Chemotherapy

Question 1

Cell-Cycle Specific Drug Classes

Answer 1

1. Antimetabolites
2. Topoisomerase Inhibitors
3. Microtubule Inhibitors

Question 2

Methotrexate

Answer 2

Antimetabolite that inhibits dihydrofolate reductase

Question 3

Pazopanib, Levantinib, Cabozantinib

Answer 3

Small molecule inhibitors of the VEGF Receptor

Question 4

Microtubule Inhibitors

Answer 4

Block microtubule polymerization and inhibit mitosis

Can cause neurotoxicity and peripheral neuropathy because microtubules are important for transport of cargo along neurons

Induce resistance via MDR1

Question 5

Imatinib, Dasatinib, Ponatinib

Answer 5

Small molecule inhibitors of BCR-Abl tyrosine kinase that causes CML

Effective single-agent therapy that causes long-lasting remission

Resistance is driven by mutations in BCR-Abl that prevent binding of the drug, but the drug can be modified to combat these mutations

Question 6

Strategies to maximize efficacy of treatment and minimize side effects

Answer 6

1. Combination Therapy
2. Rationaly Designed Therapies
3. Prophylaxis
4. Intermittent therapy
5. Optimization of dosing and route
6. Support of bone marrow function

Question 7

Cell Cycle Nonspecific Drug Classes

Answer 7

1. DNA Intercalating/Damaging Agents
2. Alkylating Agents
3. Protein Synthesis Inhibitors

Question 8

Inhibit mutant B-Raf kinase

Answer 8

Vemurafenib, Dabrafenib

Question 9

MDR1

Answer 9

Multi-Drug Resistance 1 gene

Recognizes toxic compounds and pumps them out of the cell

Expression of MDR1 increases dramatically over course of treatment

Allows cell to develop resistance to chemotherapeutics such as Microtubule Inhibitors and Topoisomerase Inhibitors

MDR1 is non-selective, so resistance to one drug gives resistance to many other drugs

Question 10

Trastuzumab

(What is it, and what are the side effects?)

Answer 10

Monoclonal antibody against HER2 receptor

Can cause heart toxicity when used with Doxorubicin

Question 11

Anti-Angiogenesis Drugs

(Mechanism)

Answer 11

Target VEGF

Theoretically stop cancer by preventing blood supply to cancer

Question 12

Purpose of combination therapy

Answer 12

Using multiple mechanisms makes cells less likely to develop resistance

Therapy is more effective because you are targeting multiple pathways

Fewer side effects because you can use less of each drug

Question 13

Topoisomerase Inhibitors

Answer 13

Topoisomerase is required for DNA replication and mitosis

These drugs induce resistance via upregulation of MDR1

Question 14

Panitumumab

Answer 14

Monoclonal antibody against Epidermal Growth Factor Receptor

Treats EGFr-expressing metastatic colorectal carcinoma

High dermatologic toxicity

Question 15

Examples of Alkylating Agents

Answer 15

1. Nitrogen Mustards
2. Nitrosoureas
3. Hydrazines
4. Platinum Compounds

Question 16

Drug that can cause cardiomyopathy due to free radical generation as well as red urine

Answer 16

Doxorubicin

Question 17

Tamoxifen

Answer 17

Hormonal therapy that acts as an antagonist to estrogen receptor

Used to prevent estrogen-receptor positive breast cancers

Less effective in pre-menopausal women cause they have more estrogen

Question 18

Estrogen Receptor Antagonist

Answer 18

Tamoxifen

Question 19

Tumor lysis syndrome

Answer 19

Occurs when a chemotherapeutic drug is so effective that proteins from lysed tumor cells can cause kidney failure

Question 20

If RAS is mutated, would targeting a growth factor receptor be effective?

Answer 20

NO; RAS is downstream of growth factor receptors and is operating independently if mutated

Question 21

Vemurafenib, Dabrafenib

Answer 21

small molecule inhibitors of mutant B-Raf kinase

This mutation is present in most melanomas

Resistance may develop months later with elevated ERK signaling

Question 22

Longest parts of cell cycle? Shortest?

