GN Cancer Chemotherapies and Flipped Classroom

Question 1

What is pharmacodynamics?

Answer 1

How drugs affect the body

Question 2

How are the vinca drugs excreted?

Answer 2

Biliary excretion

Question 3

Why are alkylating not a preferential treatment in pediatrics patients?

Answer 3

There many secondary malignancies that arise as a result of alkylating agent chemo. (This concern is inversely proportional to age of patient)

Question 4

What are the acute adverse effects of mechlorethamine?

Answer 4

Nausea, vomiting

Question 5

Are alkylating agents CCNS or CCS? What type of cells are more sensitive to alkylating agents?

Answer 5

CCNS; replicating cells

Question 6

Cardiotoxicity is the signature adverse effect of what drug?

Answer 6

Anthracyclines: doxorubicin and daunorubicin

Question 7

Topo I in inhibited by what drug?

Answer 7

Irinotecan

Question 8

What does 5-FU inhibit? What required to aid in this inhibition?

Answer 8

Thymidylate synthase; enhanced by leucovorin (folinic acid) - inactivation requires both 5-FU and folinic acid

Question 9

How can methotrexate be administered?

Answer 9

Orally, IV, or intrathecally

Question 10

How is cis-platin administered? and cleared?

Answer 10

Intravenous, cleared in urine

Question 11

Most alkylating agents are bifunctional. What is meant by bifunctional?

Answer 11

They are able to bind and cross-link adjacent bases or they can bind and cross-link bases on opposite strands

Question 12

What inactivates SN-38 (the active metabolite of irinotecan)?

Answer 12

Glucouronidation by UGT1A1

Question 13

How have STIs (single transduction inhibitors) transformed cancer?

Answer 13

From “curable” disease to a “manageable” disease

Question 14

What drug blocks growth factor signaling in chronic myelogenous leukemia (CML)?

(Buzz association: CML = philadelphia chromosome)

Answer 14

Imatinib (inhibits Bcr-Abl and other tyr kinases)

Question 15

When would an alkylating agent be ill-advised?

Answer 15

If the a cell has a p53 mutation (like Li Fraumeni), then inducing DNA damage wouldn’t result in apoptosis which is the desired effect.

Question 16

What are 3 ways to classify drugs?

Answer 16

Chemical structure, mechanism of action, and therapeutic use

Question 17

What are the four branches of pharmacology?

Answer 17

pharmacokinetics, pharmacodynamics, adverse effects, and pharmaacotherapeutics

Question 18

What might cause a patient have a fatal myelosuppression incident when administered a standard dose of 6-mercaptopurine?

Answer 18

A defect in one or both TMPT

Question 19

Though alkylating agents and antitumor antibiotics are CCNS what are they most effective against?

Answer 19

Rapidly proliferating cells

Question 20

What is used as a “rescue” to prevent the cytotoxicity of methotrexate to normal cells?

Answer 20

Leucovorin (folinic acid)

Question 21

Patient is given FOLFIRI which is made up of 5-FU, Leucovorin, and Irinotecan. The patient is genotyped and found to be UGT1A1*3*7. What would be the appropriate response to this genotype?

Answer 21

Decreasing irinotecan dosing to decrease the amount of toxic metabolites

Question 22

What does gefitinib inhibit?

Answer 22

EGF-R tyr kinase

Question 23

What drug is a cytosine analog and inhibits polymerase and is a chain terminator?

Answer 23

Gemcitabine

Question 24

How are doxorubicin and daunorubicin administered?

Answer 24

intravenous, metabolized in liver

Question 25

What causes the cystitis that results from cyclophosphamide? What drug can be administered to almeloriate these effects?

Answer 25

Acrolein; Mesna

Question 26

Which isomerase does irinotecan inhibit?

Answer 26

Topo I

Question 27

To which class do doxorubicin daunorubicin belong?

