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Chapter 45: Cancer Chemotherapy and Cytotoxic Agents

A nucleoside analog that is enzymatically converted by deoxycytidine kinase (dCK) to its active form, the 5′-monophosphate ribonucleotide is

a. leucovorin.

b. 5-fluorouracil (5-FU).

c. azacytidine.

d. gemcitabine.

e. cytarabine (Ara-C).

Answer is e. Cytarabine (1-β-D-arabinofuranosylcytosine; Ara-C) is the most important antimetabolite used in the therapy of acute myelocytic leukemia (AML). Ara-C is an analog of 2′-deoxycytidine with the 2′-hydroxyl in a position that hinders rotation of the pyrimidine base around the nucleoside bond and interferes with base pairing. The drug enters cells via a nucleoside transporter and is converted to its active form, the 5′-monophosphate ribonucleotide (Ara-CMP), by dCK. Polymorphisms of dCK may influence the rate of drug activation in individual patients.

Ara-CMP reacts with appropriate deoxynucleotide kinases to form diphosphate and triphosphates (Ara-CDP and Ara-CTP). Ara-CTP competes with the physiological substrate deoxycytidine 5′-triphosphate (dCTP) for incorporation into DNA by DNA polymerases. The incorporated Ara-CMP residue is a potent inhibitor of DNA polymerase, both in replication and repair synthesis, and blocks the further elongation of the nascent DNA molecule. The block in elongation activates checkpoint kinases (ATR and chk-1), which initiate attempts to remove the offending nucleotide. If DNA breaks are not repaired, apoptosis ensues.

When administered prior to 5-FU, this agent enhances the activation of and antitumor activity by increasing pools of PRPP.

a. Leucovorin

b. Oxaliplatin

c. Methotrexate

d. Cytarabine (Ara-C)

e. Fluxuridine

Answer is c. A number of agents have been combined with 5-FU in attempts to enhance cytotoxic activity through biochemical modulation. Methotrexate, by inhibiting purine synthesis and increasing cellular pools of PRPP (see Figure 45-6), enhances the activation of 5-FU (see Figure 45-7), and increases antitumor activity of 5-FU when given prior to but not following 5-FU.


Figure 45-6. Sites of action of methotrexate and its polyglutamates. AICAR, aminoimidazole carboxamide; dUMP, deoxyuridine monophosphate; FH2Glun, dihydrofolate polyglutamate; FH4Glun, tetrahydrofolate polyglutamate; GAR, glycinamide ribonucleotide; IMP, inosine monophosphate; PRPP, 5-phosphoribosyl-1-pyrophosphate; TMP, thymidine monophosphate.


Figure 45-7. Activation pathways for 5-fluorouracil (5-FU) and 5-floxuridine (FUR). FdUDP, fluorodeoxyuridine diphosphate; FdUMP, fluorodeoxyuridine monophosphate; FdUTP, fluorodeoxyuridine triphosphate; FUDP, floxuridine diphosphate; FUdR, fluorodeoxyuridine; FUMP, floxuridine monophosphate; FUTP, floxuridine triphosphate; PRPP, 5-phosphoribosyl-1-pyrophosphate.

Some malignant cells appear to have insufficient concentrations of N5,10 methylene tetrahydrofolate, and thus cannot form maximal levels ...

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