Term
What is defined as a malignant neoplasm, a genetic disease that is very adaptable and is a combination of a large group of different diseases/multiple mutations; unregulated cell growth (primary tumor and metastatic disease [most malignancies]) |
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Definition
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Term
What are the hallmarks of cancer (7) |
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Definition
Self sufficiency in growth signals (constitutively activated growth factor signaling)
Insensitivity to antiproliferative signals (inactivate p53 extends lifespan- 30 replicates)
Evading apoptosis (inactivated cell death pathways)
Limitless replicative potential (activation of telomerase / ALT)
Sustained angiogenesis (activated VEGF [vascular endothelial growth factor] signaling)
Tissue invasion and metastasis (loss of cell-to-cell interactions)
Genetic instability (mutation or chromosomal rearrangements) |
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Term
How are cancer cells insensitive to antiproliferative signals? |
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Definition
inactivate p53 extends lifespan |
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Term
How do cancer cells have limitless replicative potential? |
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Definition
activation of telomerase / ALT (telomerase loses function in normal cells) |
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Term
How do cancer cells invade other tissues and metastasize? |
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Definition
they lose cell-to-cell interactions |
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Term
90-95% of cancers attributed to _____________ factors |
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Definition
environmental (pollutants, industrial environment, cigarettes) |
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Term
What are cancers associated with mucosal surfaces?
glandular cells? |
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Definition
squamous cell carcinomas
adenocarcinomas
(2 main types of cancers seen in head and neck) |
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Term
**early detection of local disease- cure rate is ___% |
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Definition
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Term
What are the most common risk factors of cancers? |
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Definition
alcohol and tobacco use (why higher percent of men have head and neck cancer) |
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Term
Why is head and neck cancer the 1st or 2nd most common site for malignancy in asia? |
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Definition
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Term
Why is US head and neck cancer increasing? |
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Definition
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Term
What is associated with nasopharyngeal cancer? |
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Definition
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Term
What is associated with throat cancer? |
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Definition
gastroesophageal reflux disease (constant inflammation) |
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Term
What are the steps to diagnosing cancer? |
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Definition
Physical examination Diagnostic tests (Biopsy- Histopathology) Imaging – Staging- local or advanced disease X-rays, MRI, PET scan |
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Term
What are the parameters for staging a solid tumor? |
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Definition
T – Size of primary tumor (T1-T4) N – Involvement of regional lymph nodes (N1-N3) M – Whether distant metastases are present (M0-M1) |
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Term
What are the stages of cancer? |
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Definition
I-IV
Stage I-early development, usually curable Stage IV- poor prognosis, goal will not be to cure, it will be to improve the quality of life (palliation) |
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Term
Which parameter is a poor prognosis, more likely to get recurrent disease = resistance |
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Definition
involvement of lymph nodes |
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Term
What do the results of staging a sold tumor determine? |
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Definition
Type of treatment (modalities) - Surgery, Radiation Therapy, Chemotherapy Goal of treatment (cure vs. palliation) |
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Term
*What is the key to combination chemotherapy? |
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Definition
-you want to use combining agents with different mechanisms of action which will complement each other and reduce development of resistance -non-cross resistant -Avoid overlapping toxicities- choose drug with different types of toxicity or timing of toxicity |
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Term
What is using anticancer drugs with other cancer treatments (radiation and surgery) |
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Definition
combined modality chemotherapy
(single agent-monotherapy rarely used) |
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Term
What type of drug is applied before surgery (preoperative); initial therapy?
What type of drug is used after surgery (post-operative) to debulk the tumor first?
