• Methotrexate
• Pemetrexed
• Pralatrexate

• Cell uptake via Reduced Folate Carrier (RFC)
• Polyglutamated inside cell -- traps drug in cell
• Inhibits Dihydrofolate Reductase (DHFR), the enzyme that converts Dihydrofolate to Tetrahydrofolate --> no dTMP is formed
• Also blocks formation of IMP (precursor to purine nucleotides)

• Polyglutamated in cells
• Inhibits DHFR
• Inhibits thymidylate synthase, which results in less dTMP and dTTP

• Less transport into cells
• Decrease drug target affinity
• Less polyglutamated-drug production
• More drug efflux
• Increased DHFR production, attributed to multiple gene copies

• Bone marrow suppression
• GI side effects
• Acute and chronic liver toxicity
• Pulmonary and renal toxicity
• Skin (TEN, SJS)
• Accumulation in "third space" cavities

Leucovorin

Enters folate cycle independent of DHFR

• Thioguanine
• Mercaptopurine
• Cladribine
• Fludarabine phosphate
• Pentostatin

• After ribosylation and phosphorylation (becomes thioGMP), it inhibits IMPDH, the enzyme that converts IMP to XMP
• This results in less dGTP production needed for DNA synthesis
• ThioGMP can be further phosphorylated to thioGTP, which can be incorporated into DNA resulting in inhibition of DNA replication

• Prodrug that is converted to mercaptopurine --> this is done by reacting with sulfhydryl groups (ie glutathione)
• Mercaptopurine is then ribosylated and phosphorylated by the enzyme HGPRT to form T-IMP
• T-IMP inhibits the conversion of IMP to GMP and AMP
• T-IMP can be further phosphorylated to T-ITP which can be incorporated into DNA, causing DNA damage and interference with DNA replication

• Decreased production of HGPRT, which is needed for the conversion of thioguanine to thioGMP and mercaptopurine to T-IMP
• Decreased influx or increased efflux
• DNA damage response --> tumor cell has enhanced ability to repair damaged DNA or may not undergo apoptotic response to damaged DNA

• Bone marrow suppression
• Elevated hepatic transaminase enzymes
• Jaundice
• Veno-occlusion
• Mercaptopurine metabolized by xanthine oxidase -- allopurinol inhibits xanthine oxidase -- decrease dose of mercaptopurine if co-administering
• Some patients have gene polymorphisms in the Thiopurine methyltransferase gene, resulting in reduced activity of TPMT and less drug inactivation through methylation --> greater toxicity

• Resembles the transition state of the normal enzymatic reaction of Adenosine Deaminase (ADA) and has high affinity of ADA --> inhibits the shit out of ADA
• Inhibition of ADA causes intracellular accumulation of adenosine and deoxyadenosine --> increased adenosine and deoxyadenosine blocks ribonucleotide reductase and blocks adenosyl homocysteine hydrolase resulting in increased adenosyl homocysteine which is toxic to lymphocytes
• Pentostatin triphosphoate can be incorporated into DNA

• Converted to triphosphate form by action of deoxycytidine kinase
• The triphosphate form inhibits ribonucleotide reductase and is incorporated into DNA, causing DNA strand breaks
• Competes with endogenous nucleotides for DNA polymerase
• Deaminase resistant

• Dephosphorylated and transported into cells where it is converted to its triphosphate form by deoxycytidine kinase
• Incorporated into DNA and RNA causing chain termination or strand breakage
• Competes with endogenous nucleotides for DNA polymerase
• Deaminase resistant

• Myelosuppression
• Depletion of CD4 cells --> high risk of opportunistic infection

• Fluorouracil
• Floxuridine
• Capecitabine
• Cytarabine
• Gemcitabine HCl

• 5-FU is converted to 5-fluorodeoxyuridine (Floxuridine) by ribosylation, which is then converted to fluorodeoxyuridine monophosphate (FdUMP)
• FdUMP blocks formation of dTMP (and thus dTTP) by inhibiting thymidylate synthase
• FdUMP can be converted to its triphosphate form (FdUTP) which can be incorporated into both RNA and DNA --> consequence uncertain?

• The ribosylated form of 5-FU
• It is then converted to fluorodeoxyuridine monophosphate (FdUMP)
• FdUMP blocks formation of dTMP (and thus dTTP) by inhibiting thymidylate synthase
• FdUMP can be converted to its triphosphate form (FdUTP) which can be incorporated into both RNA and DNA --> consequence uncertain?

• Prodrug of fluorouracil
• Mechanism of action is same as 5-FU

• Loss of activating enzymes (uridine phosphorylase, uridine kinase, phosphoribosyl transferase)
• Gene amplification of thymidylate synthase
• Mutation of thymidylate synthase resulting in lower drug affinity

• Mucosal membrane ulcerations (stomatitis, esophagopharyngitis)
• Ulceration of GI --> severe diarrhea
• Hand-Foot Syndrome (AKA plantar erythrodysesthesia syndrome)

• Analog of the nucleoside cytidine
• Arabinose sugar instead of ribose
• Converted to triphosphate form and incorporated into DNA --> stops strand elongation --> thought to result from formation of a stable tri-complex consisting of polymerase, drug, and DNA

• Analog of the nucleoside cytidine
• Converted to triphosphate form and incorporated into DNA and RNA
• After incorporation, it inhibits methylation of cytosine which alters gene expression and promotes cell differentiation

• Loss of activation of enzymes
• High expression of cytosine deaminase

• Lymphomatous Meningitis (infiltration of malignant cells)
• Liposome formulation provides sustained release of cytarabine