Exam 4/ Final Flashcards
How do cells become cancerous?
Cancer begins when normal cells replicate in an uncontrolled manner. Cancer is more common in the older population due to their long life filled with replicative stress, toxins, infections, radiation, and more.
What is the difference between a benign and malignant tumor?
A benign tumor has not left its original location of replication. These are easy to treat. Malignant tumors have broken from their original location and have spread. Hard to treat.
What is an ‘in situ’ lesion?
When cells replicate in an uncontrolled manner, they form ‘in situ’ lesions that can be removed before they become invasive. These are common in the mouth, GIT, skin, and breasts. These lesions are the precursor for invasive carcinoma.
Cancer is defined by what two things?
- Gain of proliferation signals
- Loss of cell death pathways
How are cancer and EGFR related?
EGFR can undergo genetic changes (in the lungs), allowing it to be amplified. When the gene is amplified, more receptors are produced, which allows cell growth.
What is the main target of cancer chemotherapy?
Different phases of the cell cycle.
What protein is secreted in cells during the S-phase of the cell cycle?
Ki-67 protein is turned on during S-phase. It can be stained and will bind brown dye.
What does High S-Phase Fraction mean?
This means that several cells are staining brown, identifying Ki-67. It can help indicate tumor severity.
At what stage of life does your body have the largest number of cells in the S-phase?
We have a high proportion of cells in S-phase when we are sick, injuries, and during pregnancy.
How were the first chemotherapy medications originally discovered?
It was found that mustard gas given to soldiers caused them to suffer from leukopenia. This caused their white blood cells to die, and they died from infection. It was discovered that mustard gas alkylates heme in red blood cells.
What is the anti-neoplastic alkylating agent discussed during class?
Cyclophosphamide
What is the MOA of cyclophosphamide?
This drug attaches a chemical group to DNA which stalls the replication fork causing DNA breakage. The cell notices the broken DNA, which sends damage signalling causing apoptosis of the cancer cell.
What portion of the cell cycle is the drug cyclophosphamide targeting?
The S phase
What is the significance of ATM kinase and protein p53?
DNA integrity is monitored by protein p53. This gives the cell the opportunity to stop replicating DNA that is damaged. When DNA signals damage, ATM kinase phosphorylates protein p53 causing it to go into the nucleus, acting as a transcription factor. The cell will now produce proteins that go to the mitochondria where channels are produced and proteins begin to eat the cell.
What would happen in a tumor with a p53 mutation?
With a p53 mutation, alkylating drugs would have less action since it relies on the activation of protein p53.
Do all cancer drugs cause immune suppression?
Yes.
Do all cancer drugs induce nausea and vomiting?
Yes.
What are the common side effects of alkylating agents?
Alkylating agents are toxic to bone marrow. This is because there is constant cell proliferation in bone marrow and alkylating agents target the S phase of the cell cycle.
Cyclophosphamide is additionally used after an organ transplant. Why?
It suppresses the immune system giving the body a chance to accept the organ and not attack it.
What are the pharmacokinetics of cyclophosphamide?
Injected Pro-drug that is activated by P450 proteins in the liver.
Does cyclophosphamide conversion in the liver allow it to be a more specific cancer drug?
Makes it more effective but not more specific.
If someone was taking a P450 inhibitor and cyclophosphamide, what would likely happen?
The drug would not be activated well in the liver making the drug less effective.
What is another drug discussed in class that targets DNA?
Methotrexate
What is the MOA of methotrexate?
Methotrexate resembles folic acid and inhibits the dihydrofolate reductase (DHFR) therefore blocking the synthesis of tetrahydrofolate (THF). It inhibits the production of nucleotides, making cells run out of the material they need to replicate DNA. It causes the cell to undergo apoptosis.
What is a unique thing that happens to methotrexate in the cell?
In the cell, methotrexate is cross-linked to polyglutamate derivatives. These derivatives are very active against DHFR, the target enzyme for this drug. The cross-linked version stays in the cell but the parent compound is not.