Answer 22

G1 and S phase take up around 40% of the cell cycle each

M phase takes up only 2% of the cell cycle

Question 23

Rationally Designed Therapy

Answer 23

Drugs that target causitive molecular abnormality of fundamental, universal cellular processes

Require precise knowledge of cause of disease

Include:

1. Small molecule inhibitors
2. Antibodies

Question 24

Antibiotics

Answer 24

Intercalate into DNA, cause single strand DNA breaks, and prevent transcription

Toxicity associated with longterm use

Minimally myelosupressive and immunosuppressive

Question 25

Alkylating Agents

Answer 25

Highly reactive compounds that crosslink DNA and proteins Prevent DNA replication and transcription of RNA **High toxicity to bone marrow and intestinal mucosa** **All are mutagenic/carcinogenic and can induce secondary leukemia** **Cells mutant for p53 have intrinsic resistance**

Question 26

5-fluorouracil

Answer 26

Antimetabolite that inhibits **synthesis of thyidine** from uracil Potent radiosensitizer ; useful for locally advanced and accessible tumors

Question 27

Venetoclax

Answer 27

Used to treat CLL where there's an **overexpression of Bcl-2** It acts as a **Bcl-2 antagonist** in order to **allow apoptosis** May lead to **Tumor Lysis Syndrome**

Question 28

Antimetabolites

Answer 28

Analogs of molecules required for DNA Synthesis (amino acids and vitamins) **S Phase Specific** Most effective for rapidly proliferating tumors - all cause **myelosuppression** (decreased bone marrow)

Question 29

Aromatase Inhibitors

Answer 29

**Exemestane** and **Anastrozole** Block Aromatase, which is responsible for synthesis of estrogen

Question 30

Cells with a p53 mutation have intrinsic resistance to what class of drugs?

Answer 30

Alkylating Agents

Question 31

Rituximab

Answer 31

Monoclonal antibody that binds **CD 20** Found on 90% of non-Hodgkin's lymphomas Can cause **Tumor Lysis Syndrome**

Question 32

GnRH Analogs

Answer 32

**Leuprolide**, **Goserelin** Block sex hormone synthesis in testes and ovaries

Question 33

Bevacizumab

Answer 33

Humanized antibody to VEGF that prevents it from binding to receptors

Question 34

PD-1

Answer 34

Receptor on T cell that reduces cytotoxic activity when stimulated

Question 35

Support Therapy

Answer 35

Drugs designed to support bone marrow function, etc These drugs enable patients to tolerate chemotherapy, but do not play any role in killing cancer

Question 36

Nivolumab, Pembrolizumab

Answer 36

Binds **PD-1** on T cell and **prevent inhibitory signal**, thus allowing T Cells to kill cancer cells via production of **IL-2** and **Interferon**

Question 37

Trametenib

Answer 37

Inhibit **MEK1 and MEK2** (downstream substrates of B-Raf) Used in combination with B-Raf inhibitors

Question 38

Inhibits MEK1 and MEK2

Answer 38

Trametenib

Question 39

Progestins

Answer 39

**Megestrol** Inhibit pituitary release of gonadotropins and can stimulate apetite in patients with cachexia

Question 40

Antiandrogens

Answer 40

Used to treat prostate cancer **Steroidal Antiandrogens** - inhibit androgen binding to receptor (**cyproterone**) **Non-steroidal Antiandrogens** - inhibit nuclear translocation of receptor (**bicalutamide**) Basically they **inhibit Androgen Receptor-dependent gene transcription**

Question 41

Doxorubicin and Daunorubicin

Answer 41

Members of Antibiotic class (DNA Damaging drugs) **Doxorubicin** causes unusual **cardiomyopathy** due to **free radical generation** Also causes **Red Urine** Induces upregulation of **MDR1** and has **resistance**