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142 Cards in this Set
- Front
- Back
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What is better for cancer: poly or monotherapy?
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Polytherapy
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What are the principles for polypharmacy?
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Use drugs that have demonstrated activity against the particular cancer being treated
Minimize overlapping host toxicities Maximize mechanistic diversity |
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What is the definition of adjuvant therapy?
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Chemotherapy after sugery/radiation to eliminate residual disease
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What are the risks inherent to adjuvant therapy?
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You could be blasting someone with chemo who's already cured
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What is the definition of neoadjuvant therapy?
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Chemotherapy before surgery/radiation, to shrink the tumor down to a size that can be surgically removed or treated with radiation
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What is the definition of radiosensitization?
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Chemotherapy to make tumor cells more sensitive to radiation
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What are the grades of toxicity severity?
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1: mild
2: moderate 3: severe - require hospital 4: life-threatening |
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What is the definition of the maximum tolerated dose?
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The highest drug dose that doesn't cause unacceptable (grade 3-4) toxicity
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What is the definition of dose-limiting toxicity?
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Toxicity that dictates when a drug treatment should cease escalation/be reduced
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How are chemotherapy drugs normally dosed?
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Based on body surface area (rather than mass): mg/m^2
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How do you calculate body surface area?
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With a monogram!
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What are the different descriptors of responses to chemotherapy?
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Cure: 5+ years with no disease
Complete response/remission: no detectable disease < 5 years Partial response/remission: at least 50% shrinkage Stable disease: tumor stays same size Progressive disease: tumor increases in size during treatment |
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What are the major mechanistic categories of anticancer drugs?
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Direct DNA damaging agents
Antimetabolites Inhibitors of chromosomal structure/organization Signalling pathway modulators |
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What is the mechanism of the direct DNA damaging agents?
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Chemicals that cause DNA strand breaks or covalent modifications
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What is the mechanism of the antimetabolites?
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Analogs of purines/pyrimidines and their nucleosides that inhibit metabolism of normal counterparts,including substituting for them within RNA and DNA
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What is the mechanism of the inhibitors of chromosomal structure/organization?
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Microtubule antagonists
Topoisomerase inhibitors |
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What are some of the mechanisms used by signalling pathway modulators?
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Tyrosine kinase inhibitors
Angiogenesis inhibitors Immune response induction Steroid hormone response modifiers |
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What are the different classes of drugs that can cause direct DNA damage?
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Alkylating crosslinkers: nitrogen mustards, nitrosureas
Non-Alkylating crosslinkers: platinum drugs |
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What are some of the drugs that are alkylating crosslinkers?
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Mechlorethamine
Cyclophosphamide Carmustine Lomustine |
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What kinds of drugs are derived from nitrogen mustards? What class/general mechanism do they belong to?
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Mechlorethamine
Cyclophosphamide Class: Aklylating crosslinkers Mechanism: Direct DNA damage |
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What kinds of drugs are derived from nitrosoureas? What class/general mechanism do they belong to?
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Carmustine
Lomustine Class: alkylating crosslinkers Mechanism: direct DNA damage |
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What's the mechanism of the alkylating cross linkers?
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DNA-DNA interstrand crosslinking
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What types of alkylating crosslinkers require metabolic activtion?
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Cyclophosphamide
Lomustine |
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What is the mechanism of resistance to the alkylating crosslinkers?
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Increased inactivation by glutathione, other thiol-containing proteins
Increased DNA repair |
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What's the route of elimination for mechlorethamine?
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Decomposition
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What's the route of elimination for cyclophosphamide?
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Hepatic metabolism
Renal excretion |
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What's the route of elimination for carmustine?
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Hepatic metabolism and decomposition
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What's the route of elimination for lomustine?
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Renal excretion
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What side effects are shared by all of the alkylating crosslinkers?
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Myelosuppression:
1-2 week nadir in the mustard drugs 4-6 week nadir in the nitrosourea drugs Severe nausea and vomiting |
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What side effect (from among the alkylating crosslinkers) is unique to cyclophosphamide?
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Cyclophosphamide (also for ifosfamide)
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What drug are you able to give to people to protect against hemorrhagig cystitis for people on cyclophosphamide?
