Neoplasia Flashcards
Three phases of cancer formation?
1) preneoplastic epigenetic changes
2) cancer transformation (initiation)
3) Progression
Mass of detectable tumors? Mass of fatal tumors?
- At least 1 gram
- Usually 1 kg
What three major classes of genes are usually mutated in cancer?
- DNA repair genes
- Tumor suppressor genes
- Protoncogenes
What are three different ways oncogenes can stimulate cells?
- overexpression
- expression at the wrong place/time
- unresponsive to negative regulation
What receptor is overexpressed by KSHV (Kaposi’s)?
G protein receptor that signals without ligand
With HTLV-1 (human T cell lymphotrophic virus), which growth factor receptor is overexpressed? in which cells?
IL-2 receptor in infected T cells
Which EGF receptor is overexpressed in breast cancer, ovarian cancer, etc? Consequence?
ERBB2 (Her-2-Neu)
Hypersensitivity to EGF signaling
What drug targets ERBB2?
Herceptin
In CML, a chromosome translocation produces what hybrid oncogene product? Consequence?
Bcr-Abl – Abl inhibitory domain is lost and cell is constitutively activated
What drug inhibits Abl kinase?
imatinib (Gleevec)
What is B-Raf? In melanomas, colorectal cancers, and thyroid cancers, what mutation is observed in B-Raf? Consequence?
- protoncogene; member of Raf threonine/serine protein kinase family
- Regulator downstream of Ras
- V600E
- signals on its own bypassing upstream receptors
What drug/drug type is used to treat melanomas with the BRAF V600E mutation?
protein kinase inhibitor = VEMURAFENIB
What pathway is regulated by PTEN (phosphatase and tensin homolog)?
What is the function of this pathway?
- phosphatidylinositol-3-kinase (PI3K)/Akt pathway
- PTEN phosphatase protein is a tumor suppressor
- important for cell activation and apoptosis resistance
What fusion gene can be formed by translocation with the ALK (anaplastic lymphoma kinase) gene? How does this fusion gene product function and in what cancers is it often found?
- ALK gene codes for tyrosine kinase receptor of insulin super family
- EML4-ALK fusion gene
- Dimerizes without the need for a ligand and constitutively signals
- Lung cancers, particularly NSC adenocarcinomas in young, non-smokers
What protein kinase inhibitor can be used to treat EML4-ALK positive lung cancers?
crizotinib
What is an example of a common GAP (GTPase activating protein)?
NF-1
What gene regulates B-catenin? What is the function of B-catenin?
- APC (adenomatous polyposis coli) = tumor suppressor protein that acts as antagonist in the Wnt pathway
- APC docks on B-cat that isn’t bound to E cadherin and B-cat is degraded
- Wnt frees B-cat from APC to act as TF to activate various proliferating genes (wound healing)
- TF involved in cell-cell contact signaling
Defective APC is most commonly found in what cancers?
colorectal cancers and benign intestinal polyps
What is the normal function of let7 miRNA? Deleted/underexpressed in what cancer type?
- Targets 3’ UTR of Ras and downregulates Ras protein expression
- lung cancer
What 4 types of cancer respond only occasionally to chemotherapy?
- Non-small lung cancer
- melanoma
- pancreatic and hepatocellular carcinoma
- renal and prostate cancer
What are two anti-mitotic drugs?
- paclitaxel
- vincristine
How does paclitaxel work?
- Promotes tubulin polymerization and blocks disassembly required for mitosis
- Cells are arrested in mitosis
Three unusual side effects of paclitaxel?
neuropathy, hypersensitivity, arrhythmias
How does vincristine work?
Binds tubulin and inhibits microtubule formation (opposite of paclitaxel)
Unusual vincristine side effect? Cause?
neurotoxicity because microtubules are important in neuronal transport
What drugs are substrates for CYP450?
paclitaxel (anti-mitotic) - inactivated
doxorubicin (antibiotic)
cyclophosphamide (pro-drug, alkylating agent)
ondansetron (anti-emetic)
Two antibiotics used in chemotherapy? Natural source?
doxorubicin
dactinomycin
Soil microbe Streptomyces
What cancers are often treated with doxorubicin?
hematologic cancers and solid tumors
How does doxorubicin work?
Inhibits topoisomerase II, intercalates DNA, binds cell membranes, and generates free radicals
How does dactinomycin work?
Binds dsDNA by intercalating between G-C bp – inhibits RNA synthesis (RNA needed all the time)
Unusual side effects of doxorubicin? Treatment for more severe side effect?
- Cardiotoxicity, red urine
- dezroxane = iron chelator
How is doxorubicin eliminated?
Biphasic - peak half-lives at 3 and 30 hours (CYP450 in liver)
What is one alkylating agent used in cancer treatment?
Cyclophosphamide (nitrogen mustard)
How does cyclophosphamide work?
