Anti-tumour antibiotics:

we know that antibiotics kill microbes, but a certain class of antibiotics called antitumor antibiotics
can kill cancer too. Antitumor antibiotics include products that are produced from Streptomyces
bacteria like: bleomycin; anthracyclines like doxorubicin and daunorubicin; and dactinomycin, also
called actinomycin D. These medications interfere with DNA replication and often damage the DNA
itself, leading to cell death. Most of them are cell cycle non-specific. Now, the cell cycle refers to the
events that somatic cells go through in order to divide into two identical daughter cells.

The cell cycle can be divided in two phases: interphase and mitosis. Interphase starts with the G1
phase during which the cell grows and performs its cell functions. At the end of G1, there’s a control
point called the G1 checkpoint - where the cell checks to see if the DNA is damaged and it
synthesized the right proteins in the correct amount. If there is any reason for the cell not to divide,
the cell can either enter a non-dividing state, called the G0 phase, where the DNA repair mechanisms
try to fix the problem, or the cell can self-destruct in a process called apoptosis.

Now, if the cell does get the go-ahead at the G1 checkpoint, it enters the S phase during which DNA
is replicated. All right, so during DNA replication, we unzip the double helix with the enzyme DNA
helicase, and this creates a replication fork, with the two prongs of the fork being the two strands
that are separated from one another. Now, as DNA helicase does its thing, the segments of DNA
ahead of it start to overwind, meaning, the double helix becomes more tightly wound. Overwinding
of the DNA can slow down replication, so the enzyme DNA topoisomerase works ahead of DNA
helicase to loosen up the tight DNA coils.

Next, RNA primase creates a matching RNA primer on one pron of the replication fork. This is the
area where the next enzyme, DNA polymerase, can bind to the DNA to use it as a template and start
adding nucleotides that’s complementary to the DNA onto the end of the primer. Eventually we get a
completed complementary copy of the DNA. Next is the G2 phase, during which the cell grows again
before entering mitosis. However, before it can do that, it must pass the final G2 checkpoint to make
sure there is no DNA damage after replication. Now, during mitosis, the replicated DNA divides
equally for the two daughter cells, and the cell cycle ends with cytokinesis, which is when the cell
membrane actually divides to form the two new cells.

All right, now the cancer cells are also going through the phases of the cell cycle, but they undergo
this process much more frequently and without checking for errors. Therefore, cancer cells are more
sensitive to DNA damage from cytotoxic medications like the antitumor antibiotics. There are also
normal tissues that divide rapidly like bone marrow and hair follicles, and they are also more
susceptible to damage, which explains why cytotoxic medications are more toxic to these tissues. All
right, let’s start with bleomycin, which is a peptide that has an iron binding site on one end and a
DNA binding site on the other end. Bleomycin binds to the DNA strand and in the presence of
oxygen, it becomes activated and acts as an oxidase, which means it transfers electrons from the iron
to the oxygen molecule, generating free oxygen radicals. These oxygen radicals oxidize DNA bases,
causing breaks in the DNA strand. Note that bleomycin is a cell cycle specific medication that is
mostly effective in the G2 phase.

Bleomycin plays an important role in the treatment of Hodgkin’s lymphoma and testicular cancer but
it’s also used to treat squamous cell carcinoma of the skin. Now, bleomycin is inactivated by an
enzyme in our body called hydrolase, but tissues like lungs and skin have lower levels of this enzyme,
so bleomycin becomes toxic. As a result, a super important side effect of bleomycin is pulmonary
toxicity, which usually presents as pneumonitis, but can turn into life-threatening pulmonary fibrosis.
Skin toxicity presents with rash, exfoliation, and hyperpigmentation or darkening of the skin.
Bleomycin is also associated with mucous membrane toxicity, which manifests as stomatitis and
mucositis in the mouth, and alopecia or loss of hair. What is special with bleomycin is that it only
causes minimal myelosuppression, which is unusual for an anticancer medication.

Now, let’s move on to dactinomycin or actinomycin D. Dactinomycin is a peptide that intercalates

into the DNA molecule, which means that it inserts itself between the normal base pairs. As a result,
RNA and DNA polymerase cannot bind to DNA, so RNA and DNA synthesis come to a halt. In
addition, dactinomycin can also generate free radicals like bleomycin, and cause breaks in the DNA
strand. Note that dactinomycin is cell cycle non-specific, meaning they act on tumor cells during all
phases of the cell cycle, including the resting G0 phase. Dactinomycin is used primarily in the
treatment of pediatric tumors like: nephroblastoma or Wilms tumor; rhabdomyosarcoma, which is a
type of cancer that develops from skeletal muscle cells; and Ewing sarcoma, which is a malignant
bone tumor. Also, dactinomycin is associated with significant myelosuppression and alopecia.

