Hem & Onc - Pharm (Groups of Cancer Drugs)

Question 1

What are the phases of the cell cycle and the major event occurring in each? Which cancer drugs act at each phase?

Answer 1

G1 - Synthesis of components needed for DNA synthesis = NO DRUGS ACT HERE; S - DNA Synthesis = ANTIMETABOLITES & ETOPOSIDE act here; G2 - Synthesis of components needed for mitosis = ETOPOSIDE & BLEOMYCIN act here; M - Mitosis = VINCA ALKALOIDS & TAXOLS act here (Note: G0 [rest] & Differentiation exit out of the cycle)

Question 2

Which drug acts at multiple phases in the cell cycle? What are the phases in which it acts?

Answer 2

Etoposide; S & G2

Question 3

What are the steps leading up to neoplastic cell division, starting at nucleotide synthesis and ending with cellular division? What are the important drugs that act at each step?

Answer 3

(1) Nucleotide synthesis - METHOTREXATE/5-FU & 6-MP (2) DNA - ALKYLATING AGENTS/CISPLATIN, DACTINOMYCIN/DOXORUBICIN, & ETOPOSIDE (3) RNA - NONE (4) Protein - NONE (5) Cellular Division - VINCA ALKALOIDS & PACLITAXEL

Question 4

On what general process do methotrexate and 5-FU act? More specifically, what is their effect?

Answer 4

Nucleotide synthesis; Decrease thymidine synthesis

Question 5

On what general process does 6-MP act? More specifically, what is its effect?

Answer 5

Nucleotide synthesis; Decrease purine synthesis

Question 6

On what general process do Alkylating agents & Cisplatin act? More specifically, what is their effect?

Answer 6

DNA (Synthesis); Cross-link DNA

Question 7

On what general process do Dactinomycin and Doxorubicin act? More specifically, what is their effect?

Answer 7

DNA (Synthesis); DNA intercalators

Question 8

On what general process does Etoposide act? More specifically, what is its effect?

Answer 8

DNA (Synthesis); Inhibits topoisomerase II

Question 9

On what general process do Vinca alkaloids act? More specifically, what is their effect?

Answer 9

Cellular division; Inhibit microtubule formation

Question 10

On what general process does Paclitaxel act? More specifically, what is its effect?

Answer 10

Cellular division; Inhibits microtubule disassembly

Question 11

What are 4 examples of antimetabolites? In what phase of the cell cycle do all of these cancer drugs act?

Answer 11

(1) Methotrexate (MTX) (2) 5-fluorouracil (5-FU) (3) Cytarabine (arabinofuranosyl cytidine) (4) Azathioprine/6-mercaptopurine (6-MP)/6-thioguanine (6-TG); S-phase

Question 12

What is MTX? What is its mechanism?

Answer 12

Methotrexate; Folic acid analog that inhibits dihydrofolate reductase –> decreased dTMP –> decreased DNA and decreased Protein synthesis

Question 13

What are the 4 cancers for which methotrexate is clinically used? What 5 other non-neoplastic clinical uses does methotrexate have?

Answer 13

CANCERS: (1) Leukemias (2) Lymphomas (3) Choriocarcinoma (4) Sarcomas; NON-NEOPLASTIC: (1) Abortion (2) Ectopic pregnancy (3) Rheumatoid arthritis (4) Psoriasis (5) IBD

Question 14

What are the 4 toxicities/side effects associated with methotrexate?

Answer 14

(1) Myelosuppression (which is rversible with leucovorin [folinic acid] “rescue”) (2) Macrovesicular fatty change in liver (3) Mucositis (4) Teratogenic

Question 15

What is 5-FU? What is its mechanism?

Answer 15

5-fluorouracil; Pyrimidine analog bioactivated to 5F-dUMP, which covalently complexes folic acid. This complex inhibits thymidylate synthase –> Decreased dTMP –> Decreased DNA & Decreased protein synthesis

Question 16

What are the 3 cancers for which 5-FU is clinically used?

Answer 16

(1) Colon cancer (2) Pancreatic cancer (3) Basal cell carcinoma (topical)

Question 17

What are the 2 toxicities/side effects associated with 5-FU?