What is an antibiotic that can be used as an anti-neoplastic drug?
Doxorubicin. A product of the soil microbe Streptomyces.
What portion of the cell cycle does doxorubicin target?
G2 phase
What is the MOA of doxorubicin against cancer?
This drug binds to DNA, where it inhibits the topoisomerase II enzyme. This is the enzyme in the human body that reduces torsional stress during DNA unwinding. This causes the DNA to break into unuseable fragments.
What is FACS?
This is a measurement of DNA content versus the number of cells in a specific phase of the cell cycle.
What would a FACS look like after the administration of doxorubicin?
???
Doxorubicin works _________ and ________ replication.
During; after
Sarah is a 47-year-old female presenting with advanced-stage breast cancer that has a high S-phase fraction and has metastasized to the lymph nodes. What are her treatment options?
This is an unfortunate situation. A treatment option includes adjuvant TAC therapy after surgery to remove the primary tumor. TAC therapy includes Taxotere (docetaxel), Adriamycin (doxorubicin), and Cytoxan (cyclophosphamide).
What are the four phases of the cell cycle, and what happens in each?
G1 phase- cell increases in size, and cellular contents are doubled.
S phase- DNA replication
G2 phase- cell grows more, and organelles develop in preparation for cell division.
M phase- mitosis followed by cytokinesis. Formation of two identical daughter cells. (there is no nucleus here while ER and mitochondria are divided)
Do alkylating agents kill cells in the M phase of the cell cycle?
No.
What is the point of using TAC therapy?
TAC therapy is used to attack cancer cells in all different phases of the cell cycle.
How were the class of drugs called Taxols discovered?
Taxol was isolated from the bark of the western yew tree. It was found that it was really good at killing cancer cells.
What is the taxol drug discussed in class?
Paclitaxel
How was paclitaxel tested?
In order to test this drug, researchers used xenografts. Xenografts are when human cancer cells are introduced into a mouse. Mice are then made to be immune-compromised so their own body does not attack human cancer cells.
What is a phase 1 trial?
Phase 1 trials are about preventing toxicity, and testing is done on healthy individuals. This portion of the trial is not about the outcome of the drug.
What is a phase 2 trial?
Phase 2 trial asks about efficacy, dosing, effects, and different responses based on BMI, genetics, sex differences, etc. There are no placebos given in phase 2 trials. Given to sick individuals.
What is a phase 3 trial?
Phase 3 trials can use placebos.
What is the MOA of paclitaxel?
During mitosis, tubulin must polymerize, and the microtubules must be disassembled for mitosis to proceed. Paclitaxel promotes tubulin polymerization and blocks the disassembly of microtubules leaving the cell stuck in mitosis.
What would a FACS look like after the administration of paclitaxel?
What are the common side effects of anti-mitotic drugs like paclitaxel?
These drugs induce common symptoms of chemotherapy. Additionally, they can trigger neuropathy that presents as weakness, numbness, and tingling.
What is a graphical representation of chemotherapy treatment against non-resistant cancer?
What is the graphical representation of chemotherapy treatment against resistance cancer?
What would be one reason for cancer becoming resistant?
If cancer cells express a large number of p-glycoproteins, doxorubicin cannot be used to treat cancer. This protein will efflux the drug out of the cell.
What are the 5 main ways that we target cancer with drug therapy?
- Chemotherapy
- Kinase receptors
- Nuclear receptors
- Immune targeting
- Others
How is EGFR involved in cancer proliferation?
Epidermal growth factor (EGF) binds to the tyrosine-kinase receptor called EGFR. EGF binding to its receptor increases proliferation, decreases cell death and makes cells move. Cetuximab is a monoclonal antibody that binds the extracellular domain on EGFR, preventing EGF from binding.
What drugs are used when cancer is being stimulated by EGFR?
Cetuximab and chemotherapy together induces apoptosis more effectively.
What is a typical cancer that cetuximab is used for?
