Anti-Tumor Antibiotics

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Transcript
00:00Alright, so we know that antibiotics kill microbes, but a certain class of antibiotics
00:05called antitumor antibiotics can kill cancer too.
00:10Antitumor antibiotics include products that are produced from Streptomyces bacteria like
00:14bleomycin, anthracyclines like doxorubicin and donorubicin, and dactomycin, also called
00:20actinomycin D. These medications interfere with DNA replication and often damage the
00:26DNA itself, leading to cell death.
00:29Most of them are cell cycle nonspecific.
00:32Now, the cell cycle refers to the events that somatic cells go through in order to divide
00:37into two identical daughter cells.
00:40The cell cycle can be divided into two phases, interphase and mitosis.
00:45Interphase starts with the G1 phase during which the cell grows and performs its cell
00:49functions.
00:50At the end of G1, there's a control point called the G1 checkpoint, where the cell checks
00:55to see if the DNA is damaged and it synthesized the right proteins in the correct amount.
01:00If there's any reason for the cell not to divide, the cell can either enter a non-dividing
01:03state called the G0 phase, where the DNA repair mechanisms try to fix the problem, or the
01:09cell can self-destruct in a process called apoptosis.
01:12Now, if the cell does get the go-ahead at the G1 checkpoint, it enters the S phase during
01:19which DNA is replicated.
01:21Alright, so during DNA replication, we unzip the double helix with the enzyme DNA helicase,
01:27and this creates a replication fork, with the two prongs of the fork being the two strands
01:31that are separated from one another.
01:33Now, as DNA helicase does its thing, the segments of DNA ahead of it start to overwind, meaning
01:39the double helix becomes more tightly wound.
01:42Overwinding of the DNA can slow down replication, so the enzyme DNA topoisomerase works ahead
01:48of DNA helicase to loosen up the tight DNA coils.
01:51Next, RNA primase creates a matching RNA primer on one prong of the replication fork.
01:57This is the area where the next enzyme, DNA polymerase, can bind to the DNA to use it
02:01as a template and start adding nucleotides that's complementary to the DNA onto the
02:06end of the primer.
02:07Eventually, we get a completed complementary copy of the DNA.
02:13Next is the G2 phase, during which the cell grows again before entering mitosis.
02:17However, before it can do that, it must pass the final G2 checkpoint to make sure there's
02:22no DNA damage after replication.
02:25Now during mitosis, the replicated DNA divides equally for the two daughter cells, and the
02:30cell cycle ends with cytokinesis, which is when the cell membrane actually divides to
02:34form the two new cells.
02:36Alright, now the cancer cells are also going to go through the phases of the cell cycle,
02:40but they undergo this process much more frequently and without checking for errors.
02:44Therefore, cancer cells are more sensitive to DNA damage from cytotoxic medications like
02:49the antitumor antibiotics.
02:51There are also normal tissues that divide rapidly like bone marrow and hair follicles,
02:56and they're also more susceptible to damage, which explains why cytotoxic medications are
03:00more toxic to these tissues.
03:02Alright, let's start with bleomycin, which is the peptide that has an iron binding site
03:07on one end and a DNA binding site on the other end.
03:11Bleomycin binds to the DNA strand and in the presence of oxygen, it becomes activated and
03:15acts as an oxidase, which means that it transfers electrons from the iron to the oxygen molecule,
03:21generating free oxygen radicals.
03:23These oxygen radicals oxidize DNA bases, causing breaks in the DNA strand.
03:29Note that bleomycin is a cell cycle-specific medication that is mostly effective in the
03:33G2 phase.
03:36Bleomycin plays an important role in the treatment of Hodgkin's lymphoma and testicular cancer,
03:40but it's also used to treat squamous cell carcinoma of the skin.
03:44Now, bleomycin is inactivated by an enzyme in our body called hydrolase, but tissues
03:49like lungs and skin have lower levels of this enzyme, so bleomycin becomes toxic.
03:55As a result, a super important side effect of bleomycin is pulmonary toxicity, which
03:59usually presents as pneumonitis, but can turn into life-threatening pulmonary fibrosis.
04:05Skin toxicity presents with rash, exfoliation, and hyperpigmentation or darkening of the
04:10skin.
04:12Bleomycin is also associated with mucous membrane toxicity, which manifests as stomatitis and
04:17mucositis in the mouth, and alopecia or loss of hair.
04:21What's special with bleomycin is that it only causes minimal myelosuppression, which
04:26is unusual for an anti-cancer medication.
04:30Now let's move on to dactinomycin or actinomycin D. Dactinomycin is a peptide that in
04:35intercalates into the DNA molecule, which means that it inserts itself between the normal
04:40base pairs.
04:41As a result, RNA and DNA polymerase cannot bind to DNA, so RNA and DNA synthesis comes
04:47to a halt.
04:48In addition, dactinomycin can also generate free radicals like bleomycin and cause breaks
04:53in the DNA strand.
04:55Note that dactinomycin is cell cycle nonspecific, meaning they act on tumor cells during all
05:00phases of the cell cycle, including the resting G0 phase.
05:05Dactinomycin is used primarily in the treatment of pediatric tumors like nephroblastoma or
05:10Wilms tumor, rhabdomyosarcoma, which is a type of cancer that develops from skeletal
05:14muscle cells, and Ewing sarcoma, which is a malignant bone tumor.
05:19Also, dactinomycin is associated with significant myelosuppression and alopecia.
05:25Moving on to the anthracyclines, which include doxorubicin, donorubicin, idarubicin, and
05:31epirubicin.
