Exam 1 Flashcards
How is cancer defined (neoplasm v. tumor v. cancer)?
neoplasm - any new growth. it can be benign or malignant
tumor - nonspecific lump or swelling (can be benign)
cancer - any malignant neoplasm
What are the differences between hyperplasia, metaplasia, dysplasia, and anaplasia?
- hyperplasia: increase in the number of cells
- metaplasia: substitution of one type of tissue for another type
- dysplasia: abnormal cellular proliferation where there is a loss of normal organization
- anaplasia: loss of structural differentiation
What are the definitions of these different types of cancer: carcinoma, adenomacarcinoma, sarcoma, lymphoma and luekemia, melanoma, blastoma, teratoma
**Classification is from the tissue of origin
carcinoma - malignant neoplasm of squamous epithelial cell origin
adenomacarcinoma - malignant neoplasm of glandular tissue
sarcoma - malignant neoplasm with origin in mesenchymal tissues (connective tissues, blood, lymphatics, bone, and cartilage)
lymphoma and leukemia - malignant neoplasms of hematopoietic tissues (WBCs/lymph)
melanoma - cancer of pigment producing cells (melanocytes) in the skin or eye
blastoma - malignancies in precursor cells (more common in children); ex. nephroblastoma, medulloblastoma, retinoblastoma)
teratoma - germ cell neoplasm that’s made of several different differentiated cell/tissue types
How is cancer categorized and staged? (numerical, TNM, summary staging)
Staging: largely based on tumor size, location, and number. Usually, only solid tumors get staged.
0: pre-cancerous, no sign of local invasion
I: microscopic invasion of surrounding tissue
II: 4-9 surrounding lymph nodes are involved
III: 10+ surrounding lymph nodes are involved
IV: distant metastases are detected :(
TNM: T = primary tumor; N = regional lymph nodes; M = distant metastasis
_X: cannot be evaluated
_0: no evidence of primary tumor (T)/no regional lymph node involvement (N)/no distant metastasis (M)
Tis: carcinoma in situ, not cancer, no spreading yet
T1-4: size/extent of invasion of the primary tumor
N1-3: degree of regional lymph node involvement (# and location of lymph nodes)
M1: distant metastasis is present
Summary - in situ, localized, regional, distant, unknown
What is tumor grading?
well differentiated - tumor’s cells & organization of tumor’s tissue are close to those of normal cells/tissue. These tumors tend to grow and spread at a slower rate than poorly differentiated tumors.
poorly differentiated - abnormal looking cells that may lack normal tissue structures.
Grade: GX-G4
GX: grade cannot be assessed
G1: well differentiated (low grade)
G2: moderately differentiated (intermediate grade)
G3: poorly differentiated (high grade)
G4: undifferentiated (high grade)
What are the hallmarks of cancer?
- Evading growth suppressors
- Avoiding immune destruction
- Enabling replicative immortality
- Tumor-promoting inflammation
- Activating invasion & metastasis
- Inducing angiogenesis
- Genome instability & mutation
- Resisting cell death
- Deregulating cellular energetics
- Sustaining proliferative signaling
What is the difference between oncogenes vs. tumor suppressors?
Oncogene: a protein that is capable of driving proliferation and tumor progression (ex. RSV is a retrovirus that encodes the oncogene c-Src). These drive the cell cycle.
Tumor suppressors: proteins that can prevent cancer. These halt the cell cycle.
How are genetics and genome sequencing changing the face of personalized cancer treatment?
- Cancer is often a phenotype that evolves over time. The end product is a selective growth advantage, but there’s many ways to get to this end product.
- One mutation is not usually enough to cause cancer on its own.
- Can use diagnostics to determine mutations & therefore treatment
We can use our knowledge of mutations to predict/amplify susceptibility of cancer cells to our chemotherapies.
- ex. mutated EGFR catalytic domain = higher susceptibility to gefitinib
- ex. mutated loss of function to one process, then use drug to stop the 2nd process. Both processes down = death of cell (BRCA mutation + PARP inhibitors).
What is Olaparib’s MOA? What cancers do we primarily use it for?
Olaparib - PARP inhibitor
- used primarily for cancers with BRCA1/2 mutations: With PARP inhibitor, the tumor cells do not have either tumor suppressor/DNA repair pathway functioning, so cell dies.
- also can enhance toxicity of DNA-damaging therapies in other cancers
- (rucaparib, niraparib, talazoparib also in this class)
Why is the cell cycle important in cancer chemotherapy?