Answer 17

(1) Myelosuppression (which is not reversible with leucovorin; instead, overdose rescue with uridine) (2) Photosensitivity

Question 18

What is the major toxicity/side effect shared by both MTX and 5-FU? How is it handled in each case?

Answer 18

MYELOSUPPRESION; w/ MTX - reversible with leucovorin (folinic acid) “rescue… w/ 5-FU - not reversible with leucovorin, but instead overdose rescue with uridine

Question 19

What is another name for Cytarabine? What is its mechanism?

Answer 19

Arabinofuranosyl cytidine; Pyrimidine anlog –> inhibition of DNA polymerase

Question 20

What are the 2 cancers for which Cytarabine is clinically used?

Answer 20

(1) Leukemias (2) Lymphomas

Question 21

What are the 3 toxicities/side effects associated with Cytarabine?

Answer 21

(1) Leukopenia (2) Thrombocytopenia (3) Megaloblastic anemia; Think: “CYTarabine causes panCYTopenia.”

Question 22

What other drugs share the same mechanism as Azathioprine? What is this mechanism? What activates them to take this action?

Answer 22

6-Mercatopurine (6-MP) & 6-Thioguanine (6-TG); Purine (thiol) analogis –> Decrease de novo purine synthesis; HGPRT

Question 23

What 3 conditions are prevented with use of Azathioprine?

Answer 23

Preventing organ rejection, RA, SLE (azathioprine)

Question 24

Where are the 3 toxicities/side effects associated with Azathioprine, 6-MP, and 6-TG?

Answer 24

(1) Bone marrow (2) GI (3) Liver

Question 25

Which drugs are metabolized by xanthine oxidase? Given this fact, what increases toxicity of this drug, and why?

Answer 25

Azathioprine and 6-MP are metabolized by xanthine oxidase; thus both have increased toxicity with allopurinol, which inhibits their metabolism

Question 26

What are the antitumor antibiotics?

Answer 26

(1) Dactinomycin (actinomycin D) (2) Doxorubicin (Adriamycin, daunorubicin) (3) Bleomycin

Question 27

What is the brand name for Dactinomycin? What is its mechanism?

Answer 27

Actinomycin D; Intercalates in DNA

Question 28

For what 3 cancers is dactinomycin used clinically? In general, how is dactinomycin used clinically?

Answer 28

(1) Wilms' tumor (2) Erwing's sarcoma (3) Rhadomyosarcoma; Used for children tumors (Think: "children ACT out")

Question 29

What is/are the toxcity(-ies) associated with Dactinomycin?

Answer 29

Myelosuppression

Question 30

What is the brand name for Doxorubicin? What is another drug that shares the same mechanism? What is their mechanism?

Answer 30

Adriamycin; Daunorubicin; Generate free radicals. Noncovalently intercate in DNA --> breaks in DNA --> Decreased replication

Question 31

For what 3 cancers are doxorubicin/daunorubicin used clinically?

Answer 31

(1) Solid tumors (2) Leukemias (3) Lymphomas

Question 32

What is/are the toxcity(-ies) associated with Doxorubicin/daunorubicin?

Answer 32

(1) Cardiotoxicity (dilated cardiomyopathy) (2) Myelosuppression (3) Alopecia (4) Toxic to tissues following extravasation

Question 33

What is used to prevent cardiotoxicity as a result of doxorubicin/daunorubicin, and what kind of agent is this?

Answer 33

Dexrazoxane (iron chelating agent), used to prevent cardiotoxicity

Question 34

What is the mechanism of bleomycin?

Answer 34

Induces free radical formation, which causes breaks in DNA strands

Question 35

For what 2 cancers is bleomycin clinically used?

Answer 35

(1) Testicular cancer (2) Hodgkin's lymphoma

Question 36

What are 4 toxicities associated with Bleomycin? Which of these is minimal (relative to other antitumor drugs)?

Answer 36

(1) Pulmonary fibrosis (2) Skin changes (3) Mucositis. (4) Minimal myelosuppression

Question 37

What are 3 examples of alkylating agents?