05:33Anthracyclines are cell cycle nonspecific medications and act through various mechanisms.
05:37First, they intercalate with DNA, inserting themselves between base pairs and inhibiting
05:42RNA and DNA synthesis.
05:46Anthracyclines also inhibit topoisomerase too, and thus DNA will overwind during replication
05:51until it tears itself apart.
05:54In addition, anthracyclines also produce free oxygen radicals that damage the DNA strand,
05:59but they need to bind to iron found in the tissues to do so.
06:04Indications for anthracyclines include the treatment of solid tumors like breast, thyroid,
06:09lung, and ovarian cancers, but also leukemias and lymphomas.
06:13Now, an important side effect of these medications is cardiotoxicity due to the buildup of free
06:18radicals in the myocardium.
06:21Cardiotoxicity manifests as dilated cardiomyopathy that's lifetime dose-dependent and irreversible
06:27when it happens.
06:29But the good news is that cardiotoxicity can be prevented with dexrazoxane, which is an
06:34iron chelating agent that binds to iron in the myocardium and prevents the production
06:38of free oxygen radicals.
06:40Other side effects include myelosuppression and alopecia.
06:44Now let's make a simple and fun mnemonic that'll help you efficiently memorize these
06:47pharmacology facts about antitumor antibiotics.
06:50Alright, let's imagine that we're in a playground with a criss-crossing slide that
06:54looks like a DNA helix.
06:57Standing on the top of the slide, we have the anthracyclines like doxorubicin and donorubicin.
07:01They'll be represented by a little girl wearing a giant ruby necklace since they all
07:06end in rubicin.
07:08Now she's holding a balloon with O2 written on it because anthracyclines generate free
07:11oxygen radicals.
07:14Next she's got a large topaz ring for topoisomerase inhibition.
07:19And finally she's standing on the DNA slide because these drugs also intercalate DNA.
07:23Alright, going down the slide, we have an actor mouse who's dressed like Shakespeare,
07:28but he's got a large D on his clothing for dactinomycin, or actinomycin D. He's also
07:34holding a balloon with O2 on it because this drug also generates free oxygen radicals.
07:39Since he's also on the slide, he's a DNA intercalator too.
07:44Finally at the bottom of the slide, we have bleomycin, which is represented by a bleeding
07:48mouse who got injured on the slide.
07:50Like the other two, he's holding the free oxygen radical balloon, but since he's off
07:54the slide, he does not intercalate DNA.
07:57Okay, now that the mechanisms are out of the way, let's go over indications and side effects.
08:03For indications, let's use crabs to represent cancer, since in the zodiac, cancer is a giant
08:08crab.
08:09So on the top of the slide by the anthracyclines, there's a crab statue made of solid stone,
08:14since these medications treat solid tumors.
08:17Let's put a little bow tie that looks like a thyroid on the statue since these medications
08:20are good against thyroid cancer.
08:23Next the statue is holding a giant bone club with little crabs in the marrow, which represents
08:27leukemia.
08:28Finally, a crab is pinching a lymph node on the girl's neck for lymphoma.
08:32For side effects, let's give the Rubicin kid a heart-shaped balloon.
08:36This balloon is too full, and it looks like it's about to pop, which represents dilated
08:40cardiomyopathy.
08:42Tied to the string of the balloon is a broken bone for bone marrow suppression.
08:47Riding behind the Shakespeare mouse, there's a baby crab to help you remember this drug
08:50treats pediatric cancers.
08:52The baby crab is fighting an earwig to help you remember one of these pediatric cancers
08:56is Ewing's sarcoma.
08:58For side effects, let's have them fighting over a broken bone for bone marrow suppression.
09:03At the bottom of the slide, we have Bleomycin.
09:05This mouse's pet hedgehog, for Hodgkin's lymphoma, is checking to see if the bleeding
09:09mouse is okay, and it's wearing a jockstrap for testicular cancer.
09:13A little crab is pinching a tumor on the injured mouse's face, which represents skin cancers
09:18like squamous cell carcinoma.
09:20For side effects, a paramedic is at the scene to check up on the injured individuals.
09:25He put a spiderweb in the mouse's chest wound, which represents pulmonary fibrosis.
09:29He's been working outside too long and his face is very tan, which represents skin hyperpigmentation.
09:36Finally, he's wearing red lipstick on his big lips, which represents mucositis and stomatitis.
09:42Alright, as a quick recap, antitumor antibiotics are a class of medications that are produced
09:47by Streptomyces bacteria and are used in the treatment of cancer.
09:51They include Bleomycin, Dactinomycin, and anthracyclines like doxorubicin, donorubicin,
09:58idarubicin, and epirubicin.
10:01They interfere with the cell cycle through various mechanisms.
10:04They're all cell cycle nonspecific, except Bleomycin, which is cell cycle specific and
10:09acts in the G2 phase.
10:11Bleomycin is used for the treatment of Hodgkin's lymphoma and testicular cancer, and can cause
10:15pulmonary toxicity, but only minimal myelosuppression.
10:19Dactinomycin is used for the treatment of pediatric tumors and causes significant myelosuppression.
10:26Anthracyclines are widely used for the treatment of solid tumors, leukemias, and lymphomas,
10:31but side effects include myelosuppression and cardiotoxicity, which presents as irreversible
10:35dilated cardiomyopathy that can be prevented with dexrazoxane.
10:39A common side effect of all antitumor antibiotics is alopecia.
10:43But wait, there's more!
10:45Here's a mind map with all of the mnemonics.
10:48Go ahead and pause the video so you can test yourself to see what you remember, and stay
10:52tuned for the answers after the credits.