Antineoplastic Agents Part I: Chemotherapy in general

Question 1

Top 4 cancer sites

Answer 1

1. Breast cancer (female)
2. Lung and bronchus
3. Prostate
4. Colon and Rectum

Question 2

Alkylating Agents (list)

Answer 2

Nitrogen mustards:

• cyclophosphamide
• ifosfamide

Alkyl sulfonate:
- Busulfan

Platinum coordination complexes:
- Cisplatin

Question 3

Natural Products (originally isolated from plants or bacteria, etc.)

Answer 3

Vinca alkaloids:
Vinblastine
Vincristine

Taxanes: Paclitaxel

Tpipodophyllotoxins: Etoposide

Antibiotics: Bleomycin, Doxorubicin

Enzymes: L-Asparaginase

Question 4

Antimetabolites

Answer 4

Folic acid analogs: Methotrexate (MTX)

Pyramidine analogs: Fluorouracil

Purine analogs: mercaptopurine

Question 5

Differentiating agents

Answer 5

Tretinoin

Question 6

Biological response modifiers

Answer 6

Interferon-alfa

Interleukin-2

Question 7

Immunomodulators

Answer 7

Thalidomide

Question 8

Rescue agents

Answer 8

Leucovorin

Mesna

Question 9

Protein tyrosine kinase inhibitors

Answer 9

Dasatinib
Erlotinib
Imatinib
Lapatinib

Question 10

Proteasome inhibitor

Answer 10

Bortezomib

Remember it by “Borteasome”

Question 11

Monoclonal Antibodies

Answer 11

Bevacizumab
Cetuximab
Rituximab
Trastuzumab

Question 12

Agents used to minimize adverse effects

Answer 12

Filgrastim
Ondansetron
Ondansetron

Question 13

Cancer Treatment Modalities

Answer 13

Chemotherapy

• Immunotherapy
• Targeted Therapies
• Vaccines

Radiation Therapy
Surgery
Transplantation

Combinations are the norm

Question 14

Primary Induction Therapy

Answer 14

The main treatment that provides the best possible outcome

Also called first-line therapy

Question 15

Neoadjuvant Therapy

Answer 15

Treatment given BEFORE primary induction therapy in order to improve outcome
E.g., Chemo or radiation to shrink a tumor before surgery

Question 16

Adjuvant Therapy

Answer 16

Additional therapy given CONCOMITANTLY or AFTER primary induction therapy in order to reduce the probability of relapse

Question 17

Biology of Cancer: The Cell Cycle

Answer 17

Cell cycle checkpoints control transitions between cell cycle stages

DNA damage?
Spindle assembly?
Favorable conditions?
Completed replication?

Failure to pass checkpoint: cell cycle is delayed or cells apoptose

Question 18

Cycling Out of Control

Answer 18

In many forms of cancer, proteins or pathways involved in regulating the checkpoints between the phases of the cell cycle may be absent or mutated
For example: p53, CDKs

Aberrations in checkpoint regulation result in uncontrolled and unregulated cell proliferation

Cell cycle specific (dividing) vs. cell cycle nonspecific (regardless of whether they are dividing or not)

Question 19

Cell cycle specific agents

Answer 19

Antimetabolites
antitumor antibiotic-bleomycin
Taxanes
Vinca alkaloids
Toppoisomerase inhibitors

Question 20

Cell cycle nonspecific agents

Answer 20

Alkylating agents
anthracyclines
platinum analogs

Question 21

Growth fraction

Answer 21

the ratio of proliferating cells to resting cells (G0)

Growth fraction is a determinant of responsiveness to chemotherapy
Cells with high growth fraction:
- Bone marrow
- GI tract
- Hair follicles
- Sperm-forming cells

Question 22

Growth Fraction and Therapeutic Response

Answer 22

The initial growth rate of most solid tumors is rapid but decreases over time

Burkitt lymphoma (high growth fraction; curable by chemotherapy) vs. colorectal carcinoma (low growth fraction; chemotherapy has minor activity)

Some disseminated tumors can be cured by single-agent chemotherapy

The growth fraction of solid tumors can be increased by reducing the tumor burden (i.e., surgery or radiation)

Question 23

Log Cell Kill Hypothesis

Answer 23

A fraction (not an absolute number) of cells are killed
A three-log cell kill eliminates 99.9% of cells:
10^12 to 10^9 cells
10^6 to 10^3 cells

Question 24

Therapeutic Balance: Efficacy vs. Toxicity

Answer 24

Challenge: provide dose that is therapeutic without being (too) toxic

Antineoplastic drugs harm both cancerous tissues and healthy tissues

Not all drug regimens are appropriate for all patients

Factors to consider:
Renal and hepatic function
Bone marrow reserve
General performance status
Concurrent medical problems
Patient willingness

Question 25

Primary resistance

Answer 25

An absence of response on the first drug exposure | Thought to be due to genomic instability

Question 26

Acquired resistance

Answer 26

``` Develops in response to exposure to a given antineoplastic agent Often highly specific to a single drug, or class of drugs, and is usually due to an increased expression of one or more genes ```

Question 27

Examples of single agent resistance pathways include:

Answer 27

decreased drug transport into cells reduced drug affinity due to mutations or alterations of the drug target increased expression of an enzyme that causes drug inactivation increased expression of DNA repair enzymes for drugs that damage DNA

Question 28

Multidrug resistance and ATP-dependent Transporters

Answer 28

ATP-dependent transporter gene amplification in neoplasms confers resistance to a broad range of agents used in cancer treatments The P-glycoprotein is an ATP-dependent efflux pump that actively pumps antineoplastic agents out of cells (MDR1 gene) Anthracyclines, vinca alkaloids, etoposide, paclitaxel, and dactinomycin

Question 29

Toxicity of Antineoplastic Agents

Answer 29

The lack of neoplastic specificity for chemotherapeutic drugs is a major limiting factor in the treatment of cancer Rapidly proliferating normal tissues (tissues with high growth fractions) are the major sites of toxicity bone marrow, gastrointestinal tract, hair follicles, buccal mucosa, sperm forming cells Many antineoplastic agents are mutagens themselves and can give rise to neoplasms years after treatment (e.g., alkylating agents have caused AML and ALL)

Question 30

Common Adverse Effects of Chemotherapy

Answer 30

Occur during therapy with nearly all classic antineoplastic agents: ``` Nausea Vomiting Fatigue Stomatitis Alopecia ``` Myelosuppression – can lead to impaired wound healing and predisposition to infection Low sperm counts and azoospermia Depressed development of children exposed to antineoplastic agents

Question 31

Minimizing Adverse Effects of Chemotherapy

Answer 31

# Choose the route of administration that minimizes systemic toxicity as much as possible Pharmacologic agents that help decrease adverse effects: - Hematopoietic agents for neutropenia, thrombocytopenia, and anemia (will discuss later in the course) - Serotonin receptor antagonist (ondansetron) and other drugs for emetogenic effects - Bisphosphonates to delay skeletal complications Rest and recovery