Antineoplastic Agents

Question 1

Neoplasm

Answer 1

Uncontrolled and abnormal growth of tissue in animals or plants (aka tumor)

Question 2

Targets of cancer chemotherapy

Answer 2

Cellular processes that are prevalent in rapidly-dividing cells
Leads to onset of side effects (hair loss, immune deficiencies, nausea)

Question 3

What cancer chemotherapeutics must do in order to prevent remission

Answer 3

Must be able to kill every cancer cell

Unfortunately, most antineoplastic agents kill cells by first order kinetics (never actually kill every single cell)

Question 4

Tumor cell properties

Answer 4

Uncontrolled cell proliferation
Decreased cellular differentiation
Capacity to invade surrounding tissue
Ability to establish growth at remote sites (metastasis)

Question 5

How tumor cells bypass apoptosis

Answer 5

Reduce or remove tumor suppressor proteins (ex-p53)

Question 6

Intrinsic apoptosis mechanism

Answer 6

Cyctochrome c is released from the mitochondria

Question 7

Extrinsic apoptosis mechanism

Answer 7

TNF-family interacts with “death receptors”

Question 8

Alkylating agents

Answer 8

Most effective against fast-growing tumors

Alkylate nucleic acids

Question 9

Guanine alkylation

Answer 9

N-7 atom of guanine is particularly nucleophilic and prone to reaction with alkylating agents
N-7-alkylated guanine is unstable and decomposes

Question 10

Nitrogen mustards

Answer 10

Contain nitrogen atom and one or more beta-halogens
Nitrogen attacks alkyl halide carbon atom, forming an aziridinium atom, a strong electrophile
Example: chlorambucil

Question 11

Cyclophosphamide

Answer 11

Prodrug version of nitrogen mustard

Question 12

Platinum agents

Answer 12

Certain cis-platinum complexes have antitumor activity
Inhibit DNA polymerase by forming intrastrand bis-alkylated adducts
Examples: cisplatin, carboplatin

Question 13

N-alkyl-N-nitrosoureas

Answer 13

Decompose to isocyanates and diazohydroxides

Example: carmustine

Question 14

Mitomycin C

Answer 14

Requires metabolic reduction of its quinone to a hydroquinone
Double alkylating agent: can crosslink DNA

Question 15

Antimetabolites

Answer 15

Inhibit the biosynthesis of normal cellular metabolites
Most target the biosynthesis of nucleic acids
Examples: 5-fluorouracil, 6-mercaptopurine

Question 16

5-fluorouracil

Answer 16

Metabolite, 5-fluoro-deoxyuracil monophosphate (5-fluoro-dUMP), inhibits thymidylate synthase
Blocks conversion of dUMP to dTMP
Lacks the proton required for the normal uracil to thymine mechanism

Question 17

Thiol-containing purines

Answer 17

Inhibit ability to form purine metabolites

Examples: 6-mercaptopurine, thioguanine

Question 18

Vidarabine and fludarabine

Answer 18

Commonly called adenine arabinosides

Competitive inhibitors of DNA polymerase

Question 19

Folic acid antimetabolites

Answer 19

Inhibit DNA synthesis by irreversibly binding to dihydrofolate reductase
Examples: aminopterin, methotrexate

Question 20

Antineoplastic antibiotics

Answer 20

Microbial origin

Diverse methods of targeting DNA: intercalation, alkylation, strand breakage through formation of radicals

Question 21

Dactinomycin

Answer 21

Antineoplastic antibiotic
2 cyclic peptides attached to a 3-ring system
Intercalates into double-stranded DNA and inhibits topoisomerase II

Question 22

Anthracyclines

Answer 22

Glycosylated tetracyclic anthraquinone core
Intercalates double-stranded DNA and inhibits topoisomerase II
Reduction of quinone can lead to formation of hydroxyl radicals and DNA strand scission

Question 23

Camptothecins

Answer 23

Inhibitors of topoisomerase I, which normally produces short-term, single-strand breaks in DNA to add/release supercoiling
Can also intercalate (many-ringed systems)

Question 24

Bleomycins

Answer 24

Chelators of copper (blue color)

Form a chelate with Fe (II) that can bind molecular O2, leading to formation of hydroxyl and superoxide radicals

Question 25

Vinca alkaloids

Answer 25

Alkaloids: nitrogen-containing heterocycles from plants
Examples: vincristine, vinblastine
Cause mitotic arrest by promoting dissolution of microtubules

Question 26

Paclitaxel

Answer 26

World’s top-selling antitumor drug (Taxol)
Inhibits mitosis by binding tubulin and preventing its depolymerization
Different tubulin binding site than vinca alkaloids

Question 27

Mitomycins

Answer 27

3 features: quinone (redox activation), carbamate (electrophile), aziridine (electrophile)
Bisfunctional alkylating agents
Redox cycles can generate hydrogen peroxide near DNA