DNA Alkylating medications || Anti-cancer Drugs
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00:00DNA alkylating medications are a class of drugs that are mainly used as anti-cancer
00:08agents.
00:09They disrupt the structure of DNA by adding an alkyl group to the guanine base and can
00:14affect all phases of the cell cycle.
00:16Alright, the cell cycle refers to all the events that somatic cells, which includes
00:21all the cells in our bodies except the reproductive cells, go through from the moment they're
00:25formed until the moment they divide into two identical daughter cells.
00:30This cycle varies in length depending on the type of cell.
00:33For rapidly dividing cells, like skin cells, it takes less than a day, whereas for other
00:38cells, like liver cells, the cell cycle can last years.
00:43Now the cell cycle can be divided into two phases, interphase and mitosis.
00:49Interphase comprises of the G1 phase, during which the cell grows and performs its cell
00:53functions.
00:54The S phase, during which DNA is replicated, and the G2 phase, during which the cell grows
00:59again before entering mitosis.
01:03Mitosis can be broken down into prophase, metaphase, anaphase, and telophase, during
01:08which the replicated DNA divides equally for the two daughter cells, and ends with cytokinesis,
01:13which is when the cell membrane actually divides to form the two new cells.
01:18There's also a G0 phase, which is an extended G1 phase, where the cell is resting and not
01:23actively preparing to divide.
01:26Alright now, imagine a cancer cell.
01:29This cell is going through the phases of the cell without regulation, and its DNA also
01:33replicates more frequently and with less error correcting than healthy cells.
01:37Therefore it's more sensitive to DNA damage.
01:41Here's a DNA base, guanine.
01:44Alkylating agents attach an alkyl group at the number 7 nitrogen atom of guanine.
01:49Now repair enzymes recognize that something's wrong, so they attempt to replace the alkylated
01:54bases and cause fragmentation of the DNA, or DNA strand breakage.
01:59When this section of the DNA is repaired, abnormal base pairing could result, like having
02:03a thymine paired up with a guanine instead of the usual cytosine.
02:07Eventually the DNA damage results in cell death.
02:12Now another mechanism by which alkylating agents cause DNA damage is the crosslinking
02:16of DNA.
02:17In this process, an alkylating agent has two DNA binding sites, causing two guanine bases
02:22to link together, forming a covalent bond and leading to the formation of cross bridges.
02:28Crosslinking prevents DNA from being separated for replication or transcription, again eventually
02:33resulting in cell death.
02:36DNA alkylating medications are cell cycle nonspecific agents, meaning they act on tumor
02:42cells during all phases of the cell cycle, including the resting G0 phase.
02:47Ok, let's start with nitrogen mustards, which include cyclophosphamide, meclorethamine,
02:53and diphosphamide.
02:55Nitrogen mustards are related to phosgene, the lethal mustard gas that was used during
02:59World War I, but it's also the first intravenous chemotherapy treatment for cancer.
03:04Alright, now these agents are prodrugs, meaning they are administered in an inactive form,
03:09which needs to be metabolized into an active form by the liver cytochrome P450 enzymes.
03:16Now moving on to the indications.
03:20Cyclophosphamide and diphosphamide can be used in various types of cancers.
03:24They're used against leukemias, which are a type of cancer that affects the cell in
03:27the bone marrow that eventually becomes white and red blood cells, and lymphomas, which
03:31are cancers of the immune cells in the lymph nodes.
03:35It can also treat other solid tumor cancers, like ovarian and breast cancer.
03:39Apart from the treatment of cancer, high doses of cyclophosphamide is immunoablative and
03:44can be used to treat small vessel vasculitis, like granulomatosis with polyangiitis, in
03:49microscopic polyangiitis, and also in polyangiitis nodosa, which is a medium vessel vasculitis.
03:56Finally, cyclophosphamide can be used for progressive or refractory cases of systemic
04:01lupus erythematosus, an autoimmune disease affecting multiple organs, and for multiple
04:06sclerosis, a demyelinating disease of the central nervous system.
04:13In terms of toxicity, all alkylating agents depress bone marrow function and can cause
04:17aplastic anemia.
04:19However, the most dangerous thing is the risk of developing leukemia or other malignancies
04:24after prolonged use.
04:25Other common toxicities with these medications include hair loss, gastrointestinal disturbances,
04:31and depression of gametogenesis, which can cause infertility.
04:35Finally, alkylating medications are teratogens, meaning that they disrupt fetal development
04:40and can lead to birth defects.
04:43Now nitrogen mustard specifically can cause syndrome of inappropriate antidiuretic hormone
04:48secretion, which can be shortened to SIADH.
04:51This is where an inappropriate presence of antidiuretic hormone causes water retention
04:56in uvulemic hyponatremia.
04:59Cyclophosphamide can also cause bladder cancer and hemorrhagic cystitis, which is very common.
05:04However, there's also good news.
05:07Hemorrhagic cystitis can be prevented by increasing fluid intake and administering compounds that
05:11are sulfhydryl donors, like mesna or sodium 2-mercaptoethane sulfonate.
05:17Alright, let's move on to busulfan.