Answer 27

Antitumor antibiotics: anthracyclines; block Topo II

Question 28

What specific cancer is gefitinib indicated for? What are some factors that can better the outcome?

Answer 28

Non-small cell lung cancer; better when pt is an Asian non-smoking woman

Question 29

45 year old female pt will be treated with a combination of Doxorubicin, docetaxel, and cyclophosphamide. Desrazoxane may be added in order to?

Answer 29

Protect against doxorubicin cardiotoxicity. Doxorubicin generates free radicals and desrazoxane acts as a free radical scavenger.

Question 30

sterile hemorrhagic cystitis is the hallmark side effect of what?

Answer 30

Cyclophosphamide

Question 31

What is the key adverse effect of bleomycin?

Answer 31

Pulmonary fibrosis

Question 32

What three events stop STI treatments?

Answer 32

Tumor gains resistance, patient dies, patients choose to discontinue the drug (this shit ain't cheap)

Question 33

What are two ways that resistance can be mounted to 6-MP and 6-TG?

Answer 33

Decreased hprt activity (the activating step) or an increase in alkaline phosphotase

Question 34

What is the key target of alkylating agents?

Answer 34

DNA

Question 35

What is the class of drugs do the vinca drugs belong to? How do they work?

Answer 35

MT poison; inhibit/reverses tubulin polymerization leading to metaphase arrest (destabilizing)

Question 36

Why is MDR-1 important in drug resistance?

Answer 36

MDR-1 uses ATP to actively transport drug out of the cell. It can also export multiple classes of anti-cancer drugs (antimetabolites, antibiotics, alkaloids, etc.)

Question 37

When would trastuzumab not be beneficial despite the cancer being Her2/neu positive?

Answer 37

In brain metastases (monoclonal ab's cannot cross the BBB)

Question 38

Irinotecan is administered as a prodrug, what converts it into the active SN-38 form?

Answer 38

Esterase

Question 39

What is the mechanism of cis-platin?

Answer 39

It is a bifunctional "platinating agent" that cross-links DNA

Question 40

What type of drug is Tamoxifen?

Answer 40

Selective estrogen receptor antagonists (SERMs), competing ligands for ER (ER antagonist in breast)

Question 41

What are some resistance mechanisms to alkylating agents?

Answer 41

Impermeable to drug, pump drug out (MDR), or alternate targets for drug (glutathione), increased DNA repair, Lack of apoptosis

Question 42

What is the dose-limiting toxic effect of alkylating agents?

Answer 42

Decreased leukocytes and platelets

Question 43

How are the Taxanes different than the Vincas?

Answer 43

These drugs result in stabilization of the MTs and block progress through mitosis

Question 44

What type of analog is methotrexate? How does it work?

Answer 44

Folate; It acts as a **dihydrofolate reductase (DHFR)** substrate and inhibitor. Thus, limiting folic acid that typically acts the carbon carrier when you want to add one carbon. Most importantly, **blocking the formation of thymidine**

Question 45

What are the taxane drugs?

Answer 45

Paclitaxel and Docetaxel

Question 46

Although cyclophosphamide is classed as cell-cycle non-specific, is it still more effective against proliferating cells. Why is this?

Answer 46

This minimizes the time for DNA repair to occur

Question 47

If a patient becomes resistant to imatinib, what can given to overcome this resistance?

Answer 47

Dasatinib (2nd gen Bcr-Abl inhibitor)

Question 48

What drug acts as a monoclonal antibody against Her2/neu oncogene product?

Answer 48

Trastuzumab

Question 49

Vinblastine will have what side effect that wont be as sever in Vincristine?

Answer 49

Bone marrow suppression

Question 50

Renal toxicity is the hallmark side effect of what alkylating agent

Answer 50

Cis-platin

Question 51

What is Bleomycin?

Answer 51

It is an antitumor antibiotic, mixture of glycopeptides

Question 52

Vinca drugs cause what?