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MESNA
Also can give this in ifosphamide |
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Under what situations do you have to adjust the dose for:
Mechlorethamine? Cyclophosphamide? Carmustine? Lomustine? |
Mechlorethamine: none
Cyclophosphamide: renal dysfunction Carmustine: none Lomustine: renal dysfunction |
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Which of the alkylating crosslinkers have a risk of extravasation?
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Mechlorethamine: vesicant
Carmustine; irritant |
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What are the non-alkylating crosslinkers?
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Cisplatin
Carboplatin Oxaliplatin |
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What types of a drugs are cisplatin, carboplatin, and oxaliplatin?
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Non-alkylating crosslinkers
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What's the biochemical activity of the non-alkylating crosslinkers?
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DNA-DNA interstrand crosslinking
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What's the resistance mechanism to the non-alkylating crosslinkers?
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Increased inactivation by glutathione and other thiol containing proteins
Increased DNA repair |
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What's the elimination of the non-alkylating crosslinkers?
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Renal excretion
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What are the common toxicities of cisplatin?
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RENAL TOXICITY!: DLT, cumulative
Neurotoxicity Ototoxicity Severe nausea, vomiting |
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What is the dose-limiting toxicity of cisplatin?
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Renal toxicity
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What is the dose-limiting toxicity of carboplatin?
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Myelo-suppression
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What is the dose-limiting toxicity of oxaliplatin?
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Neutrotoxicity
It's also cumulative! |
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What are the toxicities of carboplatin?
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Renal toxicity
Myelosuppression (DLT!) Severe nausea, vomiting |
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What are the toxicities of oxaliplatin?
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Renal toxicity
Myelosuppression Neurotoxicity: DLT, CUMULATIVE! |
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When do you have to dose adjust the non-alkylating crosslinkers?
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Renal dysfunction
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What non-alkylating cross linker requires IV hydration and diuresis?
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Cisplatin
Because of the renal toxicity |
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What are the extravasation hazard of the non-alkylating crosslinkers?
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Cisplatin: vesicant
Carboplatin: irritant Oxaliplatin: vesicant |
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What drugs are thymidine nucleotide antagonists?
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Fluorouracil
Capecitabine Pemetrexed Methotrexate |
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What is the mechanism of fluorouracil, capecitabine, pemetrexed, and methotrexate?
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Tymidine nucleotide antagonists
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What is the mechanism of fluorouracil?
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1. Metabolism to FdUMP
2. FtUMP/TS/folate covalent complex formed INHIBITION OF THYMIDYLATE SYNTHASE |
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What is the effect of inhibiting thymidylate synthase?
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Stalled replication
Uracil-DNA incorporation DNA strand breaks |
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What is the biochemical action of capecitabine?
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1. Metabolism to 5FU
2. Metabolism to FdUMP 3. Formation of FdUMP/TS/folate covalent complex THYMIDYLATE SYNTHASE INHIBITION |
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Which of the thymidine nucleotide antagonists are uracil analogs? Folate analogs?
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Uracil analogs: fluorouracil, capecitabine
Folate: pemetrexed, methotrexate |
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What is the mechanism of pemetrexed?
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Tight binding to TS at the folate site
TS inhibition |
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What is the mechanism of methotrexate?
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1. Tight binding to DHFR at the folate site
2. Depletion of the active (reduced) folates TS inhibition |
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What is necessary for the activity of thymidylate synthase?
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Folate in the folate binding site
Nucleotide |
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What is the relationship between fluorouracil and capecitabine?
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Capecitabine is metabolized into 5FU
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What is the mechanism of resistance to 5FU and capecitabine?
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Increased thymidylate synthase
Reduced folate cofactor |
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What are the mechanisms of resistance to pemetrexed?
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Increased TS
Decreased drug uptake Decreased drug retention |
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What are the mechanisms of resistance to methotrexate?
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Increased DHFR
Decreased drug uptake, retention Decreased conjugation to glutamate groups (needs to be conjugated to stay inside the cell) |
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What's the route of elimination for:
5FU? Capecitabine? Pemetrexed? Fethotrexate? |
5FU: hepatic metabolism
Capecitabine: hepatic metabolism Pemetrexed: renal excretion Fethotrexate: renal excretion The uracil drugs are the same elimination The folate analogs are the same elimination |
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What's the relationship between thymidylate synthase and folates?