Answer 37

(1) Cyclophosphamide, ifosfamide (2) Nitrosoureas (carmustine, lomustine, semustine, streptozocin) (3) Busulfan

Question 38

What other drug shares the same mechanism as cyclophosphamide? What is their mechanism? What is required for this action to occur?

Answer 38

Ifosfamide; Covalently X-link (interstrand) DNA at guanine N-7; Require bioactivation by liver

Question 39

For what 4 cancers are cyclophosphamide and/or ifosfamide clinically used?

Answer 39

(1) Solid tumors (2) Leukemia (3) Lymphomas (4) Some brain cancers

Question 40

What are 2 toxicities associated with cyclophosphamide and/or ifosfamide?

Answer 40

(1) Myelosuppression (2) Hemorrhagic cystitis (partially prevented with mesna [thiol group of mesna binds toxic metabolite])

Question 41

What prevents hemorrhagic cystitis from cyclophosphamide/ifosfamide usage, and how?

Answer 41

Hemorrhagic cystitis, partially prevented with mesna (thiol group of mesna binds toxic metabolites)

Question 42

What are 4 examples of Nitrosoureas? What is their mechanism? What is required for this action?

Answer 42

(1) Carmustine (2) Lomustine (3) Semustine (4) Streptozocin; Cross blood-brain barrier --> CNS; Cross-links DNA; Require bioactivation

Question 43

For what cancers are Nitrosoureas used clinically?

Answer 43

Brain tumors (including glioblastoma multiforme)

Question 44

What kind of toxicity and/or side effects are associated with Nitrosoureas?

Answer 44

CNS toxicity (convulsions, dizziness, ataxia)

Question 45

What is the mechanism of Busulfan?

Answer 45

Cross-links DNA

Question 46

What are 2 clinical uses for Busulfan?

Answer 46

(1) CML (2) Ablate patient's bone marrow before bone marrow transplantation

Question 47

What are 3 toxicities associated with Busulfan? Which of these occurs in almost all cases?

Answer 47

(1) Severe myelosuppression (in almost all cases) (2) Pulmonary fibrosis (3) Hypersegmentation

Question 48

What are 2 examples of microtubule inhibitors?

Answer 48

(1) Vincristine, vinblastine (2) Paclitaxel, other taxols

Question 49

What drug shares the same mechanism as vincristine? What is their mechanism and ultimate effect?

Answer 49

Vinblastine; Vinca alkaloids that bind to Beta-tubulin, inhibit its polymerization into microtubules, thereby preventing mitotic spindle formation (M-phase arrest)

Question 50

For what 3 cancers are vincristine and/or vinblastine used clinically?

Answer 50

(1) Solid tumors (2) Leukemias (3) Lymphomas

Question 51

What toxicities are associated with vincristine versus vinblastine?

Answer 51

VINCRISTINE - Neurotoxicity (areflexia, peripheral neuritis), paralytic ileus; VINBLASTINE - BLAsts bone marrow (suppression)

Question 52

What is the mechanism and ultimate effect of Paclitaxel and other Taxols?

Answer 52

Hyperstabilize polymerized microtubules in M phase so that mitotic spindle cannot break down (i.e., anaphase cannot occur); Think: "it is TAXing to stay polymerized"

Question 53

For what 2 cancers are Paclitaxel and/or other Taxols clinically used?

Answer 53

(1) Ovarian (2) Breast carcinomas

Question 54

What 3 toxicities are associated with Paclitaxel and/or other Taxols?

Answer 54

(1) Myelosuppression (2) Alopecia (3) Hypersensitivity

Question 55

What are 2 conditions treated by 6-MP? What other drug is used to treat these same conditions?

Answer 55

Leukemia, IBD (6-MP, 6-TG)

Question 56

Draw a diagram showing the relationship between the following: (1) CH2-THF (2) DHF (3) DHF reductase (4) dTMP (5) dUMP (6) F-FU (7) MTX (8) THF (9) Thymidylate synthase.

Answer 56

See p. 403 in First Aid 2014 for diagram at bottom of page