The topological state of cellular DNA is intimately connected
with its function. Without topoisomerases, cells
cannot replicate or package their DNA, or express their
genes—and they die. Inhibitors of topoisomerases have
therefore become important pharmaceutical agents, targeted
at infectious agents and malignant cells.
Two classes of bacterial topoisomerase inhibitors
have been developed as antibiotics. The coumarins, including
novobiocin and coumermycin A1, are natural
products derived from Streptomyces species. They inhibit
the ATP binding of the bacterial type II topoisomerases,
DNA gyrase and topoisomerase IV. These
antibiotics are not often used to treat infections in

humans, but research continues to identify clinically effective variants.

The quinolone antibiotics, also inhibitors of bacterial
DNA gyrase and topoisomerase IV, first appeared in
1962 with the introduction of nalidixic acid. This compound
had limited effectiveness and is no longer used
clinically in the United States, but the continued development
of this class of drugs eventually led to the
introduction of the fluoroquinolones, exemplified by
ciprofloxacin (Cipro). The quinolones act by blocking
the last step of the topoisomerase reaction, the resealing
of the DNA strand breaks. Ciprofloxacin is a widespectrum

antibiotic. It is one of the few antibiotics  reliably effective in treating anthrax infections, and is
considered a valuable agent in protection against possible
bioterrorism. Quinolones are selective for the bacterial
topoisomerases, inhibiting the eukaryotic enzymes
only at concentrations several orders of magnitude
greater than the therapeutic doses.
Some of the most important chemotherapeutic
agents used in cancer treatment are inhibitors of
human topoisomerases. Topoisomerases are generally present at elevated levels in tumor cells, and agents targeted
to these enzymes are much more toxic to the
tumors than to most other tissue types. Inhibitors of both
type I and type II topoisomerases have been developed
as anticancer drugs. 

                                    Fig: Topotecan
Camptothecin, isolated from a Chinese ornamental
tree and first tested clinically in the 1970s, is an inhibitor
of eukaryotic type I topoisomerases. Clinical trials indicated  limited effectiveness, despite its early promise in
preclinical work on mice. However, two effective derivatives,
irinotecan (Campto) and topotecan (Hycamtin)—
used to treat colorectal cancer and ovarian cancer,
respectively—were developed in the 1990s. Additional
derivatives are likely to be approved for clinical use in
the coming years. All of these drugs act by trapping the
topoisomerase-DNA complex in which the DNA is
cleaved, inhibiting religation.
The human type II topoisomerases are targeted by a
variety of antitumor drugs, including doxorubicin (Adriamycin),
etoposide (Etopophos), and ellipticine. Doxorubicin,
effective against several kinds of human
tumors, is an anthracycline in clinical use. Most of
these drugs stabilize the covalent topoisomerase-DNA
(cleaved) complex.
All of these anticancer agents generally increase the
levels of DNA damage in the targeted, rapidly growing
tumor cells. However, noncancerous tissues can also be
affected, leading to a more general toxicity and unpleasant
side effects that must be managed during therapy.
As cancer therapies become more effective and survival
statistics for cancer patients improve, the independent
appearance of new tumors is becoming a greater problem.
In the continuing search for new cancer therapies,
the topoisomerases are likely to remain prominent targets

for research.

                                                   Fig: structure of doxorubicin

                                                Fig: Structure Of Etoposide
                                          Fig: Structure Of Ellipticine

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