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What reaction is performed by thymidylate synthase?
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dUMP --> dTMP
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What kind of cofactor is required for the activity of thymidylate synthase?
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Reduced folate (THF)
they donate a carbon |
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What enzyme regenerates folates for dTMP synthesis?
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Dihydrofolate reductase
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What agent can you give along with 5FU to incrase toxicity?
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Leucovorin
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What's the mechanism for increasing 5FU toxicity with leucovorin?
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It allows folate depleted tumor cells to keep their TS running, which increases toxicity
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What are the different mechanisms of inhibiting choromsomal structure/organization in chemotherapy?
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Microtubule antagonists
Topoisomerase inhibitors |
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What are the different agents that work on microtubules?
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Vinca alkaloids: microtubule destabilization
Taxane: microtubule stabilization |
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What's the mechanism of the TOPO1 inhibitors?
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After the topo1 makes a snip in the DNA, it can't bind on the other side of the snip, meaning that the DNA can't be annealed back together again
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How do to the topoisomerase II inhibitors work?
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They stabilize TOPOII when it's on the DNA, ultimately leading to protein disruption and a DS break
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What is the mechanism of the vinca alkaloids?
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Microtubule destabilizers
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What are the different vinca alkaloid derivatives used in chemotherapy?
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Vincristine
Vinblastine Vinorelbine |
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What is the mechanism of resistance to the vinca alkaloids?
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MDR mediated by P-glycoprotein
Mutations int he tubulin protein that decrease drug affinity |
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What's the route of elimination for the vinca alkaloids?
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Hepatic metabolism
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What is the DLT of vincristine?
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Neurotoxicity
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What is the DLT of vinblastine and vinorelbine?
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Myelosuppression
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What are the toxicities of vinoblastine and vinorelbine?
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Myelosuppression (DLT)
Neurotoxicity |
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When do you have to dose adjust the vinca alkaloids?
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When there's hepatic dysfunction
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What is the extravasation hazard for the vinca alkaloids?
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Vesicants
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What is the mechanism of the taxanes?
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Microtubule stabilizers
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What are the drugs derived from taxanes used in chemotherapy?
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Paclitaxel
Docetaxel |
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What's the mechanism of resistance to the taxanes?
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MDR mediated by PgP
Mutations in tubulin that decrease drug affinity |
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What's the route of elimination of the taxanes?
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Hepatic metabolism
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What are the toxicities of the taxanes?
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Myelosuppression
Neurotoxicity Hypersensitivity: common and severe Skin toxicity |
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What do you have to do because of the hypersensitivity reactions to the taxanes?
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Premedicate to prevent it
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When do you have to dose adjust the taxanes?
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Hepatic dysfunction
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What's the extravasation risk with the taxanes?
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Vesicants
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What's the DLT of the taxanes?
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Myelosuppression
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What is leucovorin?
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A precursor to folate
Increases the toxicity of 5-FU Rescues cells from MTX |
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How does leucovorin rescue cells from MTX toxicity?
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MTX is inhibiting their DHFR, so they need a source of folate.
In tumor cells, there aren't enough transporters to import the leucovorin, but there are in regular cells. The folate from leucovorin is enough to save those cells |
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What drugs inhibit topoisomerase 1?
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The camptothecins:
Topotecan Irinotecan |
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What is the mechanism of the camptothecins: topotecan and irinotecan?
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Inhibition of TOPOI
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What is the way that resistance is developed to the camptothecins?
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MDR mediated by PgPs
Mutations in TOPOI that decrease drug affinity Decreased expression of TOPOI |
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What are the mechanisms of resistance to irinitecan?
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MDR mediated by PgPs
Mutations in TOPOI that decrease drug affinity Decreased expression of TOPOI Decreased metabolic converstion to SN-39 |
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What is a requirement for the activityof irinotecan?
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Metabolic converstion to SN-38
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What is the route of elimination of topotecan?
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Renal excretion
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What is the route of elimination of irinitecan?
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Biliary excretion
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What are the toxicities of the TOPOI inhibitors?
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Myelosuppression
GI mucositis Nausea and vomiting (rare) |
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What is the DLT of topotecan?
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Myelosuppression
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What is the DLT of irinotecan?
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GI mucositis
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When do you have to dose adjust topotecan?
