Quiz 4: Lectures 10, 11, 12 Flashcards
1
Q
Cancer cells
A
- Cells that started off “normal” that have been transformed, showing uncontrolled growth and multiplication
- A group of cancer cells is sometimes called a “neoplasm”
- Most cancers form solid tumors, which can be benign or malignant tumors, benign tumors being localized and “not harmful,” and malignant being the ones that are harmful since they are invasive and can spread through metastasis
- Cancer can affect many tissues; people don’t just have “cancer,” they have a certain type of cancer affecting a certain tissue. Can have multiple cancers at once, however
- Cell defects associated with cancer include abnormal signaling, abnormal cell cycle regulation, evasion of apoptosis, immortality, angiogenesis, and tissue invasion
2
Q
Benign vs Malignant tumors
A
- Malignant tumors are what people have when they are considered to have cancer ( I think?). Malignant tumors are invasive and can spread to other tissues via metastasis, where the cancer cells can take up root and start growing there too
- Benign tumors are localized and are considered not harmful, although they can turn into malignant tumors if given enough time to undergo angiogenesis. These tumors can typically be removed during surgery, since they’re localized. Not considered cancerous.
3
Q
Causes/associations of cancer
A
- Some cancers can be caused by viruses, which is why we can sometimes make vaccines against viruses, like in the case of papillomavirus, in which we take HPV shots (we take these shots to prevent HPV, but it also helps prevent cancer caused by this same virus)
- Is also associated with many environmental factors, including:
- tobacco
- alcohol
- radon
- Some halogenated compounds
- Some immunosuppressive compounds
- Some herbicides
- Ionizing or UV radiation
- Environmental exposure is the most prominent cause of cancer
4
Q
Precipitant
A
- Cause of a particular action or event
- “Cause of cancer” is how we will most often be using the word
5
Q
Cancer History
A
- Most prominent cancer in men from 1930s onward in US is lung cancer. Increased until mid 90s, where it started to die off, but is still the highest cancer in men by far.
6
Q
Oncogenes
A
- Oncogenes are regulators of cellular communication with the outside environment; causes abnormal signaling
- Genes that are responsible for cancer, or can up-regulate it
- Opposite of tumor suppressor proteins
- Proto-oncogenes are genes that are potential oncogenes, but are still behaving normally. When they become dis-regulated (mutated) to the point where they cause/promote cancer, they get called oncogenes
- Proto-oncogenes are typically in charge of regulating homeostatic cell function, such as cell division and differentiation
- Oncogenes are typically produced by exposure to carcinogens
- Oncogenes cause cancer when the proto-oncogenes are stimulated in ways they should not be (over-expressed, wrongly expressed, etc)
- Examples of proto-oncogenes include ras, bcr-abl, abl-2, and myc
7
Q
Tumor supressor genes
A
- Also called anti-oncogenes
- These genes halt uncontrolled cellular growth and help prevent the formation of cancer
- When these genes get suppressed or inactivated, however, that can lead to cancer
- Examples of tumor suppressor genes include p53 and retinoblastoma (Rb)
8
Q
p53
A
- A tumor suppressor gene that is found to be nonfunctional in over 50% of cancers
- When functioning, it senses that the cell is damaged, whether this damage be due to DNA breaks, UV radiation/stress, oncogenes, etc, and up regulates genes that promote growth arrest, apoptosis, and prevention of angiogenesis.
- It can be mutated to be nonfunctional, and this mutation is usually a single point mutation. The gene can usually still sense that there is damage, but it not able to do anything about it by up regulating these processes above.
9
Q
Common defects in cancer
A
- Although all cancers are different, they all generally have some common defects. Occurs in the following progression:
1. Abnormal signaling - Can be due to the cell expressing its own growth factors, which is very bad since this means the cell can basically just grow without stimulus from the environment, which is what normally promotes growth factors
- Can have extracellular chemical messengers that activate protein kinase receptors in the cell membrane
- Can have over-expression of growth factor receptors or of their activated variants, making them constantly ON
- Can become insensitive to growth hormone
2. Abnormal cell cycle regulation - Up-regulation of cyclin and cyclin dependent-kinases and their inhibitors
3. Apoptosis disregulation: cell becomes less likely to undergo apoptosis - Extrinsic factors– molecular signals and their receptors
- Intrinsic factors– DNA damage
4. Abnormal chromosome maintenance - Telomere at 3’ end of chromosome stabilizes and protects DNA, and gets shorter during each replication
- Telomerase is up-regulated to keep chromosome ends form shrinking during all the replication the cancer cell is undergoing
5. Abnormal and increased angiogenesis - Tumor needs a good blood supply, and as it grows, to obtain the amount of blood it needs to continue growing, it vascularizes by extending existing capillaries to bring in more blood and nutrients in the blood
Most, if not all of these things need to happen for stage IV cancer to develop, and they typically occur in this order too!