What type of drug is used to increase life expectancy without curative intent (ease symptoms)? |
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Definition
neoadjuvant
adjuvant
palliative |
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Term
Will combining a cytotoxic drug with cytostatic increase activity? |
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Definition
yes- cytotoxic (induces DNA damage) cytostatic (inhibits DNA repair) |
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Term
What is anticancer concept that cytotoxic chemotherapeutics undergo first order kinetics. It will a kill a percentage of tumor cells (not 100%) and remaining cells will re-accumulate between chemotherapy doses |
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Definition
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Term
Why would you want to combine drugs? |
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Definition
concept of log-kill - so you want to have each drug killing a percentage of cells as long as you keep the dose high (do that by having different dose limiting toxicities) |
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Term
Why would you usually see surgery first and then adjuvant chemotherapy for large tumors? |
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Definition
Because cytotoxic agents only kill actively dividing cells and that often happens when you remove a portion of the tumor and the cells remaining begin dividing
(small tumors may be in neoadjuvant setting) |
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Term
What are some of the side effects due to the toxicity in rapidly dividing normal cells from cytotoxic chemotherapeutics? |
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Definition
• Bone marrow- Myelosuppresssion (decrease bone marrow activity) • Digestive tract- Mucositis (inflammation/ulcer) • Hair follicles- Alopecia (hair loss) |
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Term
When can a tumor be visually detected/diagnosed?
When is it lethal? |
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Definition
1 gm (1 billion tumor cells)
1 kg (1 trillion) |
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Term
What is it not a good time to be treating with chemotherapy alone after a tumor has been detected? |
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Definition
We need chemo debulking (surgery) to push it back down to exponential growth phase (actively growing) because by the time it is detected the rate of growth is slower
no surgery- takes a lot more cycles of chemo --> gain resistance |
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Term
What is the hypothesis that tumor cells are genetically unstable and tend to mutate into different cell clones
(Probability of resistance cells depends on ______) |
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Definition
Goldie-Coldman hypothesis
tumor size |
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Term
Why are single agents rarely used to cure cancer? |
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Definition
Genetic Diversity (heterogeneity) and limited log kill |
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Term
What are the drugs that target the S phase of the cell cycle?
How should you dose these drugs? |
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Definition
antimetabolites, hydroxyurea, topotecan /irinotecan, etoposide
no good to use these drugs unless a lot of cells replicating, better to use lower dose more often (every day) because only a fraction of cells are actively making DNA |
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Term
What are the drugs that target the M phase? |
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Definition
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Term
What anticancer drug works by directly modifying DNA. Most effective during DNA synthesis |
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Definition
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Term
What drugs block (irreversibly) DNA synthesis/prevents cell division – most effective during S-phase |
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Definition
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Term
What drugs bind DNA to prevent replication or RNA synthesis (both use DNA template-insert into DNA) |
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Definition
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Term
What drugs prevent cell division by binding to tubulin & altering function of mitotic spindle/microtubule (can't go into mitosis, chromosomes won't attach and separate) |
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Definition
mitotic inhibitors (Vinca alkaloids and taxanes) |
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Term
What drugs modify growth of hormone dependent cancers |
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Definition
Hormones and hormone antagonists |
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Term
What drugs target topoisomerases (work on structure of DNA, important for replication, untangling chromosome, and segregation |
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Definition
captothecins [topotecan, irinotecan] and etoposide |
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Term
What drugs target specific receptors (delivers linked cytotoxic directly to tumor) |
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Definition
Antibodies and antibody-drug conjugates |
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Term
What drugs are small molecules that inhibit receptor tyrosine kinases or downstream signaling molecules |
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Definition
Signal transduction inhibitors |
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Term
induce cellular differentiation to inhibit tumor cell growth |
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Definition
Differentiation agents (retinoic acid) |
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Term
What is the most active chemotherapeutic used? |
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Definition
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Term
Alkylating drugs are (narrow or broad) spectrum activity against (solid, hemtological, or both) malignancies.
Typically used in (monotherapy or combination) regimens. |
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Definition
Broad spectrum activity against a range of solid and hematological malignancies. Typically used in combination regimens. |
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Term
What is the dose limiting toxicity of alkylating drugs? |
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Definition
bone marrow suppression (it is cytotoxic so hits rapidly dividing cells-a lot of dividing in bone marrow) - we want to combine drugs that do not have bone marrow suppression with alkylating drugs |
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Term
What are the mechanisms of action for alkylating drugs?