- transfers alkyl groups to cellular constituents
- Damages and cross-links DNA
- Targets REPLICATION - fork stops at alkyl groups
Secondary use for cyclophosphamide?
immunosuppression in transplant patients
How is cyclophosphamide metabolized?
Pro-drug activated by P450 proteins in liver
Two anti-metabolites used in cancer treatment?
Methotrexate and 5-fluorouracil, also 6-MP
Methotrexate inhibits which enzyme and synthesis of which products?
Dihydrofolate reductase - THF, thymidylate, nucleotides, amino acids
Dual functions of 5-FU?
- incorporated into RNA/DNA – inhibits RNA functioning/processing
- inhibits thymidylate synthase – inhibits biosynthesis of pyrimidines
Two things to consider with methotrexate?
- can accumulate in ascetic, pleural, peritoneal fluid
- significant interactions with drugs that bind to plasma proteins (salicylate, sulfonamides, phenytoin), which can displace metho from normal binding proteins and cause increased tox
What enzyme degrades 5-FU? Clinical application?
- PRO-DRUG
- Dihydropyrimidine dehydrogenase
- individuals w/ compromised enzyme function can experience drug tox
What is dexamethasone used in some cancer therapies?
- immunosuppressant
- allows greater access to tumor by drugs by suppressing tumor-associated immune cells
What are two hormonal agents used in treating breast cancer?
Tamoxifen and anastrozole
What four factors determine the degree of myelosuppression in chemo patients?
- dose/schedule
- age
- prior therapy
- nutritional state and liver/kidney health
How are chemotherapy regimens applied to allow blood counts to recover?
6 week cycles
What can be administered to patients to inhibit myelosuppression? How do they help?
- granulocyte colony-stimulating factor (filgastrim)
- granulocyte-monocyte colony stimulating factor (sargramostim)
- enhance neutrophil recovery after chemo
Where is the vomiting receptor center/chemoreceptor trigger zones in brain? Vomiting sensors rich in what 4 receptor types?
- medulla
- histamine, 5-HT3, dopamine, cholinergic
What is the 5-HT3 receptor antagonist prototype?
Ondansetron
Why is ondansetron used in chemo patients?
anti-emetic
Pharmacokinetics of ondansetron?
- Metabolized by P450 pathway
- effects persist after it disappears from circulation suggesting prolonged interaction with receptor
What is prednisone? Why is it used in cancer patients?
- adrenocorticoseroid; potent lympholytic
- suppress nausea; decrease BC discomfort by reducing tumor inflammation
- combo therapy in leukemia/lymphoma regimens
What Ab fragment targets Her-2/neu in some breast cancer patients?
trastuzumab/heceptin
What Ab fragment targets EGFR in some cancer patients?
cetuximab/erbitux
How does tamoxifen work?
- inhibitor/partial agonist of estrogen receptor (late stage hormone responsive BC, prevention of BC in high risk patients)
- estrogenic activity in the uterus
How does anastrozole work?
- non-steroidal inhibitor of aromatase (estrogen synthesis enzyme)
- binds specifically to heme group of Cyp19/aromatase
Side effects of tamoxifen?
- hot flashes, NV, hair loss, vaginal lining atrophy
- 2-3 fold increase in endometrial cancer risk
Tamoxifen and anastrozole are given orally. Differences in half lives and clinical implications?
- Tam has 7-14 day half life
- Ana has short half life
- Don’t have to take Tam as often
What is the primary drug for lung cancer? Two combination drugs?
Cisplatin; paclitaxel and etoposide
How does the platinum derivative Cisplatin work?
Cross-links and alkylates DNA
Two unusual adverse effects of Cisplatin?
Renal toxicity (hydration) and electrolyte disturbances (check biochem notes)
Etoposide and doxorubicin both target which enzyme? Why is etoposide preferable in treating lung cancer?
- topoisomerase II
- doxorubicin is not taken up as well in the lungs as etoposide
What is the most common GI malignancy?
colorectal cancer
What is the primary drug for GI cancer?
5-FU (thymidylate synthase)
What is the Folfox regimen used for?
In 5-FU resistant cancers, Folfox contains folinic acid which synergizes with 5-FU to inhibit thymidylate synthase (second line therapy)
What is Bevacizumab/avastin used for?
- monoclonal Ab that binds VEGF
- Blocks VEGF binding to VEGFR
- Inhibits angiogenesis
What role does asparaginase play in cancer treatment?
- Used to deprive leukemic cells of asparagine, which they do not synthesize and absorb from the bloodstream
What fusion chromosome is associated with adult CML? Consequence?
- Bcr-Abl oncogene (Philadelphia chromosome)
- highly active Tyr kinase that drives cells to grow and avoid apoptosis
What Ab inhibits the Bcr-Abl oncogene in CML?
