Nucleic Acids in Chemistry and Biology

Although aminopterin was the first clinically useful folate, methotrexate was soon introduced in therapy
and it has become the major folate used in cancer therapy (Figure 3.87).
Folic acid is an essential growth factor that leads to a series of tetrahydrofolate cofactors that provide
one-carbon groups for the synthesis of RNA and DNA precursors, such as thymidylate and purines. Folic
acid is reduced in two successive steps by DHFR using NADPH to give tetrahydrofolate, which is the
active form. Thus, the enzyme DHFR is the primary site of action of most folate analogues such as
methotrexate. Methotrexate has a high affinity for the tumor cell DHFR and so blocks the formation of
tetrahydrofolate needed for thymidylate and purine biosynthesis. Cell death probably results from inhib-
ition of DNA synthesis. Methotrexate is only partially selective for tumour cells and is toxic to all rapidly
dividing normal cells, such as those of the gastrointestinal epithelium and bone marrow.

3.7.1.2 Alkylating Agents

3.7.1.2.1 Cyclophosphamide. Many anti-cancer alkylating agents are both mutagenic and car-

cinogenic, but are used in chemotherapy under controlled circumstances.^125 One example, cisplatin, is thought
to cross link DNA (Section 8.5.4) though its selectivity for tumour cells is not understood. Cyclophosphamide
is a masked nitrogen mustard and is one of the clinically most useful drugs. It can be administered orally or
parenterally. It is thought to cross-link DNA and interferes with replication. Cyclophosphamide was ori-
ginally designed to be preferentially activated in tumour tissues, as they were believed to contain elevated
levels of phosphatases. It is now known that this does not happen, but the drug does undergo metabolic
activation in the liver catalysed by cytochrome P-450 microsomal enzymes. The nitrogen mustard metabolite
formed is active as a cytotoxic agent while a second metabolic product, acraldehyde, is believed respon-
sible for cystitis, a side effect caused by cyclophosphamide. Ifosphamide, a structural analogue of cyclophos-
phamide,is also metabolized by the cytochrome P-450 system and undergoes transformations similar to
those for cyclophosphamide. However, a smaller proportion of ifosphamide is converted into undesirable
products and thus larger doses can be used clinically as compared to cyclophosphamide (Figure 3.88).

128 Chapter 3

O

O

N

O

N

N

NH 2

N

H 2 N N N

O

O

R

H

R = H, aminopterin

R = CH 3 , methotrexate

Figure 3.87 Folic acid analogues

O

P

N

O

X

H

O

P

N

O

X

H OH

O

P

HN

O

X

OOH

O

P

N

O

X

H O

N

CHCHCl

CHCHCl

O

P

NH

O

X

O

P

HN

O

X

O

O

O P

N Cl

O

NH Cl

enzymaticoxidation spontaneous

cleavage

+

phosphoramide

mustard

enzymatic

oxidation

cyclophosphamide

enzymatic

oxidation

acraldehyde

X =

Ifosphamide

Figure 3.88 Metabolic activation and deactivation of cyclophosphamide. Structure of Ifosphamide

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