Basic Pharmacology of Cancer Chemotherapies

Question 1

Are alkylating agents cell cycle dependent? How do they work?

Answer 1

NO- they are NOT CELL CYCLE DEPENDENT

they form electrophilic bonds in Guanine of DNA which HALTS CELL REPRODUCTION

Question 2

What are the Nitrogen Mustards? What drugs are included in this category?

Answer 2

Nitrogen Mustards are ALKYLATING AGENTS

CYCLOPHOSPHAMIDE

Melphalan

Chlorambucil

Question 3

Hemorrhagic cystitis is a toxicity associated with Cyclophosphamide. What causes the bladder toxicity, and how can it be prevented?

Answer 3

Acrolein is a toxic metabolite of cyclophosphomide that causes hemorrhagic cystitis.

Hemorrhagic cystitis can be partially prevented by the use of MESNA- the thiol group of mesna binds the toxic metabolite

Question 4

What are the Nitrosureas? What category of anti-cancer drugs do they belong to?

Answer 4

“-MUSTINE” + STREPTOZOCIN

CarMUSTINE

LoMUSTINE

SeMUSTINE

Nitrosureas= ALKYLATING AGENTS

Question 5

What category of drugs can cross the BBB and are therefore useful for the treatment of brain tumors?

Answer 5

NITROSOUREAS (“-mustine +Streptozocin)

Question 6

What drug destroys pancreatic beta cells & is used to treat insulinomas?

Answer 6

Streptozocin (Nitrosurea Alkylating Agent)

Question 7

What category of anti-cancer drugs is Busulfan?

Answer 7

Alkylating Agent (Alkyl Sulfonate)

Question 8

What is Busulfan primarily used to treat?

Answer 8

CML

Ablation of pt’s bone marrow before BM transplantation

Question 9

What phase of the cell cycle do Antimetabolites target?

Answer 9

S-PHASE

Highly toxic to rapidly proliferating cells (including normal tissue- hair & GI tract)

Question 10

What drugs are in the antimetabolite category?

Answer 10

Methotrexate (MTX)

5-Fluorouracil (5-FU)

Cytarabine (ara-C)

Azathioprine

6-Mercaptopurine (6-MP)

6-Thioguanine (6-TG)

Question 11

What is the mechanism of MTX? Can myelosuppression be reversed?

Answer 11

Folic Acid analog inhibits DHFR–>Decreases THF available for conversion of dUMP–>dTMP–>

Decreased dTMP, DNA & protein synthesis

Myelosuppression IS reversible with LEUCOVORIN (folinic acid rescue)

Question 12

What is the mechanism of 5-FU? Can myelosuppression be reversed?

Answer 12

PYRIMIDINE analog bioactivated to 5F-dUMP–> covalently complexes to folic acid–>

INHIBITS THYMIDYLATE SYNTHASE–> decrease in dTMP

Myelosuppression is NOT REVERIBLE w Leucovorin

Question 13

What is the mechanism of Cytarabine (Ara-C)?

Answer 13

Pyrimidine Analog (Cytidine) INHIBITS DNA POLYMERASE

Question 14

What are the toxicities associated w Ara-C?

Answer 14

Leukopenia

Thrombocytopenia

Megaloblastic Anemia

Question 15

Azathioprine, 6-MP, & 6-TG all share the SAME mechanism of action. What is the mechanism?

What enzyme are these drugs metabolized by? (What drug increases their toxicity?)

Answer 15

PURINE ANALOGS activated by HGPRT & decrease De Novo Purine Synthesis

Metabolized by XANTHINE OXIDASE (Allopurinol increases their toxicity EXCEPT for 6-Thioguanine- 6-TG)

Use 6-TG in pts taking Allopurinol

Question 16

What is the mechanism of Antitumor Antibiotics? Give examples of antitumor antibiotics

Answer 16

Intercalate DNA strands–> free radical formation

Dactinomycin

Anthracyclines (Doxorubicin, Daunorubicin & Idarubicin)

Bleomycin

Question 17

What phase of the cell cycle does Bleomycin affect? Mechanism?