Cell Cycle:
G0/G1 - cell accumulates building blocks required for division
S - “synthesis” cell replicating DNA
G2 - double checks & getting everything ready for mitosis
M - mitosis
- A healthy cell runs on a cell cycle clock that is driven by Cyclin D and CDK4/6. the R point (restriction point) is when cells decide whether or not to enter cell cycle.
- Most chemotherapies target the cell cycle in some way (S phase is major target).
What is Palbociclib’s MOA? What are some adverse effects?
Palbociclib - CDK4/6 inhibitor (kinase inhibitor)
- Inhibiting CDK4/6 inhibits the cells ability to continue the cell cycle, and therefore inhibits the cell’s replication/division
- Bad news is they just target ALL cells, so very non-specific
- Adverse effects: neutropenia, nausea, fatigue, diarrhea, vomiting (similar to traditional chemotherapies)
- (abemaciclib and ribociclib also in this class)
How do chemotherapies target cancer growth & cancer survival?
- Cancer cells don’t have normal cell cycles. They have lost their normal checkpoints & stuff like that.
- When normal cells are damaged by chemotherapy, they usually can repair the damage themselves. If not, they will go through programmed death. Cancer cells will either try to repair the damage and end up apoptosing or just continue without repairing the damage, while results in them obliterating themselves.
What are the kinetics of cancer cell proliferation (tumor growth, growth fraction, doubling time) and cancer cell killing by chemotherapy?
Cancer chemo kills a fraction of present cancer cells (not # of cells), so chemo will never get rid of 100% of cells. BUT chemo can get the # of cells low enough that the body can get rid of the rest (<10,000 cells)
- Chemo selects for cells that are resistant to the drug
- Give chemo early/frequently & give in combo with other drugs for best outcome.
- Cell kill > Cell growth (in between sessions) = success
*as tumors grow, their doubling time slows, which is bad for anticancer drugs, as most target the cell cycle.
What are the major mechanisms of drug resistance in cancer chemotherapy?
Altered Drug Metabolism
- Increased transport of drugs out of the cell by efflux pumps (ex. Pgp & MRP), reduced transport into the cell (loss of drug importer, decreased membrane permeability), decreased activation of prodrug, increased detoxification of drug molecule
Changes in Drug Target or Function
- Increased expression of drug target, making it harder to inhibit, emergence of a mutant, structurally altered target so the drug won’t bind anymore, rewiring of pathways that bypass the drug target, so drug isn’t really doing anything anymore
Physiological Changes
- metastasis of cancer cells in places the drug can’t reach (ex. BBB) or can’t effect (thymus), massive stromalization to inhibit drug transport, changes in cell cycle (ex. slowing down, increasing anti-apoptotic proteins)
What are the 2 main cancer cell survival mechanisms?
- Activation of anti-apoptotic regulators - helps cancer cells bypass cell death
- Increased repair of damage caused by chemotherapies - most common is repair of drug-DNA adducts or DNA damage. This renders chemotherapy useless :(
What are the most common dose-limiting toxicities resulting from cancer chemotherapy?
Hematopoeitic - WBCs (infections), platelets (hemostasis), RBCs (anemia)
Gastrointestinal - N/V, loss of appetite
What are the principles of combination chemotherapy?
As a single agent, chemotherapy can cause drug resistance and drug toxicity. With combo therapy, there is increased cell killing and reduced drug resistance.
When designing combo chemotherapy, the individual drugs should be used at max tolerated doses. They should have different MOAs/cell-cycle specificities.
- ex. CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)
How do antimetabolites (as a class) work? What is the major dose-limiting toxic effect of antimetabolites?
Antimetabolites inhibit the production of nucleotides in order to inhibit DNA replication.
Toxic effect - myelosuppression, due to inhibiting reproduction of rapidly proliferating cells
5-FU: What cellular substrate is it modeled after, mechanism of activation, MOA, mechanisms of resistance, and toxicities?
5-FU is a pyrimidine analog (uridine, nucleobase) that interferes with pyrimidine nucleotide synthesis. It can also be incorporated into DNA/RNA to interfere with function and DNA replication. Primarily, 5-FU inhibits thymidine synthesis from uracil.
