Anti-Cancer Drugs

Question 1

Active Cell Phases

Answer 1

M Phase - Mitosis and Cell Division

S Phase - DNA snythesis

Question 2

Antimetabolites

Answer 2

Inhibit nucleic acid synthesis

Inhibit DNA replication

Question 3

Mercaptopurine Basics

Answer 3

Analog of purine bases hypoxanthine or adnine; thiopurine
6-MP is converted to T-IMP, which is a poor substrate for guanylyl kinase.
T-IMP accumulates in cells and inhibits purine synthesis

Question 4

Mercaptopurine Details

Answer 4

Extensive first-pass metabolism by xanthine oxidase in liver limits to <20% of administered dose
Allopurinol (XO inhibitor) increases absorption by five-fold

Question 5

Folic Acid Analog

Methotrexate

Answer 5

Irreversibly binds and inhibits dihydrofolate reductase (DHFR).
Prevents FH2 from converting to FH4 during DNA synthesis.
Synthesis of thymidine and purines inhibited.

Question 6

Methotrexate Details

Answer 6

Used in cancers and autoimmune diseases.
Toxicities are frequent: including myelosuppression, GI
Photosensitivity. Long term use cause hepatic and renal toxicity.

Question 7

Leucovorin

Answer 7

Folinic acid, a derivative of FH4

Usually administered 12-20h following the end of MTX infusion to mitigate toxicities.

Question 8

Pyrimidine analog

5-fluorouracil (5-FU)

Answer 8

Metabolized to ribosyl (F-UTP) and deoxyribosyl-(F-dUMP)
F-UTP is incorporated into RNA and interferes with RNA function
F-dUMP inhibits thymidylate synthase, inhibiting synthesis of thymidine (DNA synthesis inhibited)

Question 9

5-Fluorouracil Details

Answer 9

Used for solid tumors; topical use for noninvasive skin cancer
Side effects include: myelosuppression, GI mucosal damage leading to ulcerations in mouth and diarrhea. Photosensitivity

Question 10

Pyrimidine Analog: Cytarabine

Answer 10

Analog of cytosine with modified sugar moeity. Converted to triphosphate form and incorporated into DNA in place of cytosine
Uses: Leukemia
Toxicity: Myelosuppression, GI toxicity.

Question 11

Hydroxyurea

Answer 11

Inhibits ribonucleotide reductase, which is needed for production of deoxyribonucleotides
Prevents sickle-shaped cells from forming by increasing HbF synthesis
Use: Sickle-cell anemia, myeloproliferative disorders
GI toxicities, myelosuppression, anemia, bleeding, secondary leukemias.

Question 12

Summary of Antimetabolites

Answer 12

Inhibit DNA synthesis by various mechanisms
Mercaptopurine is a purine analog that is converted into T-IMP, which accumulates, is not recognized by guanylyl kinase, and blocks synthesis of puranes
Methotrexate is an example of a folic acid analog; inhibits DHFR
5-FU is a pyrimidine analog that is converted into F-dUMP and F-UTP, inhibiting DNA synthesis and RNA function respectively.
Hydroxyurea inhibits ribonucleotide reductase

Question 13

Anti-microtubules

Answer 13

Either inhibit tubulin polymerization or stabilze microtubules to block mitosis. M phase-specific agents

Question 14

Vinca Alkaloids

Vincrisine, vinblastine, vinorelbine

Answer 14

Specifically bind to tubulin and inhibit tubulin polymerization into microtubules, blocking spindle formation.
Toxicities: Myelosuppression, GI toxicity, peripheral neuropathy.

Question 15

Taxanes

Paclitaxel, docetaxel

Answer 15

Bind beta-tubulin subunit, promoting assembly of microtubules and preventing depolymerization.
Uses: Solid tumors
Toxicities: Severe alopecia, myelosuppression, peripheral neuropathy, neutropenia, anemia

Question 16

Cytotoxic Antibiotics

Answer 16

Derived from streptomyces bacteria
Act directly on DNA
Block Mammalian cell division

Question 17

Anthracyclines

Doxorubicin, Daunorubicin

Answer 17

Contains an anthracene ring complex
Intercalate into DNA, deforming the structure and interfering with DNA and RNA synthesis
Inhibit topoisomerase II activity, blocking repair of DNA breaks
Contain quinone moieties, which induce the production of free radicals.

Question 18

Anthracycline Details

Answer 18

Use: Primary chemotherapy for breast cancer. Also Hodgkins disease, bladder, overian, and gastric carcinoma
Daunorubicin is primarily for acute myeloid leukemia
Toxicities: Cumulative, dose-related cardiac damage, severe or total hair loss, GI mucosal damage

Question 19

Bleomycin

Blenoxane, Cipla, Bleocip

Answer 19

Family of structurally metal-chelating glycopeptides
Requires metal and oxygen for activity
Chelates metals (usually iron) and reacts with O2 to produce free radicals that cause DNA damage

Question 20

Bleomycin Details

Answer 20

Uses: Testicular, ovarian, Hodgkin’s lymphoma, head and neck cancer.
Unique mechanism of action
Toxicity does not overlap with other dugs
Almost no myelosuppression
Causes pulmonary fibrosis
Inactivated by bleomycin hydrolase (found everywhere but skin and lung)

Question 21

Alkylating Agents

Answer 21

Agents that covalently attach alkyl groups to DNA, causing cross-linking.
Include: Nitrogen mustards, nitrosoureas, busulfan, cisplatin

Question 22

Nitrogen Mustards; Cyclophosphamide

Answer 22

Low doses are immunostimulatory and antiangiogenic
High doses are cytotoxic and immunosuppressive
Cyclophosphamide metabolized to produce 4-hydroxycyclophasphamide and aldophasphamide
Aldophosphamide is metabolized to phosphoramide mustard, which crosslinks nucleic acid molecules

Question 23

Platinum Agents: Cisplatin

Answer 23

Platinum binds DNA to form intra- and inter-strand cross-links/adducts with purine bases, disrupting DNA synthesis and inducing cell death.
Uses: 1st line for testicular, ovarian, bladder, also used for melanoma
Toxicities: Nephrotoxicity due to reactive oxxygen species
One of strongest emetogenic
Ototoxicity

Question 24

SERMS (selective estrogen receptor modulator)

Answer 24

Tamoxifen
Used to treat ER+ (estrogen receptor) breast cancer
Binds to ER and blocks estrogen binding
Side effects: Blood clots and stroke, endometrial and uterine cancers
SSRI antidepressants interfere with metabolism

Question 25

Aromatase Inhibitors

Answer 25

Anastrozole
Nonsteroidal competitive inhibitors of the enzyme aromatase
Aromatase converts androgens to estrogens.

Question 26

Targeted Therapies Imatinib

Answer 26

Small molecule tyrosine kinase inhibitor

Toxicities: nausea, vomiting, cramps, rash and diarrhea

Question 27

Targeted Therapies Trastuzumab

Answer 27

Blcoks mitogenic, proliferative, and anti-apoptotic effectrs of HER2 signaling
1st line therapy for HER2-overexpressing metastatic breast cancer.
Cardiotoxicity

Question 28

Targeted Therapies: Bevacizumab

Answer 28

Vascular endothelial growth factor stimulates angiogenesis. Bevacizumab is monoclonal antibodies against VEGF
Inhibits new vessel development
First line therapy in combination with chemotherapy for metastatic colorectal, breast, and NSCLC
Toxicities: HTN, increased risk of bleeding, bowel perforation.