate in colon cancer
Toxicities for Pemetrexed
Similar to MTX
Rash in 40% of patients, skin reactions
SEVERE bone marrow suppression, GI
Neuropathy
Describe the structure of 5-Fluorouracil
Uracil with a fluorine in position 5 of the uracil ring
It is attached to ribose/deoxyribose to form fdUMP
Precursor to thymidine!
Describe the structure of Cytarabine
Cytosine analog in which natural ribose is replaced by D-arabinose
How do pyrimidine analogs work?
They are activated by tumor cell enzymes, decrease the activity of DNA polymerase (?) and are incorporated into DNA
Describe the MOA of 5-fluorouracil
5-FU is attached to ribose/deoxyribose to form fdUMP
fdUMP competes with dUMP to inhibit thymidine synthetase, reducing thymidine production for DNA synthesis and RNA synthesis.
Does 5-fluorouracil have a rescue?
NO.
Leucovorin POTENTIATES toxicity of 5-FU in cancer cells lacking tetrahydrofolate
How is 5-fluorouracil administered?
IV and Topical
Short half life
Infused over 5 days to get cells in S phase bc it is cell cycle specific
Indications for 5-fluorouracil?
Slow growing, solid tumors (breast, stomach, esophageal, pancreas, head, and neck)
Topical - premalignant skin lesions
What is Floxuridine?
FUdR (FU + deoxyribose)
Given via hepatic artery infusion
Used for metastatic colon carcinoma in the liver, liver cancer
What is Capecitabine?
Prodrug of FUdR - used for non responsive metastatic breast cancer, metastatic colorectal cancer
Toxicities of 5-Fluorouracil?
Nausea, vomiting, diarrhea Myelosuppression Alopecia Mucosal damage (oral and GI) Hepatotoxicity Hand-food syndrome (pain and sensitivity in palms and soles, more frequently with Capecitabine and Floxuridine tho)
What is Cytarabine?
Cytosine plus D-arabinose sugar
What is the MOA of Cytarabine?
Inhibits DNA polymerase, you have unbalanced growth (one strand is affected, the other isn’t) - so it’s cytotoxic
It’s incorporated into the DNA and the arabinose sugar inhibits elongation
How is Cytarabine administered?
IV over 5-7 days to phase cell cycle
Indications of Cytarabine?
Acute myelogenous leukemia (most effective)
Also chronic myelogenous leukemia, acute lymphocytic leukemia, meningeal leukemia, and non-Hodgkin’s lymphoma
Toxicities of Cytarabine?
Moderate nausea, vomiting, diarrhea, stomatitis
CEREBELLAR TOXICITY (ataxia, seizures, slurred speech) after intrathecal administration
Potent myelosuppression
Oral and GI ulcerations, hepatotoxicity
Dyspnea, fever, pulmonary fibrosis
What is Gemcitabine?
Difluoroanalogue of cytidine incorporated into DNA, terminates the strand and increases apoptosis
NOT S PHASE SPECIFIC!!!!!
How is Gemcitabine administered?
IV on days 1, 8, and 15 of a 28 day cycle
Indications for gemcitabine?
Metastatic pancreatic, lung, ovarian, bladder cancer
Toxicities for gemcitabine?
Myelosuppression, hepatotoxicity, flu-like syndrome, potent radiation sensitizer, dyspnea
What is 6-mercaptopurine?
Thio analog of hypoxanthine, converted into nucleotides, inhibit DNA synthesis
What is Thioguanine?
Thio analog of guanine
What is Fludarabine?
Fluorinated adenosine arabinose, inhibtits DNA polymerase
What is Cladribine?
(2-chlorodeoxyadenosine)
Inhibits DNA polymerase
What is Clofarabine?
2 chloro 2 fluoroarabinosyladenine
Inhibits DNA polymerase
What is Nelarabine?
6-methoxy-arabinosyl guanine
Inhibits DNA polymerase
What is the MOA of 6-mercaptopurine?
6-MP is phosphorylated and added to sugar to form thio-IMP
It is a substrate for hypoxanthine-guanine phosphoribosyl transferase
It inhibits adenosine and xanthine formation
This prevents DNA synthesis, and can also be incorporated into RNA
How is 6-mercaptopurine administered?
Oral and IV
Indications for 6-mercaptopurine?
Acute lymphocytic leukemia (ALL)
Acute and chronic myelogenous leukemia (AML, CML)
How is 6-mercaptopurine metabolized?
P-450
Xanthine oxidase - purines into uric acid - hyperuricemia, hyperuricosuria
Does 6-mercaptopurine have a rescue?
Yes - allopurinol can be given to increase 6 MP levels and decrease uric acid levels
This can increase the drug concentrations without increasing the dose
Toxicities with 6-mercaptopurine?
Bone marrow suppression Hematological toxicity, bleeding Nausea, vomiting, anorexia Long term hepatotoxicity Opportunistic infections
Indications for thioguanine?
Acute myoblastic and lymphoblastic leukemia (AML, ALL)
Toxicities for thioguanine?
Hematological suppression
Bleeding
GI effects
MOA for Fludarabine?
It’s incorporated into DNA, terminates the chain
Indications for Fludarabine?
Acute and chronic lymphocytic (ALL, CLL) lymphomas
Nausea, vomiting, myelosuppression
Indications for Cladiribine?
Hairy cell leukemia
CLL
Toxicities for Cladiribine?
Nausea
Vomiting
Infections myelosuppression
Indications for Clofarabine?
Pediatric ALL after 2 previous failed treatments
Pediatric and adult AML
Toxicities with Clofarabine?
Bone marrow suppression, hypotension, capillary leak syndrome
Indications for Nelarabine?
T-cell leukemia and T-cell malignancies
Toxicities for Nelarabine?
Myelosuppression
Abnormal liver function tests
Seizures, delirium, peripheral neuropathy
