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Part 2: Antimetabolites
Dr. Abramson Handout
48
Pharmacology
Graduate
01/05/2011

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Cards

Term
The antimetabolites used to treat cancer have structures that are very similar to those of compounds involved in the biosynthesis of ______.
Definition
The 4 nucleic acids
Term
Name the 3 categories of antimetabolites...
Definition
antifolates, antipyrimidines, and antipurines
Term
Folic acid (pteroylglutamic acid), a member of the B-vitamin complex, is widely distributed in plants and is comprised of three components:
Definition
pteridine ring system, para-aminobenzoic acid (PABA), and glutamic acid
Term
The addition of glutamate residues (by either polyglutamation or polyglutamylation) increases what 2 things? 
Definition

1) molecular weight

2) overall negative charge of the molecule (which decreases efflux from the cell)

Term
Folic acid is activated in the cell by conversion to its dihydro- and tetrahydro- forms by sequential reduction by which enzyme?
Definition
Dihydrofolate reductase (DHFR)
Term
What antimetabolite drug class does methotrexate belong to?
Definition
Anti-folates
Term
What was the first anti-folate drug to demonstrate effectiveness in acute leukemias in 1948?
Definition
Aminopterin
Term
Methotrexate is a potent DHFR inhibitor. It produces an acute _______ _______ of folate coenzymes.
Definition
intracellular deficiency
Term
MTX's antiproliferative effects have been used in treating what other conditions (not cancer)?
Definition
Psoriasis and a number of inflammatory conditions (including RA)
Term
Name some cancers in which MTX is useful...
Definition

Breat cancer

Acute lymphocytic leukemia in CHILDREN

Choriocarcinoma in WOMEN

Osteogenic sarcoma

Term
MTX is considered a ____ ____ specific drug because it targets DNA/RNA synthesis during the __ phase of mitosis (the phase in which DNA synthesis is the highest).
Definition

cycle specific

S

Term
MTX also blocks the synthesis of the pyrimidine base thymidine by blocking which 2 enzymes?
Definition

DHFR

TS (thimidylate synthetase)

Term
High-dose methotrexate often is used with _____, also known as _____, citrovorum factor, or folinic acid to treat osteogenic sarcoma and acute leukemias.
Definition

N-formyltetrahydrofolate

leucovorin

Term
What is leucovorin rescue therapy?
Definition
It involves the administration of potentially lethal doses of MTX to block reduced folate synthesis in both normal and neoplastic cells. Subsequent administration of leucovorin selectively rescues the normal cells from the toxic effects of MTX while leaving the cancer cells to die. Leucovorin's ability to selectively rescue normal cells as opposed to tumor cells probably resides in its poor transportability into malignant cells
Term
Tumor cells acquire resistance to MTX through a variety of different mechanisms...
Definition

(1) Impaired transport of the drug into cells

(2) Production of altered forms of DHFR having decreased affinity for MTX.

(3) Increased concentrations of DHFR. Upon initial MTX exposures, DHFR appears to bind to its own mRNA and improve its translational efficiency. Longer exposures result in production of multiple copies of the DHFR gene (gene amplification).

(4) Decreased ability to synthesize MTX polyglutamates

(5) Decreased thymidylate synthetase activity.

Term
What drug is approved for the treatment of mesothelioma, a cancer caused by the exposure to asbestos?
Definition
Pemetrexed (Alimta)
Term
Major toxicity of pemetrexed is _______. Patients taking this drug should take ______ and ______ daily to reduce toxicity effects.
Definition

Myelosuppression

Folic acid and Vitamin B12

 

Term
What class of antimetabolites does pemetrexed belong to?
Definition
Anti-folates
Term
What class of antimetabolites does pralatrexate (Folotyn) belong to?
Definition
Anti-folates
Term
What type of cancer is pralatrexate used for?
Definition
Peripheral T-cell lymphoma
Term
Oldest drug of the pyrimidine antagonists drug class is...
Definition
5-fluorouracil (5-FU)
Term
5-FU is administered ________ mostly in combination chemotherapy for treatment of ______ and ______ cancers.
Definition