This is why cancer takes time to develop, and the sooner you catch it, the less “broken” it is, and the easier it is to treat because it may only be at, say, abnormal cell cycle regulation, and not to apoptosis dis-regulation yet
This also explains why cancer therapies are so toxic to the patient: they need to go after a variety of mechanisms
10
Q
cyclin
A
any of the proteins associated with the cycle of cell division which are thought to initiate certain processes of mitosis
11
Q
Leukemia
A
- Cancer that affects the blood and bone marrow. Leukemia begins in a cell in the bone marrow. The cell undergoes a change and becomes a type of leukemia cell.
12
Q
Lymphoma
A
- A cancer that begins in infection-fighting cells of the immune system, called lymphocytes
- Lymphocytes are in the lymph nodes, spleen, thymus, bone marrow, and other parts of the body
- When a person has lymphoma, lymphocytes change and grow out of control
13
Q
Solid tumor
A
- An abnormal mass of tissue the usually does not contain cysts or liquid areas
- Solid tumors may be benign (non-cancerous), or malignant (cancerous).
- Different types of solid tumors are named for the types of cells that form them. Examples of solid tumors include sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) typically do NOT form solid tumors
14
Q
Sarcoma
A
- A tumor that occurs in connective tissue (bone or soft tissue)
15
Q
Carcinoma
A
- A tumor that starts in the cells that make up the skin or the tissue lining organs?
16
Q
Therapeutic approaches for treating cancer
A
- The main types are surgery and radiation ( for localized tumors), chemotherapy (for systemic cancers), and immunotherapy (for both localized and systemic?)
- If a person has a localized tumor, surgery is usually done first to remove this tumor. Surgery is far from perfect, however, as it can leave a lot of cancerous cells left. If more than 10E4 cells are left, the cancer will typically come back. There is a kind of “tumor margin” for trying to determine how much to cut out, because it can be difficult to tell where the tumor ends, and this tumor margin can be more difficult to work with depending on where the cancer is
- After the tumor is removed, radiation is typically done on the site to try and kill off any cancer cells that may have been left over
- As a kind of adjuvant therapy, or in the case of where the cancer is known to have spread, chemotherapy is carried out, since it is a method used on systemic cancers.
- Typically have patient come in weekly or a few times a week and give chemotherapy drugs via IV for a certain amount of time, and then put them on a pill chemotherapeutic that they can take for 5-10 years after
- Book: Chemotherapy is used in three main clinic settings: 1. Primary induction treatment for advanced disease or for cancers for which there are no other effective treatment approaches, 2. neoadjuvant treatment for patients who present localized disease, surgery or radiation alone, or together are inadequate; 3. Adjuvant treatment to local methods of treatment like surgery and radiation, as described above
- Substances used as chemotherapeutics are sometimes called antineoplastics
- They can be used as an “insurance policy” after surgery and radiation to try and kill off any cells that might have spread
- Cytotoxic compounds interfere with the synthesis and function of DNA, RNA, and/or essential proteins
- Since these antineoplastics are very toxic and have severe side effects, people are typically given small doses of different antineoplastic agents that target different molecules/mechanisms with the hope that the therapeutic effect will be additive but the side effects will not be
17
Q
Drug Combination
A
- When prescribing drugs for chemotherapy, antineoplastics that target different mechanisms and have side effects that affect different parts of the body are generally used together in doses that are within the range of toxicity for each drug
- This is done so the therapy is additive, but the side effects hopefully aren’t, and so one part of the body (say, the liver) isn’t the only part of the body bearing the side effects
- Also done to try and cover as many aspects of the cancer as possible; “cover more ground”
- Since drug combination therapy involves prescribing multiple drugs that go after various mechanisms, this therapy is better to handle heterogenous cell populations, since some cells of a cancer may be different from one another due to metastasis from the original tumor to different parts of the body
- Book: A given ages follow a log cell-kill kinetics; a given agent can be predicted to kill a constant fraction of cells as opposed to killing a constant number
18
Q
Guiding principles of prescribing drugs for combination therapy
A
- Efficacy- only drugs that are known to be somewhat effective when used alone should be used in chemotherapy
- Toxicicity- when several drugs of a given class are available and equally effective, the drug that has toxicity that does NOT overlap with the toxicity of another drug used in the combination therapy should be selected. Although this leads to a wider range of side effects, it minimizes the risk of a lethal effect caused by multiple insults to the same organ, allowing dose intensity to be maximized
- Ex: don’t want two drugs that both have side effects on the liver - Optimum scheduling- drugs should be used in their optimal dose and schedule, and combinations should be given at consistent intervals so its more convenient for the patient so patient compliance will be higher
- Mechanism of Interaction- there should be a clear understanding of the MCA (mechanism of action) between all drugs in the combination to allow for maximal effect
- You want to know this so you can use drugs that hit as many factors/mechanisms as possible. For example, having multiple drugs target angiogenesis may not be as effective as having one drug target angiogenesis, one drug target cell cycle regulation, and one drug target ras - Avoidance of arbitrary dose change- An arbitrary reduction in the dose of an effective drug in order to add other less effective drugs may reduce the dose of the most effective agent below the level of effectiveness and destroy the ability of the combination to cure the cancer.