Imatinib (complete response in half of patients)
How is Hodgkin’s lymphoma treated? Efficacy?
ABVD = doxorubicin, bleomycin, vinblastine, dacarbazine
Response in 80-90%
Cures in 60%
Combined with radiation
How is non-Hodgkin’s lymphoma treated?
- worse prognosis than Hodgkin’s
- CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone
What is the first line of therapy in androgen-dependent prostate cancer?
- Androgen deprivation therapy (ADT) using gonadotropin releasing hormone (GnRH) agonists or androgen receptor inhibitors
What is an example of a GnRH agonist and how do they work?
- Leuprolide
- Resemble GnRH and trigger a surge in LH resulting in FSH release
What is an important side effect to consider when treating with GnRH agonists? How can it be managed?
- Initially, GnRH agonists - LH – FSH - cause a increase in testosterone release
- BUT eventually cells become desensitized and stop producing LH/FSH, decreasing testosterone production
- Androgen receptor inhibitors can be used to manage initial testosterone increase
Two classes of AR inhibitors? Examples?
- steroidal
- non-steroidal = FLUTAMIDE
How do AR inhibitors work?
Bind to AR and prevent it from translocating to the nucleus and binding DNA
What are three side effects of flutamide?
- non-steroidal AR inhibitors
- ND, reversible liver damage
Why does chemotherapy work poorly for brain cancers?
Most drugs do not cross BBB (work being done on drug delivery = implantable wafer)
What is the nitrosurea drug most useful in treating brain cancer?
Carmustine
How do nitrosurea drugs work (carmustine)?
alkylation of DNA on O6-guanine
What four transporter proteins play a role in drug resistance? Transporter type?
- MRP1, MRP2, P-glycoprotein, BCRP (breast cancer)
- ABC, ATP-binding cassette transporter proteins (efflux pumps)
What 5 anti-neoplastic drugs are P-glycoprotein substrates?
- vincristine, etoposide, taxol, doxorubicin, dactinomycin
What anti-neoplastic drug ia NOT P-glycoprotein substrates?
Methotrexate
What are three resistance mechanisms against alkylating agents?
- increased DNA repair
- Increased permeability of drug
- Increased glutathione production (inactivates drug)
What are three resistance mechanisms against methotrexate?
- decreased polyglutamate-methotrexate formation (highly active form of drug)
- Increased DHFR synthesis
- Mutations in DHFR
What is a resistance mechanism against the pro-drug 5-FU?
changes in the enzymes that convert 5=FU to its active nucleotide form
What are two resistance mechanisms against paclitaxel?
- mutations in Beta-tubulin (target protein)
- increased expression of anti-apoptotic survival proteins (survivin)
In acute promyelotic leukemia, what mechanism prevents terminal differentiation of cancer cells?
- 15:17 translocation generates PML-RARA (retinoic acid receptor alpha) fusion gene
- Fusion receptor product does not respond to physiological retinoic acid which causes differentiation of normal promyelocytes
How can acute promyelocytic leukemia be treated?
PML-RARA responds to high doses of all-trans retinoic acid = terminal differentiation
Successful tumors must attract a blood supply to grow past __ mm
1 mm
What antibody is used against VEGF in cancer treatment?
bevacizumab
What are 2 ways stromal cells may participate in the epithelial-mesenchymal transition?
- macrophages in tumor secrete proteases
- Tumor factors stimulate mesenchymal stem cells in tumor stroma to secrete CCL5 chemokines which stimulates invasive behavior
What are melanomas derived from embryologically? What TF gives then inherent invasive activity?
Neural crest cells; Slug
What enzymes contribute to metastasis by degrading ECM?
matrix metalloproteases
MOST CIRCULATING CANCER CELLS DO NOT SUCCESSFULLY IMPLANT
ovarian cancer ascites and shunting to venous circulation example
Three routes of spread of cancer?
Body cavities, lymphatics, blood
What two cancer types commonly metastasize to bone? Chemokine-receptor pathway?
Breast, prostate
- SDF-1 is made by bone and attracts breast/prostate cancer cells that express CXCR4 chemokine receptor
What is one potential advantage of tumors preferentially using glycolysis?
Metabolite = lactate which may be a building block for fat, DNA, protein in tumors
Why do tumors light up on PET scans using a glucose analog?
Because they increase GLUT1 transporters to import glucose for glycolysis
How do E5, E6, and E7 HPV proteins promote cancer?
- E6 binds p53 and accelerates degradation
- E7 binds and inhibits Rb
- Both E6 and 7 impede apoptosis
- E5 prevents endosome acidification = EGFR inappropriately stimulates proliferation
What are 3 ways the HTLV Tax protein contributes to cancer development?
- activates IL-2 receptor gene
- promotes p53 degradation
- activates other oncogenes
What two cell types are infected by EBV?
epithelial and B cells
What is the major oncogene in EBV?
LMP1