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Renal dysfunction
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When do you have to dose adjust irinitecan?
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Hepatic dysfunction
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What are the extravasation hazards of the TOPOI inhibitors?
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They're only irritants
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What are the TOPOII inhibitors?
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Doxorubicin
Etoposide |
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What is the mechanism of Doxorubicin and Etoposide?
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TOPOII inhibitors
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What is the mechanism of Doxorubicin?
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TOPOII inhibition
Oxygen free radical formation-->DNA strand breaks |
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What is the mechanism for etoposide?
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TOPOII inhibition
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What is the mechanism of resistance to doxorubicin?
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MDR mediated by PgP
Mutations in TOPOII that decrease affinity Decreased expression of TOPOII Incrased inactivation by glutathione |
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What is the mechanism of resistance to etoposide?
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MDR mediated by PgP
Mutations in TOPOII that decrease affinity Decreased expression of TOPOII |
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What is the route of elimination for doxorubicin?
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Biliary excretion
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What is the route of elimination for Etoposide/
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Renal excretion
Hepatic metabolism |
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What are the toxicities of Doxorubicin?
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Myelosuppression
Cardiotoxicity GI mucositis Nausea and vomiting |
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What are the toxicities of Etoposide?
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Myelosuppression
GI mucositis Nausea and vomiting |
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In what conditions do you need to adjust the dose of the TOPOII inhibitors?
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Renal or hepatic dysfunction
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What are the extravasation hazards for doxorubicin?
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Vesicant
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What are the extravasation hazards for etoposide?
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Irritant
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What are different ways that signalling pathways can be altered in anticancer drugs?
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Tyrosine kinase inhibitors
Angiogenesis inhibitors Immune response induction Steroid hormone response modifiers |
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What is most common way to alter signalling pathways with drugs?
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Antibodies!
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What particular tyrosine kinase causes problems in cancer, commonly? What causes it?
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BCR-ABL
It comes from the Philly chromosome |
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What are the drugs that inhibit the TK Bcr-Abl?
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Imatinnib
Nilotinib Dasatinib |
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What is the action of imatinib, nilotinib, and dasatinib?
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Inhibition of Bcr-Abl, a tyrosine kinase
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What additional enzyme does dasatinib inhibit?
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Src kinase
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What is the mechanism of resistance to the tyrosine kinase inhibitors?
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Bcr-Abl mutations
Increased Bcr-Abl expression |
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What is the route of elimination for the tyrosine kinase inhibitors?
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Hepatic metabolism
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What are the toxicities for the tyrosine kinase inhibitors?
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Myelosuppression
CNS toxicity Skin toxicity Lung toxicity CV toxicity |
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In what situations do you need to dose adjust the tyrosine kinase inhibitors?
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Hepatic dyrfunction
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What are the different angiogenesis inhibitors?
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Bevacizumab
Sunitinib Sorafenib |
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What is the class of Bevacizumab, Sunitinib, and Sorafenib?
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Angiogenesis inhibitors
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What is the mechanism of bevacizumab?
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Binding to free VEGF-->inhibition of angiogenesis signalling
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What is the mechanism of Sunitinib and Sorafenib?
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Binding to VEGF receptor-->inhibiting angiogenic signalling
Inhibition of other receptor kinases |
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What's the mechanism of resistance to:
Bevacizumab? Sunitinib? Sorafenib? |
Bevacizumab: unknown
Sunitinib: unknown Sorafenib: expression of targeted kinases |
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What's the route of elimination for bevacizumab?
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Gradual degradation
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What's the route of elimination for sunitinib?
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Hepatic metabolism
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What's the route of elimination for sorafenib?
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Hepatic metabolism
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What are the toxicities to the angiogenesis inhibitors?
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CV toxicitiy (HTN, thromboembolism)
CNS toxicity (headaches, fatigue) Hemorrhage Myelosuppression |
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When should you dose adjust the angiogenesis inhibitors?
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Sunitinib: hepatic dysfunction
Sorafenib: hepatic dysfunction |
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What signalling pathway do the angiogenesis inhibitors act against?
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VEGF signalling
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Myelosuppression
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Killing of the bone marrow
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Nonmyelosuppressive toxicities
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Ways that toxicities occur
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Routes of elimination
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Ways that elimination occurs
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You can bleed out!
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Not good.
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