Lung cancer
What is a specific anti-TNF antibody used to combat cancer?
Adalimumab (Humira) is an antibody that binds to alpha-TNF and neutralises it. With TNFR being neutralized, the transcription of many genes in inflammation, survival, and apoptosis is halted.
Why is TNF-directed therapy an improvement over methotrexate?
TNF-directed therapy is much more specific than methotrexate. Methotrexate stops the production of nucleotides for all cells in the body while TNF therapy specifically binds TNF and stops its action.
Why does cancer still replicate even after EGFR is inhibited?
MET is another tyrosine kinase receptor-like EGFR. It can provide growth signals once EGFR is disabled.
How does chronic myeloid leukemia (CML) begin?
Some chromosomes have the ability to break more than others, specifically chromosomes 9 and 22. The break between these two chromosomes creates a perfect fusion forming a new fusion protein called Bcr-Abl. Bcr and Abl are genes. The new 9-22 fusion creates the new signalling protein called Bcr-Abl. Abl is an intracellular tyrosine kinase that is now signalling out of control. Now together, Bcr-Abl protein promotes growth and prevents cell death. This causes chronic myeloid (bone marrow) leukemia.
What are the risk factors for chronic myeloid leukemia?
Age, male, and DNA damage
What can Bcr-Abl be stopped by?
A kinase inhibitor called Imatinib.
What is the drug Imatinib used for?
This drug is a kinase inhibitor that blocks Bcr-Abl intracellular tyrosine kinase.
What is the drug Tamoxifen used for?
This type 1 nuclear receptor steroid receptor antagonist binds and blocks the estrogen receptor. This prevents estrogen from going into the nucleus to act on protein expression. Tamoxifen is typically used in estrogen-dependent breast cancer.
What are cancer cell checkpoints?
When cancer initially breaks out of its original location, immune cells are sent out to destroy them. Cancer cells actually have an immune checkpoint on them that basically disguises their identity. This stops the immune system from recognizing cancer.
What is an immune checkpoint inhibitor?
This is a type of drug that stops cancer cells from becoming invisible to the immune system.
What is the immune checkpoint inhibitor discussed in class?
Nivolumab
What is the basic physiology of stomach acid secretions?
Parietal cells within the lining of the stomach secrete stomach acid. Before being triggered, they are just chilling there with their mitochondria and proton pumps. It has several important receptors triggering its release of H+ ions, like muscarinic and histamine (H2) receptors. Some sort of outside signalling will trigger the vagus nerve to produce acetylcholine (ACh) that will bind to the muscarinic receptor. ACh also binds to histamine receptors which trigger them to release histamine that will bind to the H2 receptor in parietal cells. When histamine binds to the H2 receptor, the parietal cell totally changes shape. New canaliculus acid channels are formed and proton pumps will translocate to line those channels. Now the proton pumps pump H+ ions into the stomach.
CASE STUDY: 72-year-old woman experiences acid indigestion after a meal. She has taken antacids frequently for 30 years. She now has acute pain beneath the sternum and blood streaked-stools. Antiacids are no longer effective. She needs more powerful therapy. What would that entail?
We could give her omeprazole.
What is special about the proton pump in the parietal cells?
They are ATPase pumps that require a lot of energy. This is why parietal cells have a lot of mitochondria.
What is a proton-pump inhibitor (PPI)?
This is a type of drug that eventually blocks the proton-pumps from releasing H+ ions into the stomach.
What is the specific PPI discussed during class?
Omeprazole.
What are the unique characteristics of PPIs?
PPIs need an acidic environment to be activated but are not absorbed from the stomach. Additionally, PPIs do not work instantly, and concentration needs to build up. This is why PPIs must be taken BEFORE a meal. It is also an irreversible drug that binds to the proton pump and permanently inhibits it.
What type of drug is Omeprazole?
This is a proton-pump inhibitor. It is a weak base that is absorbed in the intestines.
What are the pharmacokinetics of omeprazole?
