Antineoplastic agents

Question 1

Alkylating Agents

Nitrogen mustards

Answer 1

Cyclophosphamide

Ifosfamide

Question 2

Alkylating Agents

Alkyl sulfonate

Answer 2

Busulfan

Question 3

Alkylating Agents

Platinum coordination complexes

Answer 3

Cisplatin

Question 4

Natural Products

Vinca alkaloids

Answer 4

Vinblastine
Vinorelbine
Vincristine

Question 5

Natural Products

Taxanes

Answer 5

Paclitaxel

Question 6

Natural Products

Epipodophyllotoxins

Answer 6

Etoposide

Question 7

Natural Products

Antibiotics

Answer 7

Doxorubicin

Question 8

Natural Products

Anthracenedione

Answer 8

Bleomycin

Question 9

Natural Products

Enzymes

Answer 9

L-Asparaginase

Question 10

Antimetabolites

Answer 10

Folic acid analogs
  Methotrexate
Pyrimidine analogs	
  Fluorouracil (5-fluorouracil; 5-FU)
Purine analogs
  Mercaptopurine (6-MP)

Question 11

Rescue agents

Answer 11

Leucovorin

Mesna

Question 12

Protein tyrosine kinase inhibitors

Answer 12

Imatinib

Question 13

Monoclonal Antibodies

Answer 13

Trastusumab

Question 14

Agents used to minimize adverse effects

Answer 14

Filgrastim
Erythropoietin or darbepoetin alfa
Serotonin antagonists
Ondansetron

Question 15

Alkylating Agents MOA

Answer 15

Form covalent linkages with DNA

Question 16

Specific alkylating agent toxicities

Answer 16

Cyclophosphamide – hemorrhagic cystitis
Cisplatin – renal tubular damage, ototoxicity
Busulfan – pulmonary fibrosis

Question 17

Antimetabolites: 3 major classes

Answer 17

Folic acid analogs (methotrexate)
Pyrimidine analogs (5-Fluorouracil)
Purine analogs (6-mercaptopurine)

Question 18

Antimetabolites MOA

Answer 18

Structural analogs to compounds necessary for cell proliferation

Block or subvert pathways that are involved in, or lead to, cell replication (nucleotide and nucleic acid synthesis)

Cell cycle specific (S phase)

Question 19

Methotrexate

Answer 19

Inhibits dihydrofolate reductase (DHFR)
Indications:
  Cancer
  Rheumatoid arthritis
  Psoriasis

Question 20

Methotrexate & Leucovorin Rescue

Answer 20

Leucovorin: reduced folate can bypass DHFR

Used to rescue normal cells from high-dose MTX

Antidote for accidental MTX overdose

Question 21

Pyrimidine Structural Analogs

Answer 21

Prototype: 5-Fluorouracil (5-FU)

Prodrug

Question 22

Fluorouracil: Mechanisms of Action

Answer 22

Active compound (FdUMP) covalently binds thymidylate synthetase and blocks de novo synthesis of thymidylate

Active compounds (FdUTP and FUTP) are incorporated into both DNA and RNA, respectively

Leucovorin can’t rescue

Question 23

Drug Interaction: 6-MP & Allopurinol

Answer 23

Biotransformation of 6-MP includes metabolism to the inactive metabolite 6-thiouric acid by xanthine oxidase (first pass effect)

Allopurinol, a xanthine oxidase inhibitor, is often used as supportive care in the treatment of acute leukemias to prevent hyperuricemia due to tumor cell lysis

Simultaneous administration of allopurinol and oral 6-MP results in increased levels of 6-MP and increased toxicity

Reduce oral 6-MP dose by 50-75%; IV dose unaffected

Question 24

Antimetabolites: Pharmacodynamics

Answer 24

Cell cycle specific (S-phase)
Relatively little acute toxicity after an initial dose
Oral, intravenous, intrathecal (methotrexate) are common routes of administration
Common toxicities include diarrhea, myelosuppression, nausea, vomiting, immunosuppression, thrombocytopenia, leukopenia, hepatotoxicity

Question 25

Vinca Alkaloids: Adverse Effects

Answer 25

Alopecia Myelosuppression (vinblastine > vincristine) Vincristine exhibits neurotoxicity (numbness and tingling of the extremities, loss of deep tendon reflexes, motor weakness, autonomic dysfunction has also been observed)

Question 26

Vinca Alkaloids: Mechanism of Action

Answer 26

Bind to β-tubulin and inhibit microtubule assembly | Cell cycle specific mitosis inhibition (M-phase)

Question 27

Taxanes: Mechanism of Action

Answer 27

Bind to β-tubulin and stabilize microtubule assembly | Cell cycle specific mitosis inhibition (M-phase)

Question 28

Taxanes: adverse effects

Answer 28

Paclitaxel Hypersensitivity reactions in hands and toes, change in taste Docetaxel Greater cellular uptake; retained intracellularly longer than paclitaxel permitting smaller dose, which reduces AEs Hypersensitivity, neutropenia, alopecia

Question 29

Topoisomerase Inhibitors

Answer 29

Type I Type II - Inhibitors: Epipodophyllotoxins (etoposide, teniposide) Anthracycline antibiotics (doxorubicin, daunorubicin) Cell cycle specific (primarily S phase, also G1 and G2)

Question 30

Anthracyclines: MOA

Answer 30

Inhibit topoisomerase II Intercalate DNA Oxygen free radicals bind to DNA causing single- and double-strand DNA breaks Cell cycle nonspecific (but cycling cells are more susceptible) Free radicals are linked to significant cardiotoxicity Cumulative cardiac damage can lead to dysrhythmias and heart failure

Question 31

Antitumor Antibiotics: Bleomycin

Answer 31

MOA: Free radicals cause single- and double-strand DNA breaks Cell cycle specific (G2 arrest) Causes minimal myelosuppression – useful in combination Can cause significant pulmonary toxicity (5-10%, usually presents as pneumonitis with cough, dyspnea, dry inspiratory crackles)

Question 32

Antineoplastic Enzymes | L-aspariginase

Answer 32

MOA: hydrolyzes circulating L-asparagine into aspartic acid and ammonia, effectively inhibiting protein synthesis Cell cycle specific (G1)

Question 33

Antineoplastic Enzymes: Adverse effects

Answer 33

Acute hypersensitivity reaction Delayed toxicities include an increased risk of clotting and bleeding, pancreatitis, and CNS toxicity including lethargy, confusion, hallucinations, and coma

Question 34

Antineoplastic Enzymes: Indication

Answer 34

Targeted therapy for acute lymphoblastic leukemia (ALL) | ALL tumor cells lack the enzyme asparagine synthetase and thus require an exogenous source of L-asparagine

Question 35

Erlotinib and Gefitinib

Answer 35

MOA: Inhibit Epidermal Growth Factor Receptor (EGFR), a receptor tyrosine kinase Preferred single-agent first-line therapy for NSCLC patients with somatic activating EGFR mutations Produce dermatologic toxicities

Question 36

Bcr-Abl, CML, and Imatinib (Gleevec)

Answer 36

The BCR-ABL fusion protein results from the t(9:22) translocation and is found in 95% of patients with CML Imatinib is a small molecule inhibitor of the ABL tyrosine kinase and has been hailed as a conceptual breakthrough in targeted chemotherapy Imatinib can also inhibit the RTKs PDGFR and c-KIT