Med Chem of Chemo Agents

Question 1

Cancer

Answer 1

• Second leading cause of death in U.S.
• All forms involve out-of-control growth, patterns of spread, and responses to different types of treatment
• No single treatment good for all forms of cancer

Question 2

Cell Cycle

Answer 2

• Birth of new cell to the time the new cell divides
• 5 steps: G0, G1, S, G2, and M
• Most antineoplastic agents works on actively replicating cells (not G0 cells)
• Severe SE of chemo drugs are from damaging normal cells in the replicating phases

Question 3

Chemotherapy

Answer 3

• Vary by chemical composition, how they’re taken, usefulness, and SE
• Sometimes the first choice for many cancers and is almost always systemic treatment
• Antitumor drugs are best at killing cells during DNA synthesis (when a tumor is “young”)
• Chemotherapy is limited by its lack of use for larger tumors, lack of selectivity between normal/malignant cells, and its SE

Question 4

Major Chemotherapy Drug Classes

Answer 4

• Alkylating agents
• Antimetabolites
• Antitumor Antibiotics
• Mitotic inhibitors
• Hormones
• Monoclonal antibody therapy

Question 5

Alkylating Agents

Answer 5

• Work on DNA to prevent cancer cell from reproducing
• Not phase specific
• Can cause intrastrand linking and cross-linking

Question 6

Mechlorethamine/Chlorambucil

Answer 6

• Original nitrogen mustard
• Not as widely used as they once were
• Cause Guanine-Guanine linkage

Question 7

Cyclophosphamide

Answer 7

• One of the most widely used alkylating agents
• Used to treat many tumors
• Enzymatically oxidized with cleavage of N-P bond to give active metabolite

Question 8

Carmustine/Lomustine

Answer 8

• BCNU/CCNU
• Nitrosoureas
• Broad spectrum of activity
• High lipid solubility, able to cross BBB (useful for brain tumors)

Question 9

Busulfan

Answer 9

• Methanesulfonate ester
• Used to treat chronic granulocytic leukemia
• High-dose chemotherapy

Question 10

Thiotepa

Answer 10

• Weak alkylator

- Employed to treat breast and ovarian cancers

Question 11

Probcarbazines

Answer 11

• Alkylates DNA through free radical mechanism

- Occurs during its metabolism

Question 12

Cisplastic/Carboplatin

Answer 12

• Platinum compounds
• Mechanism of action and toxicity profile distinctly different from alkylating agents
• Promote intrastrand cross-linking via covalent platinum-nitrogen bonds, mainly at N7 on guanine residues

Question 13

Antimetabolites

Answer 13

• Class of drug that interferes with DNA and RNA growth by substituting for building blocks in DNA/RNA structure
• Includes folate, purine, and pyrimidine nucleoside pathways
• S phase specific

Question 14

Methotrexate

Answer 14

• Irreversible binds to dihydrofolate reductase
• Prevents formation of coenzyme tetrahydrofolic acid
• Essential for DNA synthesis and replication of cells

Question 15

6-Mercaptopurine/6-Thioguanine

Answer 15

• 6MP/6TG
• Antagonists to purines
• Essential constituents of DNA
• Both compounds used almost exclusively to treat leukemia

Question 16

5-Fluorouracil

Answer 16

• 5-FU
• Fluorine substitution in pyrimidine of uracil
• Stable C-F bond precludes methylation of 5 position, preventing formation of thymidine
• 5-FU must be phosphorylated to the nucleotide to be active

Question 17

Antitumor Antibiotics

Answer 17

• Antimicrobial and cytotoxic activity
• Interfere with DNA by chemically inhibiting enzymes and mitosis or altering cellular membranes
• None are phase specific

Question 18

Doxorubicin/Daunorubicin

Answer 18

• Anthracene derivatives
• Important class of antineoplastics due to broad spectrum of activity
• Planar ring structure of compounds can intercalate between base pairs in DNA double helix
• Activity and SE attributed to capability to initiate free radical reactions

Question 19

Mitoxantrone

Answer 19

• Anthracene-derived antitumor drug
• Have lower toxicity
• Structurally similar to doxorubicin/daunorubicin but is formally an anthracenedione

Question 20

Dactinomycin

Answer 20

• Actinomycin D
• Isolated from S. parvullus
• Most active of a series of cyclic pentapeptides
• Binds with DNA by intercalation and blocks RNA production
• Inhibits protein synthesis

Question 21

Bleomycin

Answer 21

• Group of glycopeptides
• Derived from fermented product of S. certicillus
• Used to manage certain epithelial cell and testicular carcinomas
• Also used for malignant lymphomas
• Can form a complex with oxygen and iron which can form free radicals
• Free radicals attack phosphodiester bonds between G-C and G-T sequence, leads to strand breaks

Question 22

Mitomycin C

Answer 22

• Bioreductive alkylating agent
• Requires enzymatic activation to active metabolite that then cross links DNA
• Leads to DNA strand breaking
• Quinone group also generates free radicals

Question 23

Antimitotic Agents

Answer 23

• Arrest cell division process
• Bind to tubulin and block protein to polymerize into microtubulin
• Ex: Paclitaxel (Taxol)

Question 24

Hormonal Therapy

Answer 24

• Effective in hormone-dependent cancers (breast/prostate)
• Antiestrogens and aromatase inhibitors are useful in breast cancer treatment (Tamoxifen)
• Gonadotropin-release hormone antagonists and antiandrogens are useful in prostate cancer (Flutamide)

Question 25

Monocloncal Antibody Therapy

Answer 25

• Immunotherapy that empowers immune system to attack cancer cells
• Designed to target certain antigens that live on the cancer cells’ surface
• Growing drug class for cancer, more than a dozen have been approved by FDA

Question 26

Kinase Inhibitors

Answer 26

• Small molecule inhibitors of protein kinase enzymes
• Often deregulated in cancer cells and accelerate cell signaling cascades and cellular growth
• Targeted therapeutic molecules used in patients who were carefully screened for specific genomic markers
• Bind to hydrophobic hinge region that connects the N- and C-terminal lobes of the kinase
• Minimum of five potential binding pockets surround this site which allow for surprising amount of selectivity shown by KIs