Answer 17

G2 & M phase

Complexes with iron & reacts with oxygen–>Induces free radical formation which causes BREAKS in DNA strands

Question 18

What drugs are Microtubule Inhibitors aka ANTIMITOTICS?

Answer 18

Vinca Alkaloids (Vincristine & Vinblastine)

Paclitaxel & Taxols

Question 19

What phase of the cell cycle do Vinca Alkaloids (Vincristine & Vinblastine) affect? Mechanism?

Answer 19

M-phase

Bind to TUBULIN & block polymerization of microtubules so that mitotic spindle cannot form.

(Think of Microtubles= M-phase as the VINes of your cells)

Question 20

What are the toxicities associated with Vincristine & Vinblastine?

Answer 20

Vincristine= NEUROTOXIC (areflexia, peripheral neuritis, paralytic ileus)

VinBLASTine BLASTS Bone marrow (suppression)

Question 21

What phase of the cell cycle do the Taxenes (Paclitaxel & Docetaxel) act on? Mechanism?

Answer 21

G2 & M-Phase

Bind TUBULIN–> hyperstabilizes polymerized microtubules so the mitotic spindle cannot break down & anaphase can not procede

Question 22

Does the action of anticancer drugs follow first-order or second- order kinetics?

Answer 22

First Order- rate of elimination is directly proportional to the drug concentration (constant FRACTION of drug is eliminated per unit time)

Question 23

What is responsible for multidrug resistance of chemotherapeutic agents (ie pumping drugs out of cells)?

Answer 23

P-glycoprotein is an ATP-dependent membrane efflux transporter responsible for pumping drugs out of cells

Question 24

Cancer Chemotherapy agents commonly associated with stomatitis & esophagitis?

Answer 24

MTX

5-FU

Dactinomycin

Question 25

Hepatotoxic Chemo agents?

Answer 25

Etoposide L-Asparaginase

Question 26

Pancreatitis associated chemo agents?

Answer 26

6-MP Busulfan Cyclophosphamide

Question 27

Cutaneous Toxicity (Hand-Foot Syndrome)

Answer 27

L-Asparaginase 5-FU

Question 28

Dilsufiram-Type Rxn

Answer 28

Procabazine

Question 29

What is the antidote that binds to and inactivates the toxic metabolites responsible for cisplatin induced nephrotoxicity?

Answer 29

AMIFOSTINE

Question 30

Which agent is used to decrease the incidence & severity of doxorubicin-induced cardiomyopathy in pts w metastatic BC who have received a lifetime cumulative Doxo dose \>300mg?

Answer 30

DEXRAZOXANE- iron chelating agent

Question 31

What RXN does DHFR catalyze?

Answer 31

Conversion of folic acid to tetrahydrofolic acid (active form)

Question 32

What drug is used as a "rescue medication" in pts taking MTX?

Answer 32

**Leucovorin** acts as an active form of folic acid (replenishing the folate pool) that has bypassed the inhibited DHFR & is more readily taken up by normal cells than by malignant cells

Question 33

What are the adverse effects of MTX?

Answer 33

Stomatitis BMS Urticaria Alopecia NVD Nephrotoxicity Hepatotoxicity Pulmonary Toxicity Neurotoxicity

Question 34

What immunosuppressive drug becomes active only after being converted to 6-MP?

Answer 34

Azathioprine

Question 35

What enzyme activates 6-MP to its corresponding nucleotide form by adding a ribose phosphate to its structure?

Answer 35

Hypoxanthine-Guanine Phosphoribosyl Transferase (HGPRT)

Question 36

What are the major s/e of 6MP?

Answer 36

NVD Hepatotoxicity BMS

Question 37

Are the antitumor antibiotics CCS (Cell Cycle Specific)?

Answer 37

Yes- S Phase

Question 38

What is the MOA of Anthracycline Antibiotics?

Answer 38

inhibition of DNA topoisomerase 2 formation of free radicals--\> DNA strand breaks DNA intercalation Inhibition of DNA & RNA synthesis

Question 39

Give example of anticancer alkylating agents:

Answer 39

Cyclophosphamide Isofosfamide Mechlorethamine Nitrosoureas (-mustine + Streptozotocin) Cisplatin & Carboplatin

Question 40

What plant are the vinca alkaloids derived from?