05:20Unlike cyclophosphamide, busulfan does not require any bioactivation in order to fight
05:25tumor cells.
05:26It's highly toxic to the bone marrow, but not the other organs.
05:29Therefore it's one of the most potent agents against leukemia, and is especially effective
05:33against chronic myelogenous leukemia, or CML, a type of blood cancer that affects granulocytes.
05:40It decreases the formation of granulocytes and platelets at low dosage, and red blood
05:44cells at higher dosage.
05:47Now busulfan is used before bone marrow transplant as part of a myeloblade of conditioning, where
05:51both the cancer cells and healthy bone marrow are destroyed to make room for the new bone
05:55marrow.
05:59The side effect is, of course, the suppression of the bone marrow, leading to decreased platelets,
06:03red blood cells, and white blood cells.
06:06Other less frequent toxicities include pulmonary fibrosis, where excess collagen or scar tissue
06:12form in the interstitial tissue of the lung, and hyperpigmentation, or darkening of the
06:16skin.
06:18Now, nitrosoureas, which include carmastine and lomastine, also require activation in
06:25the liver by the cytochrome P450.
06:28They are highly lipid-soluble medications, meaning they can cross the blood-brain barrier,
06:32and that's why they're primarily used to treat brain tumors, like glioblastoma multiforme.
06:37However, they are also neurotoxic and can cause convulsions, seizures, and ataxia, or
06:43poor coordination of muscle movements.
06:46Now let's make a simple and fun mnemonic that'll help you efficiently memorize these
06:49pharmacology facts about DNA-alkylating medications.
06:54So first, let's imagine we're in a store that sells alkaline batteries.
06:58The first customer is a cyclops for cyclophosphamide.
07:01He's wearing a mechanic's outfit to represent meclorethamine.
07:04He wants to buy batteries for his knock-off iPhone to represent ifosfamide.
07:09He lets loose a mighty fart cloud that's mustard yellow in color, to help you remember
07:14that these are nitrogen mustards.
07:16For indications, let's use crabs to represent cancer, since in the zodiac, cancer is a giant
07:21crab.
07:22For leukemia, let's have the cyclops holding a bone club in one hand, with little crabs
07:27in the marrow.
07:28Next, he's got a large lymph node on his neck with a crab pinching it, for lymphomas.
07:33The crab is also in his chest pocket, pinching in appropriately, to help you remember the
07:37solid tumors like breast cancer.
07:39For the non-cancer indications, let's use the cyclops' pet wolf, which represents
07:43lupus.
07:44On its back are multiple scarecrows for multiple sclerosis.
07:48The wolf has bulging arteries on its body to represent the different vasculitides that
07:52cyclophosphamide can also treat.
07:55For side effects, the cyclops is wearing a diaper, for the syndrome of inappropriate
07:59antidiuretic hormone.
08:00There's a big bloody spot on it to help you remember hemorrhagic cystitis.
08:05Now let's move on to busulfan, which is a businessman who's also a sultan.
08:10He's riding a camel that's just a skeleton, to help you remember it's very toxic to bone
08:14marrow.
08:15The camel represents CML, but it's also effective against other leukemias.
08:19Finally, the fact that it's all bones will help you remember busulfan is used before
08:23bone marrow transplants.
08:25For side effects, a spider built a web on the camel's chest to represent pulmonary
08:29fibrosis, and the skull is scorched black for hyperpigmentation.
08:34The last group of medications are the nitrosoyerias, like carmastine and lomastine.
08:39So let's have a nitro-powered Mustang limo crash through the store.
08:44The VIP is a crab with a giant brain, since their main indication is brain cancers.
08:49These drugs can cause CNS toxicity, like seizures, which is why the driver crashed.
08:53Ok, so let's use a couple who owns the store to represent the side effects common to all
08:58the DNA alkylating agents.
09:01One of them is a balding man, which represents hair loss.
09:05The man is saying he wants a vasectomy to help you remember infertility.
09:09His wife is pregnant, to help you remember these medications are teratogenic, and she's
09:13so angry she snapped a bone in half, to represent bone marrow suppression.
09:18Finally, the arguing couple is surrounded by crabs, since all the alkylating agents
09:22increase the risk of developing malignancies.
09:25Alright, as a quick recap, DNA alkylating agents are a class of medications used primarily
09:32in the treatment of cancer.
09:34They are cell cycle nonspecific agents, meaning they target all phases of the cell cycle.
09:39Cyclophosphamide and other nitrogen mustards can treat leukemias, lymphomas, and solid
09:43tumor malignancies.
09:45Busulfan targets bones and is primarily used for leukemias and myeloblative conditioning
09:50before bone marrow transplant.
09:53Nitrosoyurias cross the blood-brain barrier and are mainly used in brain cancers.
09:58Side effects of all alkylating agents include myelosuppression, hair loss, gastrointestinal
10:04disturbances, and, after prolonged use, sterility and high risk for developing leukemia or other
10:11malignancies.
10:12But wait, there's more!
10:15Here's a mind map with all the mnemonics.
10:17Go ahead and pause the video so you can test yourself and see what you remember.
10:21Stay tuned for the answers after the credits.