Packaged into acid-resistant formulation so it can be better absorbed in intestines (unstable in low pH). It is taken into circulation, where it accumulates in parietal cells due to its love for the proton pump and the acidic state of the parietal cell. The drug is inactive until parietal cells begin secreting H+ ions, where it then undergoes a chemical change. This change allows omeprazole to cross-link to the proton pump and inhibit its actions.
What type of volume of distribution does omeprazole have?
A low Vd of 0.3 kg/L means it does not readily enter peripheral tissues and likes to stay in circulation. A low Vd means it also has a short half-life.
If PPIs bind irreversibly to proton pumps, why do the drugs only last 24-48 hours?
The turnover rate of proton pumps is really high, just like the rest of the things in the stomach. Once the proton pump is degraded again, the medication is no longer viable.
What is the MOA of omeprazole?
Irreversibly binds and cross-links the proton-pump stopping its H+/K+ secretions into the stomach.
What are some of the consequences of raising the pH of the stomach?
The body cannot take up nutrients as readily. Hypergastremia is also likely, which can cause cancer. Gastric bacterial overgrowth of C. Diff can also occur with PPI use.
CASE STUDY: The 72-year-old woman returned 2 weeks later and said the PPI was not working. After eating, her stomach still hurt, so she decided to start taking antacids in the evening. What happened?
Since PPIs need an acidic environment to be activated, taking an antiacid will not allow the drug to be activated which would stop it from producing its proper effects.
What are Helicobacter pylori bacteria?
This is a type of bacteria that can cause peptic ulcers. It can be treated with antibiotics combined with a PPI. Antibiotics commonly used are metronidazole, clarithromycin, or amoxicillin. Metronidazole is used because it is activated in anaerobic environments. Once the drug is reduced to its active toxic radical, it will attack the bacterial H. pylori DNA. This interferes with replication and causes DNA fragmentation. Clarithromycin targets the 50s subunit of bacterial RNA, and amoxicillin targets the PBP preventing cell wall formation.
CASE STUDY: Erika is a 24-year-old woman who is flying on a vacation in Montana. The trip will require a flight in a small airplane. She is worried about motion sickness as she sometimes gets carsick, even under normal highway conditions. What type of therapy might she consider?
Dramamine
How do nausea and vomiting work on a basic level?
It appears that vomiting associated with pregnancy or motion sickness functions through a histamine H1 receptor and muscarinic cholinergic receptor.
What is Dramamine (Diphenhydramine)
This is an H1 receptor inverse agonist. Additionally, it has anticholinergic effects (inhibits muscarinic acetylcholine receptors). Dramamine is packaged with 8-chlorotheophylline which acts like a stimulant.
CASE STUDY: 5 year old has a poor diet of chicken nuggets, fries, and cookies. He remains constipated for days at a time and even has experienced nausea as a result. What is the treatment?
Miralax
What type of drug is Miralax?
This is an osmotic agent. Other osmotic agents include non-digestible sugars and milk of magnesia.
What is the MOA of Miralax?
Miralax is polyethylene glycol. It is a non-digestible fiber that is poorly absorbed by the GIT. These substances also pull in water to the GIT causing a peristaltic effect.
CASE STUDY: Patricia is a 34-year-old woman who travelled to Mexico, drank unbottled water, and ate from street vendors. She has now been experiencing diarrhea for 12 hours. What are her treatment options?
Imodium (Loperamide)
What is the MOA of loperamide (Imodium)?
This drug binds to opioid receptors in the gut. By doing this, it reduces peristalsis and increases intestinal transit time.
Does Loperamide (Imodium) cross the blood-brain barrier?
It gets into the brain at the correct doses and is immediately effluxed by p-glycoproteins.
What would happen to the body if someone was on an additional drug inhibiting p-glycoproteins while taking Imodium?
Imodium would be able to cross the blood-brain barrier and stay there. It would cause constipation similar to what opioid users experience.
The circulatory system is composed of what two components?