- You may have to change the drugs/ doses of drugs the patient is on due to the side effects they are experiencing, and this is where this comes in; it can be difficult to do so without bringing the level of the most effective drug down too low
19
Q
Resistance to anti-cancer drugs
A
- Resistance can be intrinsic or acquired
Intrinsic: - Intrinsic resistance is when the tumor shows little response to the anti cancer agent from the beginning due to some intrinsic aspect of that person’s body.
- Can be due to the down-regulation of enzymes that are essential for activation of the anti cancer drug, or transportation of it
- Can be due to some regions of the tumor mass being in resting state
Acquired: - Acquired resistance is when the tumor is first receptive to the drug and later becomes resistant to it
- Once a cancer becomes resistant to that drug, the drug doesn’t work anymore ( in that person, I’d assume)
- This typically occurs due to the heterogeneous-ity of cells: some cells may be susceptible to the drug and may die off, but once they die off, the cells that weren’t susceptible may start proliferating, so you need to find a new drug to go after them
- Could be due to a change in drug uptake and efflux, in which the cancer cell may recognize that the drug is bad for it and may change its transporters so it doesn’t take much in, or if it does it just shuttles it back out
- Can also be due to inhibition of cell repair mechanisms, or apoptosis
20
Q
Chemical Warfare and Chemotherapy
A
- In WWI, mustard gas was seen to cause bone marrow depression two weeks after exposure, in which then mortality peaked
- Autopsies revealed atrophy of lymphoid and testicular tissue and hypoplasia of bone marrow
- In 1929, sulfur mustard was discovered to inhibit tumor growth, and further experiments suggested that this was mediated by an effect on the animal rather than an effect on the carcinogenic substance
- More chemical warfare research during WWII suggested that the cellular effects of the mustards resembled those of X-rays
- Chemical warfare agents and chemotherapy agents are basically the same thing, they are just used differently and administered differently.
21
Q
Alkylating Agents
A
- Anti-cancer drugs that promote DNA cross-linking
- Book: alkylations of DNA within the nucleus probably represent the major interactions that lead to cell death
- Most of these drugs are nitrogen mustards, which were used in chemical warfare
- These nitrogen mustards are extremely reactive electrophilic reagents
- They react with DNA nucleobases, especially the N7 of guanines
- They tend to alkylate and attach themselves to two different guanines on the complementary DNA strands to cross-link them together
- Alkylation of guanine can result in miscoding though abnormal base pairing with thymine or in depurination by excision of guanine residues. This can lead to DNA strand break through scission of the sugar-phosphate backbone of DNA
- Their halogen is always chlorine
- Aromatic nitrogen mustards are less reactive, allowing them to be administered orally. They can also be transported by amino acid transporters since they kind of look like amino acids
- Nitrosoureas are also cross-linking agents
- They decompose into two different active compounds: isocyanate, and an alkylating agent. The alkylating agent is what does cross-linking. The isocyanate actually attaches itself to lysine in proteins via carbamolyation
- Cisplatin is also a cross-linking drug that binds to the N7 of guanines
22
Q
Nitrosoureas
A
- Anticancer agents that can promote cross-linking from alkylation
- They actually decompose into two different active compounds: isocyanate, and an alkylating agent.
- The alkylating agent is what does cross-linking.
