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84 Cards in this Set

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What are the five major classes of chemotherapeutic agents?
Alkylating Agents
Antimetabolites
Plant Derivatives
Antibiotics
Hormones
Are tumors with high or low growth factors most sensitive to chemo?
High
Does growth fraction increase or decrease with size of tumor?
Decrease
Is the growth fraction increased or decreased by surgery and radiation?
Increased
Do tumor populations become more or less heterogeneous with time?
More heterogeneous, which increases the chances of occurance of drug-resistant cell variants
Why is interval treatment done in chemo?
To allow bone marrow recovery and minimize normal cell toxicity
What can be given to a patient to potentially reduce neutropenia associated with chemotherapy?
G-CSF (primarily used in chemo)
GM-CSF (primarily used in transplantation)
What can be given to a patient to help alleviate the nausea and vomiting commonly associated with chemotherapy?
5-HT (seratonin) antagonists (ondansetron)
D2-receptor antagonists (prochlorperazine and metoclopramide)
What two anticancer drugs cause cardiac toxicity?
Doxorubicin
Daunorubicin
(both anthracyclines)
Which two anticancer drugs cause nervous system toxicity?
Vincristine
Vinblastine
(both vinca alkaloids)
Which anticancer drug causes pulmonary toxicity?
Bleomycin
Which anticancer drug causes urinary tract toxicity?
Cisplatin
Which anticancer drug causes hypersensitivity reactions?
L-asparaginase
True of False: Anticancer drugs have the narrowest therapeutic index in all of medicine.
TRUE
What are the four mechanisms of drug resistance in tumor cells?
1. Decreased concentration of drugs in cells
2. Decreased levels of active drug in cell
3. Altering the target
4. Repair of damage
What is the largest class of anticancer drugs?
Alkylating agents
What is the mechanism of alkylating agents?
Cause DNA damage by causing DNA cross-linking
Are alkylating agents CCNS or CCS?
CCNS
What are the mechanisms of tumor resistance to alkylating agents? (3)
1. Increased capability to repair DNA
2. Decreased permeability of drug
3. Increased production of glutathione
What are the five groups of alkylating agents?
Nitrogen mustards
Alkylsulfonates
Ethylenimines
Nitosureas
Triazenes
Name three nitrogen mustards.
Cyclophosphamide
Methchlorethamine
Chorambucil
What is the most widely used alkylating agent?
Cyclophosphamide
True or false: Cyclophosphamide is a prodrug that requires conversion by hepatic cytochorome P450.
TRUE
Name three nitrosoureas?
Carmustine
Lomustine
Semustine
True or False: Nondividing cells will always be killed by nitrosureas, regardless of DNA repair activity of the cells.
FALSE
"cytotoxicity is see only upon cell division, therefore nondividing cells can escape death if DNA repair occurs"
Why are nitrosureas commonly used in the treatment of brain tumors?
Because they can penetrate the CNS
Cisplatin is most toxic at which phases of the cell cycle?
G1 and S
What is the major toxicity of cisplatin?
Neprotoxicity
What can be used in place of cisplatin in order to avoid that drug's nephrotoxicity?
Carboplatin
(is myelosuppressive, however)
What is the major limitation to successful treatment with cisplatin?
Resistance
Are antimetabolites CCS or CCNS?
CCS
What is the major toxicity of antimetabolites?
Myelosuppression
What is the most commonly used folate analog?
Methotrexate
Folate analogs lead to the depressed synthesis of what?
DNA
RNA
Proteins
What is the mechanism of methotrexate (folate analog)?
Blocks DHFR
(enzyme that converts folic acid into its active form)
What are the mechanisms of resistance for folate analogs? (3)
1. Increased DHFR levels
2. Mutant DHFR with decreased drug binding
3. Decreased uptake
What are the commonly used purine analogs?
6-mercaptopurine
6-thioguanine
What are the two mechanisms of purine analogs?
Block enzymes involved in purine synthesis
Are incorporated into RNA and DNA, leading to damage
What is the most common mechanism of resistance to purine analogs?
Decreased HGPRT activity
(enzyme that converts analogs into unnatrual nucleotides)
Name four pyramadine analogs.