Answer 52

Metaphase arrest

Question 53

What CCNS drug is most effective in the G2 stage?

Answer 53

Bleomycin

Question 54

Since rapidly growing cells are most effected by alkylating agents, what sites are most effected in the body?

Answer 54

BM, GI tract, spermatogenesis

Question 55

What are two aromatase inhibitors? What types of breast cancer are they indicated for?

Answer 55

Anastrazole, Letrozole; treatment for ER+ primary and metastatic breast cancers

Question 56

What alkylating agent is inject in a prodrug form that will be metabolized by the host's liver?

Answer 56

Cyclophosphamide

Question 57

What is the half-life of mechlorethamine?

Answer 57

Several minutes. The drug was be administered rapidly because of this.

Question 58

Imatinib and Dasatinib are what type of drugs?

Answer 58

Tyrosine kinase inhibitors

Question 59

How can cyclophosphamide be administered?

Answer 59

Oral or intravenous

Question 60

Which drugs are the anthracyclines that block topo II?

Answer 60

Doxorubicin and daunorubicin

Question 61

What are the adverse effects of cyclophosphamide?

Answer 61

Nausea, vomiting, alopecia, **sterile hemorrhagic cystitis (signature adverse effect)**

Question 62

What does imatinib inhibit?

Answer 62

Inhibits BCR-ABL and also blocks growth factors associated with CML.

Question 63

How do the side effects of aromatase inhibitors compare to chemotherapy side effects?

Answer 63

They are way more mild, symptoms are similar to menopause

Question 64

What are the side effects of Vincristine?

Answer 64

Peripheral neuropathy. Ideal because of no bone marrow depression

Question 65

What is an antimetabolite?

Answer 65

An analog of a normal component in the target cell, which will compete with the normal component. Ultimately, it can _block_ or _alter_ that pathway.

Question 66

What is the important enzyme that metabolizes Taxomifen?

Answer 66

CYP2D6

Question 67

In the drug combination FOLFIRI is made up of 5-FU, Leucovorin, and irinotecan. Which of these drugs is activated by an esterase?

Answer 67

Irintotecan - Activated by carboxylesterase enzymes

Question 68

What is synergism and its use in chemotherapy?

Answer 68

The total effect of the combination is greater than the sum of its parts. It allows for lower doses of the individual drug minimizing toxicity and resistance to the drug

Question 69

What is the importance of Dasatinib?

Answer 69

This is a second generation BCR-ABL inhibitor, and overcame some of the Imatinib resistance

Question 70

Delivery of paclitaxel in cremophor can result in what?

Answer 70

It can result in a hypersensitivity reaction

Question 71

What is the key activating metabolizer of tamoxifen?

Answer 71

CYP2D6

Question 72

What is Gemcitabine? What is its mechanism?

Answer 72

Cytosine analog, inhibits polymerase and chain terminator

Question 73

Gefitinib does what?

Answer 73

Inhibits EGF-R tyrosine kinase.

Question 74

Anastrazole and letrozole are what?

Answer 74

Aromatase inhibitors

Question 75

Is toxicity to pathogen vs. host relative or absolute?

Answer 75

Most often it's relative, there are many factors that can influence toxicity

Question 76

In the drug combination FOLFIRI is made up of 5-FU, Leucovorin, and irinotecan. What is the purpose of leucovorin?

Answer 76

It maximizes thymidylate synthase inactivation and provides the reduced folate helping the performance of 5-FU

Question 77

What are the two pyrimidine analogs? How does their toxicity compare to the purine analogs?

Answer 77

5-fluorouracil and Gemcitabine; Far more toxic (GI, BM)

Question 78

What are some antineoplastic targets?

Answer 78

Synthesis of bases, the conversion of ribose nucleotides to deoxyribose nucleotides, block RNA and DNA txn, Bind DNA directly

Question 79

What percentage of chemotherapeutic agents are toxic?