Answer 40

Periwinkle plant

Question 41

Which plant is paclitaxel a derivative of?

Answer 41

Needles of the Western or Pacific Yew Tree

Question 42

What are the adverse effects of Paclitaxel?

Answer 42

Neutropenia Alopecia Hypersensitivity RXNs

Question 43

What adverse s/e doe vincristine & vinblastine have in common? Are they vesicants?

Answer 43

NVD Alopecia Phlebitis Cellulites They are STRONG Vesicants

Question 44

How are hypersensitivity rxns prevented in pts receiving paclitaxel cancer chemotherapy?

Answer 44

Pretreatment w DIPHENHYDRAMINE & DEXAMETHASONE

Question 45

Give 2 examples of epipodophylotoxin cancer chemotherapeutic agents

Answer 45

1. Etoposide 2. Teniposide

Question 46

What is the MOA of the epipodophyllotoxin cancer chemotherapeutic agents?

Answer 46

Inhibition of DNA topoisomerase 2--\> increase DNA degradation

Question 47

Give 2 examples of chemotherapeutic agents that inhibits DNA topoisomerase 1

Answer 47

1. Topotecan 2. Irinotecan

Question 48

What is the MOA of L-asparaginase?

Answer 48

Hydrolyzes asparagine to aspartic acid & ammonia, thereby depriving tumor cells of asparagine required for protein synthesis

Question 49

Give a brief summary of what happens during each of the following phases of the cell cycle. What cancer drugs act at each phase?

Answer 49

G0- Cells are not actively dividing (resting state) G1- Enzymes & proteins required for DNA replication are synthesized S- Replication of DNA (ANTIMETABOLITES & ETOPOSIDE) G2- Enzymes & proteins required for mitosis are synthesized (BLEOMYCIN & ETOPOSIDE) M- Mitosis Occurs (VINCA ALKALOIDS & TAXOLS)

Question 50

What is the MOA of Bavacizumab? What is its clinical use?

Answer 50

Monoclonal antibody against **VEGF**- **inhibits angiogenesis** used for solid tumors

Question 51

What is the MOA of VEMURAFENIB?

Answer 51

small molecule **inhibitor** of forms of the **B-Raf kinase** with the **V600E mutation** used for **METASTATIC MELANOMA**

Question 52

MOA of RITUXIMAB? Clinical Use?

Answer 52

Monoclonal antibody against **CD20** (found on most B-cell neoplasms) Used for **Non-Hodgkin's Lymphoma & RA (w MTX)**

Question 53

MOA of IMATINIB? Clinical Use? S/E?

Answer 53

Philadelphia chromosome **bcr-abl TYROSINE KINASE inhibitor** Use for CML, & GI stromal tumors Toxicity= Fluid Retention

Question 54

What is the major toxicity associated with TRASTUZUMAB (Herceptin)?

Answer 54

CARDIOTOXICITY

Question 55

What is the MOA of Trastuzumab? What type of cancer is it useful for?

Answer 55

Monoclonal antibody against HER2 (Human Epidermal growth factor Receptor 2) (c-erbB2) a TYROSINE KINASE Usesful to kill HER-2 positive breast cancer cells that overexpress HER-2, possibly through antibody-dependent cytotoxicity

Question 56

What is the MOA of Tamoxifen & Raloxifene?

Answer 56

SERMs- receptor blockers in breast & agonists in bone (promote bone growth) Block the binding of estrogen to estrogen receptor-positive cells

Question 57

Which SERM increases the risk of endometrial cancer?

Answer 57

TAMOXIFEN due to its partial agonist activity in endometrium (Raloxifene has no increased risk of endometrial carcinoma because it is an endometrial antagonist)

Question 58

MOA of Hydroxyurea?

Answer 58

**inhibits RIBONUCLEOTIDE REDUCTASE** decreases DNA Synthesis **S-Phase Specific**