Parenterally

GI and breast

Term
Floxuridine (FUDR) is used primarily by _____ _____ into the hepatic artery for treatment of metastatic carcinoma of the _____.
Definition

continuous infusion

colon

Term
Capecitabine (Xeloda) is a prodrug of _____ and is used ______ for the treatment of _______ ______ cancer for patients who have not responded to other agents such as taxol or anthracyclines.
Definition

5-FU

orally

metastatic breast

Term
What antimetabolite drug class does capecitabine belong to?
Definition
pyrimidine antagonists
Term
Cytarabine (cytosine arabinoside, ARA-C) is used in which type of cancer treatment?
Definition
acute myelocytic leukemia
Term
Which antimetabolite drug class does cytarabine belong to?
Definition
pyrimidine antagonists
Term
Catalyzed by deoxycytidine kinase, ARA-C is activated by the conversion first to the _____________.
Definition
5'-monophosphate nucleotide (ARA-CMP)
Term
Gemcitabine (Gemzar) is administered by IV infusion and is used in treating which types of cancer?
Definition

Metastatic pancreatic cancer

Non-small cell lung cancer

Melanoma

Ovarian cancer

Term
Gemcitabine is a member of which antimetabolite drug class?
Definition
pyrimidine antagonists
Term
In the cell, gemcitabine is converted into its 5'-di- and tri-phosphates. The ___________ is a potent inhibitor of ribonucleotide reductase.
Definition
Di-phosphate
Term
This antimetabolite drug is considered the sulfur analog of hypoxanthine...
Definition
6-mercaptopurine (6-MP)
Term
6-MP is used orally as maintenance therapy in the treatment of which cancer?
Definition
acute lymphocytic leukemia
Term
This antimetabolite drug is considered the sulfur analog of guanine...
Definition
Thioguanine
Term
Thioguanine is used orally in the treatment of which cancer?
Definition
Acute granulocytic leukemia
Term
6-MP and thioguanine belong to which antimetabolite drug class?
Definition
purine antagonists
Term
Allopurinol (Zyloprim) blocks the conversion of 6-MP to 6-thiouric acid and the production of uric acid from hypoxanthine and xanthine. Allopurinol belongs to which drug class?
Definition
xanthine oxidase inhibitor
Term
Deficiency of this gene will cause severe toxicity with 6-MP administration.
Definition
thiopurine methyltransferase (TPMT)
Term
Pentostatin (Nipent) is a transition-state analog of the intermediate formed in the conversion of adenosine to inosine by which enzyme?
Definition
Adenosine deaminase (ADA)
Term
Pentostatin is used in the treatment of which type of cancer?
Definition
Hairy cell leukemia
Term
Pentostatin belong to which group of antimetabolites?
Definition
Purine antagonists
Term
This is the preffered drug for treatment of hairy cell leukemia and it is also effective in treating MS.
Definition
Cladribine (Leustatin)
Term
Fludarabine (Fludara) is a purine analog and is used in the treatment of which type of cancer?
Definition
Chronic lymphocytic leukemia
Term
Clofarabine (Clolar) is a purine antagonists approved for pediatric patients for relapsed or refractory __________, after at least 2 prior regimens.
Definition
acute lymphoblastic leukemia
Term
Nelarabine (Arranon) is a purine antagonist that is FDA approved for refractory or relapsed ____________ and __________ cancers that have not responded to 2 prior regimens.
Definition

T-cell acute lymphoblastic leukemia

T-cell lymphoblastic lymphoma

Term
_________ _________ is a key cellular enzyme that converts ribonucleotides to 2'-deoxyribonucleotides, a reaction vital for DNA synthesis.
Definition
ribonucleotide reductase
Term
Two well-established inhibitors of nucleotide reductase are...
Definition
gemcitabine and hydroxyurea
Term
Hydroxyurea can be used (orally) in a variety of conditions. 
Definition
chronic myelocytic leukemia, sickle cell disease, essential thrombocytosis
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