II' Antimetabolites

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II. Antimetabolites

• Def Compounds that prevent the biosynthesis or
  use of normal cellular metabolites
• Structural Analogues
• Metabolites or cofactors
• Inhibit Enzymes
• Combine with the active site
• Bind an allosteric regulatory site
• Incorporate into DNA
• Most are S-Phase specific
• Three Sub-Classes
• Purine Analogues 6-Mercaptopurine
• Folic Acid Analogues - Methotrexate
• Pyrimidine Analogues 5-Fluorouracil

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The Cell Cycle (flashback)
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Cell Cycle Specificity
Cell cycle specific
Cell cycle nonspecific
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De Novo Nucleotide Synthesis
Amido phosphoribosyl transferase
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De Novo Purine Synthesis
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De Novo Nucleotide Synthesis
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De Novo Pyrimidine Synthesis
Aspartate
Carbamoyl phosphate
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Purine/Pyrimidine Salvage
Ex Hypoxanthine Guanine phosphoribosyltransfera
se Adenine phosphoribosyltransferase Deficiencies
lead to disease states Lesch - Nyhan
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Purine Analogs

• Adenine, Guanine, and Hypoxanthine
• DNA/RNA synthesis
• Some are prodrugs!
• Act
• Inhibit synthesis (S-Phase)
• DNA/RNA
• Inhibit pyrimidine de novo synthesis
• Inhibits phosphoribosylamine formation
• Inhibit the salvage pathway
• Disrupt NA function

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Purine Analogs
Also known as 6-MP tablet dose
form Indications ALL, AML MOA competes with
hypoxanthine and guanine for the enzyme
hypoxanthine-guanine phosphoribosyltransferase -
leads to incorrect DNA synthesis false negative
feedback inhibitor Hepatic metabolism
S-methylation and oxidation by xanthine oxidase
-at higher doses hepatotoxicity Bone marrow
suppression - watch for neutropenia, drink plenty
of fluids
Also known a TG Indications Acute
nonlymphocytic leukemia MOA As above Forms
Thio-GTP Thio-dGTP Bone marrow suppression main
toxicity, monitor liver function Notify MD if
diarrhea, fever and weakness becomes pronounced
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6-Mercaptopurine

• Converted to ribonucleotide for activity
• Requires H-GPT
• Produces 6-thioinosinate (6-TI)
• Cells lacking H-GPT resistant
• 6-TI Inhibits phosphoribosylamine formation
• De novo synthesis
• Incorporated into RNA/DNA ? termination
• 6-TI acts as a substrate for methyltransferase
• Primarily the reason this is an antimetabolite
• Drug and metabolites interact with some 20
  enzymes tough to pin down!

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6-Mercaptopurine
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De Novo Nucleotide Synthesis
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6-Mercaptopurine Analog
6-Mercaptopurine
Azathioprine - Imuran

• Azathioprine
• Designed to limit effects from catabolic
  reaction of 6-MP
• Has antitumor activity, predominantly used for
  immune supression