- Activation: conversed to FdUMP in a 2-step transformation
- MOA: Instead of folate binding to TMP in a ternary complex & donating a methyl group to TMP, FdUMP (active 5-FU) binds to TMP, so no thymidine is able to be produced; ALSO F-5U converts into F-UMP and F-UTP, which interferes with RNA professing and function
- Resistance: Down regulation of activating enzymes to convert 5-FU to its active form FdUMP; Upregulation of thymidylate synthase (to make dTMP for thymidine)
- Toxicities: Antimetabolite toxicities like myelosuppression; Some polymorphisms cause deficiency in the enzyme that breaks down 5-FU, which increases toxicity
**capecitabine is the orally active prodrug of 5-FU and it actually selects a little more for tumor cells
Why would you give supplemental thymidine to a patient who is starting 5-FU?
If you give the patient supplemental thymidine, the body will stop making it themselves. Then when you take away the thymidine and start 5-FU, the body really will not have enough thymidine to make uracil.
- supplemental thymidine can also save a pt from 5-FU overdose
Cytarabine: What cellular substrate is it modeled after, mechanism of activation, MOA, mechanisms of resistance, and toxicities?
Cytarabine is a cytosine (nucleoside) analog that primarily inhibits DNA synthesis through inhibiting DNA polymerase function.
- Activation: converted to Ara-CTP intracellularly
- MOA: competitive inhibitor of DNA polymerase α. It’s especially toxic in meningeal leukemia and lymphoma due to decreased levels of cytidine deaminase, which would break Ara-CTP down
- Resistance: Downregulation of activating enzymes, upregulation of cytidine deaminase, downregulation of transporter that moves the drug into cells
**gemcitabine is structually similar, but has a greater potency
What can you give with cytarabine to increase its efficacy?
Giving tetrahydrouridine with cytarabine increases efficacy and decreases resistance. Tetrahydrouridine is a cytidine deaminase inhibitor, so it inhibits the enzyme that inactivates cytarabine.
6-Mercaptopurine: What cellular substrate is it modeled after, mechanism of activation, MOA, mechanisms of resistance, and toxicities?
6-MP is a thio analog of adenine (purine analog). It inhibits multiple enzymes in de novo purine biosynthesis to block the synthesis of purine nucleotides.
- Activation: The enzyme HGRT converts 6-MP to its active metabolite (thioinosine monphosphate)
- MOA: Blocks de novo purine synthesis
- Resistance: loss of HGRT, increased inactivation by TPMT
- Toxicity: Those with LOF mutations in TPMT will require smaller dose (increased risk of hematologic toxicity)
What drug interaction is important to look for with 6-mercaptopurine?
Allopurinol is a xanthine oxidase inhibitor. Xanthine oxidase is the enzyme that breaks down 6-MP. Therefore, those taking allopurinol are at risk for 6-MP toxicity.
**allopurinol does NOT block the breakdown of 6-TG, which is a thio analog of guanine in the same class as 6-MP
Why are folate intermediates important for cell proliferation?
Folate is an essential cofactor for many enzymatic reactions.
Folate/forms of folate are essential for RNA and protein synthesis as well as purine and pyrimidine base synthesis.
Methotrexate: What cellular substrate is it modeled after, mechanism of activation, MOA, mechanisms of resistance, and toxicities?
Methotrexate mimics folic acid (aka an antifolate) that binds to DHFR, but can’t be reduced, so it inhibits the enzyme.
- Activation: No activation needed
- MOA: Inhibiting DHFR to stop RNA/protein/purine/pyrimidine synthesis
- Resistance: Amplification of DHFR gene or mutation to DHFR to a resistant form of the enzyme, decreased polyglutamation to decrease the availability of methotrexate.
How does Leucovorin work?
With 5-FU: Leucovorin acts as folate, so when you give leucovorin while the patient is getting 5-FU, it increases the efficacy of 5-FU bc more covalent ternary complexes are formed. (increases 5-FU activity)
Methotrexate: Used to “rescue” normal tissues from MTX toxicity. It increases intracellular pools of tetrahydrofolate and reverses the toxic effects of DHFR inhibition. (decreases MTX activity)
What are the functional groups of DNA alkylating agents? Why are they bifunctional?
Alkylating agents are drugs that generate reactive electrophilic intermediates that react with nucleophilic groups on DNA and proteins. This results in adding an alkyl group to DNA and protein.
They are bifunctional due to having two alkylating groups that produce DNA intra and interstrand linkages. This cross-linking inhibits DNA replication & transcription (not cell cycle specific)
What are the primary targets for DNA alkylating agents?