All right, moving on to anthracyclines which include doxorubicin, daunorubicin, idarubicin, and
epirubicin. Anthracyclines are cell-cycle non specific medications and act through various
mechanisms. First, they intercalate with DNA inserting themselves between base pairs and inhibiting
RNA and DNA synthesis. Anthracyclines also inhibit topoisomerase II and thus DNA will overwind
during replication until it tears itself apart. In addition, anthracyclines also produce free oxygen
radicals that damage the DNA strand, but they need to bind to iron found in the tissue to do so.
Indications for anthracyclines include the treatment of solid tumors like breast, thyroid, lung, and
ovarian cancers, but also leukemias and lymphomas. Now an important side effect of these
medications is cardiotoxicity due to the buildup of free radicals in the myocardium. Cardiotoxicity
manifests as dilated cardiomyopathy that is lifetime dose dependent and irreversible when it
happens. But the good news is that cardiotoxicity can be prevented with dexrazoxane, which is an
iron chelating agent that binds to iron in the myocardium and prevents the production of free oxygen
radicals. Other side effects include myelosuppression and alopecia.

Now, let’s make a simple and fun mnemonic that’ll help you efficiently memorize these
pharmacology facts about antitumor antibiotics. All right, let’s imagine we’re in a playground with a
crisscrossing slide that looks like a DNA helix. Standing on the top of the slide, we have the
anthracyclines like doxorubicin and daunorubicin. They will be represented by a little girl wearing a
giant ruby necklace since they all end in “rubicine.” Now, she’s holding a balloon with O2 written on
it because anthracyclines generate free oxygen radicals. Next, she’s got a large topaz ring for
topoisomerase inhibition. And finally, she’s standing on the DNA slide because these drugs also
intercalate DNA. All right, going down the slide, we have an actor mouse who’s dressed like
Shakespeare, but he’s got a large “D” on his clothing for dactinomycin, or actinomycin D. He’s also
holding a balloon with O2 on it because this drug also generates free oxygen radicals. Since he’s also
on the slide, he’s an DNA intercalator too! Finally at the bottom of the slide, we have bleomycin,
which is represented by a bleeding mouse who got injured on the slide. Like the other two, he’s
holding the free oxygen radical balloon, but since he’s off of the slide, he does not intercalate DNA.

Okay, now that the mechanisms are out of the way, let’s go over indications and side effects. For
indications, let’s use crabs to represent cancer, since in the zodiac, cancer is a giant crab. So on the
top of the slide by the anthracyclines, there’s a crab statue made of solid stone, since these
medications treat solid tumors. Let’s put a little bowtie that looks like a thyroid on the statue since
these medications are good against thyroid cancer. Next, the statue is holding a giant bone club with
little crabs in the marrow, which represents leukemia. Finally, a crab is pinching a lymph node on the
girl’s neck for lymphoma. For side effects, let’s give the rubicine kid a heart-shaped balloon. This
balloon is too full, and looks like it’s about to pop, which represents dilated cardiomyopathy. Tied to
the string of the balloon is a broken bone for bone marrow suppression. Okay moving on, next we
have dacinomycine in the middle of the slide. Riding behind the Shakespeare mouse, there’s a baby
crab to help you remember this drug treats pediatric cancers.

The baby crab is fighting an earwig to help you remember one of these pediatric cancers is Ewing’s
sarcoma. For side effects, let’s have them fighting over a broken bone for bone marrow suppression.
Okay, moving on. At the bottom of the slide we have bleomycin. This mouse’s pet hedgehog, for
Hodgkin’s lymphoma, is checking to see if the bleeding mouse is okay, and it’s wearing a jockstrap for
testicular cancer. A little crab is pinching a tumor on the injured mouse’s face, which represents skin
cancers like squamous cell carcinoma. For side effects, a paramedic is at the scene to check up on the
injured individuals. He put a spiderweb on the mouse’s chest wound, which represents pulmonary
fibrosis. He’s been working outside too long and his face is very tan, which represents skin
hyperpigmentation. Finally, he’s wearing red lipstick on his big lips, which represents mucositis and
stomatitis.

All right, as a quick recap…. Antitumor antibiotics are a class of medications that are produced by
Streptomyces bacteria and are used in the treatment of cancer. They include bleomycin,
dactinomycin, and anthracyclines like doxorubicin, daunorubicin, idarubicin, and epirubicin. They
interfere with the cell-cycle through various mechanisms. They are all cell-cycle non-specific, except
bleomycin which is cell-cycle specific and acts in the G2 phase. Bleomycin is used for the treatment
of Hodgkin’s lymphoma and testicular cancer and can cause pulmonary toxicity, but only minimal
myelosuppression. Dactinomycin is used for the treatment of pediatric tumors and causes significant
myelosuppression. Anthracyclines are widely used for the treatment of solid tumors, leukemias, and
lymphomas, but side effects include myelosuppression and cardiotoxicity, which presents as
irreversible dilated cardiomyopathy that can be prevented with dexrazoxane. A common side effect
of all antitumor antibiotics is alopecia.