5-fluorouracil
Cytarabine
Gemicitabine
Capecitabine (oral 5-FU)
True or false: 5-FU requires intracellular activation to its activated form.
TRUE
What are the two mechanisms of 5-FU?
Inhibits thymidylate synthase → inibits DNA synthesis
Incorporated (5-FUTP) into RNA
What is the mechanism of cytarabine?
Competitive inhibition of DNA polymerase
What is the mechanism of resistance to cytarabine?
Depletion of activating enzyme deoxycytidine kinase
What is the common mechanism of resistance to plant derivate chemo agents?
P-glycoprotein upregulation
What phase of the cell cycle are vinca alkaloids specific to?
M
What is the mechanism of vincristine and vinblastine?
Prevent polymerization of tubulin to form microtubules, thus inhibiting mitosis
What is the dose-limiting toxicity for vinblastine and vincristine?
Vinblastine = myelosuppression
Vincristine = peripheral neuropathy
What is the mechanism of resistnace to the vinca alkaloids?
Decreased uptake and retention (MDR)
What are the two podophyllotoxins we need to know?
Etoposide
Teniposide
What is the target of etoposide?
Topoisomerase II
Is etoposide CCS or CCNS?
CCS
What is the mechanism of resistance to etoposide?
Decreased accumulation (MDR)
What is the mechanism of action of taxanes?
Promote tubulin polymerization and stabalization → cells become frozen in mitosis
Which antibiotic is CCS?
Bleomycin
(all others CCNS)
At which phases do doxorubicin and daunorubicin have maximal activity?
S and G2
What is the mechanism of cardiac toxicity by antracycline antibiotics?
Oxygen radical formation
What is the most important mechanism of anthracycline antibiotics?
Formation of covalent topo II-DNA complexes to prevent religation
What is the mechanism of resistnace to doxorubicin?
Increased efflux
MDR
What is the mechanism for actinomycin?
Intercalation into DNA
What phase does bleomycin cause cells to accumulate in?
G2
What is the mechanism of bleomycin?
Production of single- and double-strand DNA breaks that result from the production of free radicals
What is the primary toxicity of bleomycin?
Pulmonary toxicity
Name four antiestrogens.
Tamoxifen
Anastrazole (aromatase inhibitor)
Exemestane
Letrozole
How does the affinity of tamoxifen for the ER compare to that of estrogen?
Affinity is 10-fold lower
Estrogen ablation still required
What is the most prominent side-effect of tamoxifen?
3-fold increase in potential for endometrial cancer
What is the primary use of tamoxifen?
As adjuvant therapy after surgery for breast CA
Name two gonadatropin-releasing hormone agonists.
Leuprolide
Goserelin
Is testicular andgrogen synthesis increased or decreased by treatment with GnRH agonists?
Decreased
Is release of follicle-stimulating hormone and leutenizing hormone stimulated or inhibited by GnRH agonists?
Inhibited
Does prednisone require activation?
Yes
What is the mechanism of hydroxyurea?
Inhibition of the enzyme ribonucleotide reductase
Is hydroxyurea phase specific?
Yes - S phase
What is the mechanism of L-Asparaginase?
Catalyzes deamination of extracellular asparagine, which some tumor cells can't make on their own (ALL)
Does L-asparaginase induce myelosuppression?
No
What is the mechanism of resistance to L-Asparaginase?
Increased expression of asparagine synthetase gene
Trestuzumab (Herceptin) is used in the treatment of what?
Inhibitor of HER2 in breast cancer
Cetuximab (Erbitux) is used in the treatment of what?
Inhibitor of EGFR in colorectal cancer
Bevacizumab (Avastin) is used in the treatment of what?
Inhibitor of VEGF in colorectal cancer
Gefitinib is used in the treatment of what?
Inhibitor of EGFR in non-small cell lung cancer
Imatinib (Gleevec) is used in the treatment of what?
Inhibitor of Bcr-Abl in CML
Erlotinib is used in the treatment of what?
Inhibitor of EGFR in non-small cell lung cancer
Name three monoclonal antibodies used as anticancer drugs?
Trastuzumab
Cetuximab
Bevacizumab
Name two kinase inhibitors that inhibit EGFR.
Gefitinib
Erlotinib