are unique to retroviruses and they are also tolerant to a wide range of nucleoside triphosphate analogues,
which identifies them as targets for chemotherapy (Section 3.7.2).
3.6.2 RNA Polymerases
DNA is transcribed into RNA by RNA polymerases (Sections 6.6.2 and 10.7.2). Several antibiotics are
highly potent inhibitors of transcription. Actinomycin Dis an intercalator that binds tightly and selectively
inhibits ribosomal RNA chain elongation. In contrast, rifampicin interacts directly with one of the subunits
of RNA polymerase and inhibits initiation of RNA synthesis. Cis-Diamminedichloroplatinum (II) (cisplatin)
has strong anti-tumour activity. It cross links two adjacent guanines present in the same DNA strand at their
N-7 positions and interferes with transcription (Section 6.6).
Some viruses encode their own RNA-dependent RNA polymerase. These are also potential targets for
chemotherapy, as these enzymes are generally specific for viral RNA. For example, 2-C-methylnucleo-
side derivatives are terminators of hepatitis C virus (HCV) RNA polymerase and are in clinical trials for
HCV treatment.
3.7 Therapeutic Applications of Nucleoside Analogues
At the beginning of the twenty first century, all countries faced the scourges of cancer and of many viral and
parasitic diseases. Nucleoside analogues form a substantial core of the clinician’s armoury against viral infec-
tions and cancer. In the remainder of this chapter we will examine the modes of action of these compounds and
also some important non-nucleoside drugs, and assess rational design for anti-cancer and anti-viral therapy.
In the anti-cancer field, our knowledge of metabolic differences between normal and cancer cells is grow-
ing, particularly for those proteins that are altered in pattern of regulation during oncogenesis. We also have
a better understanding of chromosomal translocations that cause cancers. This is encouraging the develop-
ment of chemical agents that specifically target cancer cells and, for example, trigger apoptosis (programmed
cell death).
Anti-viral chemotherapy has made particularly good progress in the past decade and there are now over
twice the number of new anti-viral agents in the clinic since the publication of the second edition of this book.
The need for viable anti-cancer and anti-viral chemotherapy is huge and will remain so for some time, not least
because of the limitations in the use of anti-viral vaccines. We can take advantage of the understanding of
the metabolic pathways of normal, virus-infected and cancer cells gained earlier in this chapter to study
the role of many anti-cancer and anti-viral drugs.
3.7.1 Anti-Cancer Chemotherapy
Most anti-cancer drugs act by inhibiting DNA synthesis in some way. They exhibit a greater toxicity for
faster growing tissues such as bone marrow, gastrointestinal epithelium, hair follicles and gonadal tissue.
Many of these drugs cause nausea and vomiting – especially a problem with the alkylating agents and cis-
platin. The majority of drugs target DNA directly: many antibiotics form physical complexes that inhibit
polymerases and topoisomerases (Section 9.10.2), or generate covalent interactions with DNA and RNA
(Section 8.7) or a combination of both of these activities. Some drugs are alkylating agents that react cova-
lently with DNA (Section 8.10). The antimetabolites are an important class of agents designed to impede
the supply of monomers for DNA biosynthesis and so arrest cell division. Finally, several alkaloid drugs
act by interfering with the cell cycle – as for example with the formation of tubulin or topoisomerases. The
use of combinations of these different types of drug in cancer chemotherapy has been a major advance in
this field and offers several important advantages.
● Decreased incidence of resistance
● A greater than additive or synergistic effect of the drugs
● Use of drugs with different types of toxic effects reduces overall toxicity or at least the toxicity to
any one system.Nucleosides and Nucleotides 125