DNA is the main target. The major mechanism usually involves alkylation of purine bases in DNA.
*Guanine N7 is most common site of alkylation
these crosslinkers can non-specifically prevent replication or transcription and can act specifically to cause mispairing and DNA fragmentation
What are the differences between cross-links caused by alkylating agents and those caused by the platinum antitumor agents? What are the structural and mechanistic bases of these differences?
Alkylating agents - Cross-linking can cause intrastrand linking between two bases on the same strand and interstrand linking of two separate strands.
- Mustards used for therapy have nitrogens that can form 2 covalent bonds
- These react with many nucleophiles. Thiols are very reactive, also amines, cysteine and lysine residues, and glutathione (can “quench” activity).
- Toxicity to cancer cells results from DNA alkylation and cross-linking.
- Non cell cycle specific
Platinum agents - These are covalent crosslinkers, but they don’t have alkyl groups to alkylate with. These are platinum complexes that can bind in two spots, causing the crosslinking (especially with thiols).
- In cells, the aquo form of these platinums are favors. The aquo form reacts primarily with Guanine N-7 and Adenine N-7.
- Most commonly causes intrastrand, then the cell doesn’t know what to do
Which alkylating agents/platinum antitumor agents require activation by an enzymatic process?
Alkylating agents:
- Cyclophosphamide - requires hydroxylation by hepatic CYP450, then this hydroxylated metabolite must be converted to PM in the tumor (PM can do the cross-linking; this also produces acrolein)
*more modest side effect, but also causes hemorrhagic cystitis (acrolein is toxic to bladder mucosa)
- Ifosfamide - similar to cyclophosphamide
Which was the first prototype of the platinum anticancer drugs? What is the cell cycle specificity? What side effects differentiate platinums from alkylating agents?
Cisplatin - non-enzymatically converted to aquo form in cell, then primarily produces intrastrand cross-links.
- cell cycle non-specific, but a little more disruptive in G1, since it messes with transcription
- Side effects: dose-limiting nephrotoxicity (unique), N/V, peripheral neuropathy, ototoxicity, minimal bone marrow toxicity (this is good for combo products)
What are the most important mechanisms for resistance to alkylating agents and platinum antitumor agents?
- Increased expression of DNA repair enzymes
- Increase intracellular concentration of non-protein thiols, especially glutathione. This detoxifies the drugs. The reactive thiols intercept the reactive intermediates of alkylating agents
- Increased expression of cellular glutathione S-transferase (GST), which speeds up the reaction with thiols
What are the side effects of using alkylating agents?
- Bone marrow and gut mucosa are especially sensitive due to rapidly proliferating cells (myelosuppresion, N/V)
- Monoadducts are mutagenic and carcinogenic, meaning there are incidences of second malignancies…… meaning it causes cancer
What can we give Mesna to help with?
Mesna contains a charged sulfonate group, so it doesn’t penetrate cells. It ends up accumulating in the urine. This is good for patients on cyclophosphamide, since one of the byproducts of cyclophosphamide’s acitvation is acrolein, which causes hemorrhagic cystitis (in bladder).
Mesna has a free thiol that reacts and inactivates acrolein metabolites in the urine, thus blocking hemorrhagic cystitis.
What is the role and functions of topoisomerases in DNA replication?
Topoisomerases reduce localized supercoiling that occurs during transcription and translation. They also provide access to double stranded DNA by enzymes that are needed for replication, etc.
Type I Topoisomerase - Cuts one strand of double stranded DNA, relaxes the remaining strand, then puts it back together.
Type II Topoisomerase - Catalyzes double-stranded DNA breaks, which relieves torsional strain and untangles DNA. It can undo catenated DNA (chain-linked)
What are the MOAs of topoisomerase inhibitors?
Topoisomerase I inhibitor - Binds to topo I and the DNA, which locks topo I onto the sites at the breaks in ssDNA. This stops DNA replication. These inhibitors can also insert themselves into the DNA, called intercollating, (due to polycyclic aromatic motif) so they act as a physical barrier preventing replication.
- Ex. camptothecin (not used), topotecan, irinotecan (prodrug)
Topoisomerase II inhibitor - Only inhibitors that produce double stranded DNA breaks are considered cancer chemotherapies. This type of inhibitor intercalates DNA, causes DNA damage due to free radicals, most importantly inhibits topo II
- Ex. Doxorubicin (“the red devil”), daunorubicin, epirubicin, idarubicin, liposomal doxorubicin
