Chapter 7. 3. Anticancer Antibiotics

1

• Chapter 7. 3. Anticancer Antibiotics
• ??????

Anticancer antibiotics are drugs derived from
microbial sources.
2
Dactinomycin D, ????D (????)

3
Mechanism of action DNA intercalation

4
Anthracyclines, ???
Daunorubicin was isolated from Streptomyces
coeruleorubidus and S. peucetius. This
significant discovery was made independently in
France and Italy in 1963. The most important
member of the anthracycline, doxorubicin
(adriamycin) was isolated from S. peucetius var.
caesius in 1969 in Italy.

5
The history of doxorubicin can be traced back to
the 1950s, when an Italian research company,
Farmitalia Research Laboratories, began an
organized effort to find anticancer compounds
from soil-based microbes. Daunorubicin was found
first. Researchers at Farmitalia later
discovered A new strain of Streptomyces. This new
strain produced a different, red-colored
antibiotic. They named this new compound
Adriamycin, after the Adriatic Sea, and the name
was later changed to doxorubicin.

6
Doxorubicin Hydrochloride ?????

7
Mechanism of action Anthracyclines inhibit
DNA and RNA synthesis by intercalating between
base pairs of the DNA/RNA strand, thus preventing
the replication of rapidly-growing cancer cells.
They also create iron-mediated free oxygen
radicals that damage the DNA and cell membranes
which also cause toxic side-effects.

8

Cartoon diagram of two doxorubicin molecules
intercalating DNA
9
Clinical use Doxorubicin is one of the most
effective anticancer agents. It is effective for
the treatment of acute leukemias, Hodgkins
disease and other lymphomas, Wilms tumor,
neuroblastoma, sarcomas, breast carcinoma,
ovarian carcinoma, bladder carcinoma, and
etc. Major toxicity cardiotoxicity

10
Bleomycin, ???? (????)

11
Bleomycin is produced by the bacterium
Streptomyces verticillus. Bleomycin refers to a
family of structurally related compounds. When
used as an anti-cancer agent, the
chemotherapeutical forms are primarily bleomycin
A2 and B2. The drug is used in the treatment of
Hodgkin lymphoma, squamou cell carcinomas, and
testicular cancer, pleurodesis as well as plantar
warts. Bleomycin was first discovered in 1962
when the Japanese scientist Hamao Umezawa found
anti-cancer activity while screening culture
filtrates of S. verticullus. Umezawa published
his discovery in 1966. The drug was launched in
Japan by Nippon Kayaku in 1969. In the US
bleomycin gained Food and Drug Administration
(FDA) approval in July 1973. Bleomycin acts by
induction of DNA strand breaks. Some studies
suggest that bleomycin also inhibits
incorporation of thymidine into DNA strands. DNA
cleavage by bleomycin depends on oxygen and metal
ions, at least in vitro. It is believed that
bleomycin chelates metal ions (primarily iron)
producing a pseudoenzyme that reacts with oxygen
to produce superoxide and hydroxide free radicals
that cleave DNA.

12
DNA minor-groove binding drugs
ET-743 (Yondelis) is used for the treatment of
soft tissue sarcoma.

13

14

15

• Chapter 7. 4. Plant products
• ??????

16
Vinca Alkaloids and Their Analogues

17
Vinblastine (???) was first discovered when it
was crushed into a tea. Consumption of the tea
led to a decreased number of white blood cells
therefore, it was hypothesized that vinblastine
might be effective against cancers of the white
blood cells such as lymphoma. It is an
anti-mitotic drug used to treat certain kinds of
cancer, including Hodgkins lymphoma, non-small
cell lung cancer, breast cancer and testicular
cancer.

Vincristine ????
18

• Camptothecin
• ???

19

• CPT was isolated from a Chinese tree,
  Camptothecca acuminata in 1966 by Wall et al at
  the Southern Research Institute in the US. CPT
  is not used in clinic because of toxicity.
• 10-hydroxycamptothecin (HCPT) was also isolated
  from Camptothecca acuminata, and is used in China
  an an anticancer drug.

Camptothecin (CPT)
10-hydroxycamptothecin (HCPT)
20
Mechanism of action of CPTs
CPTs act by inhibiting topoisomerase I, an enzyme
which plays a key role in maintaining the
structure of DNA during translation,
transcription, and replication. Topoisomerase I
solves the problem caused by tension generated by
winding/unwinding of DNA. It wraps around DNA and
makes a cut permitting the helix to spin. Once
DNA is relaxed, topoisomerase reconnects broken
strands. When camptothecin binds to
topoisomerase I, it will be able to cleave but
not to religate DNA. Thereby, camptothecin causes
single strand breaks in DNA.

21
Irinotecan is mainly used for the treatment
of colon cancer, particularly in combination
with other chemotherapy agents. This includes the
regimen FOLFIRI which consists of infusional
5-fluorouracil, leucovorin, and irinotecan.
Irinotecan was first introduced in Japan by the
Pharmaceutical arm of Yakult Honsha as Campto.
In 1994, it received accelerated FDA approval in
the United States, where it is now marketed by
Pfizer as Camptosar. It is also known as CPT-11.
Major Toxicity Severe diarrhea, which
may happen in one out of four patients.
Topotecan (Hycamtin) is used to treat ovarian
cancer and lung cancer, as well as other cancer
types
22
Irinotecan is the first FDA-approved colorectal
cancer therapy in over 40 years. Irinotecan is a
prodrug, which is converted by carboxylate
esterases to SN-38 (7-ethyl-10-hydroxycamptothecin
), a metabolite that is a two-fold to 2,000-fold
more potent inhibitor of the nuclear enzyme
topoisomerase I than is the parent compound.
Activation of irinotecan