When are cells most susceptible? |
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Definition
Transfers alkyl groups to a nucleophile (modifies DNA-nitrogen in DNA)
Bifunctional crosslinks DNA (*N7 guanine* position) to other reactive groups that interfere with base pairing and cause strand breaks Cells in late G1 and S phase most susceptible and cause G2 arrest |
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Term
What are the mechanisms of resistance against alkylating drugs? |
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Definition
DNA repair, decreased uptake (efflux), and detoxification (highly reactive-glutathione conjugation via glutathione S transferase induction instead of interacting with DNA) |
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Term
Cyclphosphamide is an _______ agent |
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Definition
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Term
*When is cyclophosphamide, an alkylating agent (nitrogen mustard), active |
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Definition
It is a prodrug so it must be activated by CYP in the liver (metabolites are active) |
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Term
What drug crosslinks N7 guanine on DNA (get a single covalent attachment) and has a broad range activity against solid tumors, especially squamous cell carcinomas and used synergesitically with other classes/used in combination? |
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Definition
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Term
What is the dose limiting toxicity of platinums, especially Cisplatin? |
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Definition
nephrotoxicity (want to use with another drug that has different dose limiting toxicity) |
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Term
What is the primary mechanism of resistance of platinums? |
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Definition
DNA excision repair mechanisms |
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Term
What are the different groups of antimetabolites? |
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Definition
purine analogs
pyrimidine analogs (interfere with enzymes involved in pyrimidine synthesis)
Folic acid antagonists (interfere with synthesis of nucleotides) |
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Term
What drug has broad spectrum activity against a range of solid and hematological malignancies. Typically used in combination regimens because of bone marrow suppression and GI toxicity? |
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Definition
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Term
What is mechanism of action of antimetabolites and when are cells most susceptible? |
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Definition
Inhibit nucleotide synthesis (Purine Antagonists, Folic Acid Antagonists, Pyrimidine Antagonists)
Cells in late G1 and S phase most susceptible |
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Term
How does MTX (methotrexate) and 5-FU work synergestically to treat colon cancer? |
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Definition
MTX inhibits dihydrofolate reductase (DHFR- 1st rate limiting step/initiation of deoxyribonucleotide)
5-FU inhibits thymidylate synthetase later in pathway
They inhibit 2 ESSENTIAL enzymes in the same pathway so if you get resistance to 1 drug the other one will still work. |
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Term
What is the dose limiting toxicity for antimitotics (vinca alkaloids and taxanes)? |
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Definition
Bone marrow suppression and GI toxicity |
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Term
How is the mechanism of resistance of antimitotics different from alkylating agents? |
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Definition
antimitotics-Increased efflux via P-gylcoprotein
alkylating agens- increase in DNA repair |
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Term
Taxanes or Vinca alkaloids
Mechanism of action: -Inhibition of microtubules polymerization, disruption of mitotic spindle and chromosome separation, M phase cell cycle arrest
-Stabilizes GDP-bound tubulin, inhibition of mitosis and cell division (M phase block). “frozen Mitosis” |
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Definition
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Term
What inhibits topoisomerase II by DNA intercalation (inserts itself between 2 bases and DNA molecule), alters in membrane fluidity and ion transport, and generation of free radicals? |
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Definition
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Term
what is the dose limiting toxicity of antitumor antibiotics? |
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Definition
Bone marrow suppression & *Cardiac toxicity* (doxorubicin) |
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Term
What is the main difference between alkylating agents and molecularly targeted therapeutics? |
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Definition
Alkylating agents are not sequence specific, they induce a lot of damage
Molecularly targeted- inhibit specific pathways, main effort is to target receptor tyrosine kinases that are associated with growth factor receptors |
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Term
What are some tumor-related factors as to why chemo fails? |
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Definition
-Decreased intracellular drug levels (efflux of drugs out of cells) -Increased drug inactivation (of prodrug like cyclophosphamide) or decreased conversion to active forms -Enhanced repair of the drug-induced defect -large tumor size -tumor location (vascularization-could be wrapped around large artery) |
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