- Systemic circulation- moves blood from the heart to the rest of the tissues. It then returns deoxygenated blood back to the heart.
- Pulmonary circulation- moves blood between the heart and the lungs. It transports deoxygenated blood to the lungs, where it gets oxygenated and then goes back to the heart.
What is blood pressure?
It is the pressure exerted by the blood against the blood vessel walls. It is needed to ensure steady blood perfusion to the tissues.
What are the two main components of blood pressure?
Cardiac output (heart rate x stroke volume) and peripheral resistance
What is stroke volume?
The amount of blood ejected from the heart in each pump from the left ventricle.
What are the ranges for blood pressure stages?
What is considered normal blood pressure?
Less than 120/ <80 (AND)
What is considered elevated/ pre-hypertensive blood pressure
120-129/ <80 (AND)
What is considered stage 1 hypertension?
130-139/ 80-89 (OR)
What is considered stage 2 hypertension?
140 </ 90< (OR)
What is a hypertensive crisis where emergency care is needed?
180 </ 120 (AND/OR)
What is primary/essential hypertension?
This is when patients have no specific cause for the hypertension.
What is secondary hypertension?
This is when patients have a specific cause of hypertension. Could be caused by renal disease or primary aldosteronism. Usually occurring issues in kidneys, arteries, heart, or endocrine system.
What is systolic blood pressure?
This is the pressure that blood is exerting against the artery walls when the heart is beating (contraction) and pumping blood out.
What is diastolic blood pressure?
This is the pressure that blood exerts against the artery walls when the heart is at rest (relaxation).
Blood pressure can change all the time based on the most random things. How many consistent measurements of hypertension need to be collected before it can be diagnosed?
Three different elevated readings are needed to be diagnosed.
What are hypertension’s general signs and symptoms, even though it is typically asymptomatic?
Headaches in the morning, ringing in ears, unexplained dizziness, spontaneous nosebleeds, fatigue, nausea, vomiting, blurred vision, irregular heart beat, and flushing of the face.
Is elevated systolic or diastolic blood pressure worse?
Having hight diastolic pressure is worse because even when the heart is relaxed, pressure is still to high.
What are the rates of hypertension in males and females before menopause?
1 in 4 males
1 in 5 females
What is the WHO rule of 1/3s?
1/3 of all adults suffer from hypertension. 1/3 of those adults do not know they have hypertension. 1/3 of adults treating their hypertension cannot keep it under 140/90.
What are some of the different causes of hypertension?
Genetics and family history, age and gender, obesity, dietary habits, physical inactivity, drug-induced (NSAIDs, cyclosporine, hormonal contraceptives, nicotine, smoking), and psychosocial stress.
What is the MOA of diuretics?
All diuretics work in the nephrons of the kidneys (at different spots) and inhibit sodium reabsoprtion. This then increases urinary sodium and water excretion.
What is the composition of blood?
Blood contains 55% plasma, 4% WBC (leukocytes), platelets (thrombocytes), and 41% RBC (erythrocyte).
What is a tyrosine kinase receptor?
Span the plasma membrane. Has two distinct domains; the extracellular domain for ligand binding and the intracellular kinase domain for the enzymatic reaction.
What are G-protein coupled receptors?
These receptors span the cell membrane. It has an outside part that ligands bind to that converts it to the ‘on’ state, where the alpha subunit releases GDP and GTP replaces it.
What are the dose-response curves for a full agonist, partial agonist, antagonist, and inverse agonist?
Full agonist is the full curve
Partial agonist is partial curve
Antagonist is a straight line
inverse agonist is negative curve
What is the equation for clearance?
How is the loading dose calculated?
In the graph above, A represents maximum activity of a target protein, and B represents the same effect in the presence of an inhibitor. Based on the mechanism of the drugs listed below, which one is best represented by curve B?
A. Amoxicillin
B. Diphenhydramine
C. Methotrexate
D. Omeprazole
D. Omeprazole