Answer 79

All

Question 80

Hormonal require what to be effacious?

Answer 80

Functional hormone receptor

Question 81

Active hprt pathway is required for which drugs to work?

Answer 81

6-mercaptopurine and 6-thioguanine

Question 82

What class of drug is flutamide?

Answer 82

Androgen receptor antgonist (non-steriodal ligand for AR, diminished androgen effects)

Question 83

What alkylating agents is injected only intravenously in an active form that is caustic to the skin? What is it molecular composition?

Answer 83

Mechlorethamine, nitrogen mustard

Question 84

What is used to inactivate and clear purine analongs?

Answer 84

Thiopurine methyltransferase (TPMT)

Question 85

What is the signature adverse effect of anthracyclines (doxorubicin and daunorubicin)? What drug is used to counteract this effect?

Answer 85

**Cardiotoxicity** (the anthracyclines concentrate in the mitochondria of cardiomyocytes causing them to burst. Killing the energy source of the cardiomyocytes); **Dexrazoxane**

Question 86

How does the mechanism of 6-mercaptopurine and 6-thioguanine differ?

Answer 86

6-MP inhibits synthesis of AMP and GMP 6-TG gets incorporated into RNA and DNA altering function

Question 87

What drugs act as tyrosine kinase inhibitors?

Answer 87

Imatinib, dasatinib, and gefitinib (-inibs)

Question 88

When striving for toxicity, what is the ideal type of toxicity? Define it.

Answer 88

Selective toxicity: targeting the pathogen (in this case, tumor) rather host

Question 89

Once doxorubicin and daunorubicin intercalate into DNA and block Topo II, what do they generate?

Answer 89

Free Radicals

Question 90

How can cells become resistant to methotrexate?

Answer 90

Decreased drug accumulation, amplified DHFR, altered DHFR

Question 91

What is special about the delivery of taxane drugs?

Answer 91

They have to be administered in cremophor or nanoparticles

Question 92

What are the three classes of analogs of anticancer antimetabolites?

Answer 92

Folate, purine, pyrimidine

Question 93

What are the two purine analogs? What do they require to become activated?

Answer 93

6-mercaptopurine and 6-thioguanine; purine salvage pathway (hprt) - this takes these purine analogs and adds a ribose phosphate

Question 94

Most antitumor antibodies are CCNS, bleomycin is an exception to that. What cell cycle stage is bleomycin specific to?

Answer 94

G2

Question 95

Following resection of stage 3 NSCLC, adjuvant chemotherapy is prescribed. The drugs chosen are cis-platin, paclitaxel, methotrexate and leucovorin. Why is leucovorin included?

Answer 95

Leucovorin is thought to minimize the effects of methotrexate on normal cells.

Question 96

What is the mechanism of action of alkylating agents?

Answer 96

Covalently bind to/modify biological molecules

Question 97

Following resection of stage 3 NSCLC, adjuvant chemotherapy is prescribed. The drugs chosen are cis-platin, paclitaxel, methotrexate and leucovorin. If renal toxicity is to be minimized, the patient should do what?

Answer 97

Be aggressively hydrated prior to treatment

Question 98

What drug acts as a dihydrofolate reductase substrate inhibitor blocking the formation of thymidine?

Answer 98

Methotrexate

Question 99

What is pharmacokinetics?

Answer 99

How the body affects drugs

Question 100

SN-38 (the active metabolite of irinotecan) is known to be toxic to bone marrow and GI intestinals cells (dose-limiting diarrhea). A mutant form of UGT1A1 would have what effect on dosing?

Answer 100

Mutants are typically less effective. Since UGT1A1 is protective against the diarrhea, a mutant UGT1A1 would likely reduce the tolerable dosage of that individual

Question 101

What is the signature adverse effect of cis-platin? How can it be limited?

Answer 101

Renal Toxicity; overhydrate patients before administering the cis-platin