- The isocyanate attaches itself to lysine in proteins via carbamolyation
- Nitrosoureas have very good efficacies for cancers of the brain, and are thus used for such
- They are lipophilic and can cross the blood brain barrier (BBB) fairly easily
23
Q
emetogenic
A
- Promotes vomiting
24
Q
Cisplatin
A
- An anti-cancer drug that promotes cross-liking through alkylation
- Contains a platinum center connected to two chlorines and two amines
- Also attaches itself to the N7 of guanines, like the nitrogen mustards
- Undergoes a process called “equation” in which its chlorines are replaced by water, and then these waters are removed to attach the cisplatin to the DNA in cross-linking
- This is a very common chemotherapy for a number of cancers and is also one of the most emetogenic chemotherapy agents
- However, it is typically used as a “last option” type of drug, because although it is effective, it has a high chance of killing the patient
- Book: has major anititumor activity in a broad range of solid tumors
25
Q
DNA intercalating agents
A
- Anti-cancer drugs that intercalate
- Typically contain a planar three ring system that can intercalate between the bases of DNA in base stacking, and a part that “sticks out” that can sometimes do minor or major grooves binding
- By doing this groove binding, this helps stabilize the complex and prevent the unwinding of DNA
- If the DNA can’t unwind, then transcription and replication can’t occur, so DNA intercalating agents disrupt the replication and transcription process
- Examples of intercalating agents include dactinomycin, which has a “sticking out group” that are cyclic peptides
- Anthracyclins are also intercalating agents, and their groups that stick out are a ring that can have different groups attached to it
- One type of anthracyclin is doxorubicin, which is one of the most effective chemotherapeutic agents known
- Topoisomerase I poisons are poisons that stabilize the enzyme-DNA complex to prevent the DNA from relaxing by not only intercalating and interacting with the DNA, but also by interacting with the topoisomerase.
26
Q
Doxorubicin
A
- An anthracyclin, and one of the most effective chemotherapeutic agents known
- Binds in the major groove and intercalate using its planar ring system
- Its positively charged amino group on its ring is important in major groove binding to stabilize the DNA so it can’t unwind.
27
Q
Dose intensity
A
- One of the main factors limiting the ability of chemotherapy or radiation therapy to achieve cure, since it can be difficult to balance effectiveness of drug and toxicity effects
28
Q
Anti-metabolites
A
- A class of anti-cancer drugs that go after/ inhibit enzymes that make metabolites and other pre-cursors for various biosynthetic pathways
- These pathways are often up-regulated in cancers
- Antimetabolites disrupt the synthesis of DNA and its components, often via inhibition of the synthesis of essential cofactors
- Examples of antimetabolites include methotrexate and 5-Fluorouracil
29
Q
Methotrexate
A
- An anti-metabolite drug that inhibits the formation of dTMP
- Methotrexate is an analog of folic acid, which is used to make dTMP
- Methotrexate is able to bind to the enzyme DHFR (dihydrofolate reductase) that is used in the pathway of folic acid —> dTMP, inhibiting it and blocking the pathway from continuing
-Book: Inhibits the synthesis of tetrahydrofolate (THF), which is involved in de novo synthesis of thymidylte, purine nucleotides, and the amino acids serine and methionine - Methotrexate interferes with the formation of DNA, RNA, and key cellular proteins
- ## Methotrexate also indirectly effects other key enzymes
30
Q
5-fluorouracil
A
- An anti-metabolite drug that inhibits the formation of dTMP by inhibiting the enzyme thymidylate synthase
- 5-fluorouracil, as its name suggests, has a fluorine on carbon 5 instead of a hydrogen. This hydrogen is essential in the formation of dTMP from dUMP.
- 5-fluorouracil gets turned into FdUMP, which forms a covalently bound tertiary product with thymidylate synthase instead of dUMP, it stops the reaction from proceeding forward
- Results in inhibition of DNA synthesis and function
- This drug works VERY well in combination with other drugs, and hence is used in a lot of “cocktails”
31
Q
Pharmacogenetics
A
- The study of how different people react to different drugs differently due to their genetic makeup
32
Q
Hormone-based therapies
A
- Used when the cancer is hormone dependent, meaning it requires certain hormones to be present for the cancer to be able to proliferate and take over
- If a cancer requires a specific hormone, we can administer a hormone that has the opposite effect, or that is an antagonist to block the action of the required hormone
- Hormone antagonists are especially important in breast cancer
