Chemo Pharmacology

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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 â†’ 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 â†’ 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

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