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Purine Analogs
Also known as CdA or 2-chlorodeoxyadenosine Indica
tions Hairy cell leukemia (DOC) and other
cancers MOA converted to triphosphate
intracellularly and is 1. incorporated into
repaired ss-DNA fragments 2. into newly
synthesized DNA causing cell death Infusion
delivery, causes bone marrow suppression, fever,
nephrotoxicity and neurotoxicity. Active in
resting and proliferating cells! Indications
CLL and other off label cancers via continuous
infusion over 7 days MOA converted to
triphosphate inhibits DNA polymerase A,
ribonucleotide reductase and DNA primase stopping
DNA synthesis Clear dose-dependent toxicity
Bone marrow suppression, blindness, coma
death Excretion renally and corresponds to
creatinine clearance
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Remember this?
Indications acute keratoconjunctivitis,
recurrent epithelial keratitis, superficial
keratitis Ointment MOA Mechanism unknown but
appears to inhibit DNA synthesis Mutagen, notify
MD is symptoms have not improved in 7 days, do
not stop use without informing MD due to possible
resistance
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Flashback Antivirals
DNA Virus Agent
DNA Virus Opthalmic Agent
RNA Virus Agent
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Purine Analogs
Also known as DCF or 2-deoxycoformycin a
natural product from Streptomyces Indications
Adult patients with alpha-interferon refractory
hairy cell leukemia MOA potent transition-state
analog inhibitor of adenosine deaminase leading
to a buildup of deoxyATP which inhibits
ribonucleotide reductase Many adverse reactions
most serious bone marrow suppression and CNS,
renal, hepatic and pulmonary toxicity
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Role of Folic Acid
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Folic Acid Analogues
Indications Various cancers including acute
lymphocytic leukemia, breast cancers, cancers of
the head and neck, lung cancers control of
disabling psoriasis, rheumatoid arthritis
unlabeled uses non-metastatic
osteocarcinoma. MOA inhibition of dihydrofolate
reductase and thymidylate synthase (S-Phase) High
dose therapy Leucovorin rescue PO, IV, IT, IM
Produces bone marrow depression, hepatotoxicity
and DEATH, diarrhea, lung disease not reversible
- very nasty drug - inform patient of risks
involved Do not take with food, avoid alcohol,
salicylates and sun exposure, USE contraception,
inform MD of any signs of neutropenia, bleeding,
shortness of breath, yellow skin
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Almost Twins?
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Action of Methotrexate
Q What factors might cause Methotrexate
resistance?
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Folic Acid Analogues

• Also inhibit de novo purine synthesis

Remember this?
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Pyrimidine Analogs

• Cytosine, Thymine, Uracil
• DNA/RNA synthesis
• All are prodrugs!
• Act
• Inhibit synthesis
• Pyrimidines
• DNA/RNA
• Disrupt NA function

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Pyrimidine Analogs
Also called 5-FU or 5-fluroruracil Indications
Colon, breast, rectum, stomach, pancreas
carcinoma IV only use extreme care to avoid
extravasation MOA blocks the methylation of
deoxyuridylic acid to thymidylic acid, prevents
DNA synthesis suicide substrate Leucovorin can
increase the toxic effects of 5-FU Drink plenty
of fluids, transient alopecia may occur, USE
contraception, notify MD of signs of neutropenia,
liver failure or edema occur For all practical
purposes a prodrug of 5-FU Indications
Palliative treatment of GI carcinoma metastatic
to the liver using intra-arterial delivery
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5-FU Activation
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Action of 5-FU
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Thymidylate Synthetase
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5-FU ? suicide substrate
As fluorine is such a poor leaving group, the
intermediate formed cannot release the enzyme.
This produces an enzyme-substrate complex that
kills enzymatic activity.
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Action of 5-FU
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Pyrimidine Analogs
Also called ara-C Indications A cell-cycle
specific agent (G1 and S phase) used in leukemias
(AML) MOA Inhibits DNA-dependant polymerase,
causes miscoding chain terminator. Side effects
Chemical arachnoiditis (N/V, headache, fever can
be fatal if untreated) cytarabine syndrome
fever, myalgia, bone pain, chest pain, rash, N/V,
conjuctivitis Watch patients for neurotoxicity
signs, Stomatitis
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Pyrimidine Analogs
Indications pancreatic and non-small cell lung
cancer, some solid tumor activity (unlike
Ara-C) IV use only can be administered on an
outpatient basis MOA Cell specific agent
killing cells in S-phase by inhibiting
ribonucleotide reductase and produces termination
of DNA synthesis by competing with dCTP requires
phosphorylation! Principle side effects are
myelosuppression, paresthesias, and severe
rash Use caution in renal/hepatic failure no
studies conducted in these patients Indications
Metastatic breast cancer An oral systemic
prodrug that is converted into 5-FU Elderly
patients are more sensitive to 5-FU side
effectsuse caution in renal and hepatic
impairment Inform patients that if N/V or
diarrhea occur more than 4-6 times a day contact
MD may want to discontinue Inform patient of
hand-and-foot syndrome (painful swelling) or
stomatitiscontact MD important DI with
warfarinsignificant increase in prothrombin time
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Conversion to 5-FU