Principles of Cancer Chemotherapy

Question 1

What is “selective toxicity” with respect to neoplasis and explain what normal cells are most susceptible to certain anti-neoplastics

Answer 1

• selective toxicity can be described in terms of chemotherapeutic index (CTI)
• CTI = (toxicity to cancer cells, i.e. lethal dose)/(toxicity to normal cells)
• fastgrowing/developing cells are most susceptible, i.e. blood cells, follicle cells, GI cells, sperm

Question 2

What are 3 advantages of using combinations of anti-cancer drugs?

Answer 2

1. It provides maximum cell kill within the range of toxicity tolerated by the host for each drug.
2. It offers a broader range of coverage of resistant cell lines in a heterogeneous tumor proliferation.
3. It prevents or slows the development of new-drug resistant cell lines.

Question 3

Compare primary vs. acquired drug resistance.

Answer 3

• primary resistance: absence of response on the FIRST EXPOSRUE to currently available standard agents
• acquired resistance: develops after exposure and is not innate

Question 4

How does p-glycoprotein function as an energy-dependent efflux pump for anti-tumor agents?

Answer 4

P-glycoprotein is expressed on tumor cells and is associated with multidrug resistance. It is expressed via the MDR1 gene. It uses ATP to expel a variety of foreign molecules. It has 2 binding sites for ATP, but only one binding site is involved in drug transport.

Question 5

What are 3 types of cells that are possibly reduced during myelosuppression and what would be the Sx associated with each?

Answer 5

1. Low WBC count (leukopenia): infection, fever, sore throat, cough or shortness of breath, ansal congestion, urination burning, shaking chills, redness, swelling and warmth at injury site.
2. Low RBC counts (anemia): fatigue, dizziness, headache, irritability, shortness of breath, increase in HR/breathing
3. Low platelet counts: bruise easily, bleed longer after cuts, bleeding gums, nose bleeds, echymyoses (large bruise), petechiae (small bruise), internal bleeding

Question 6

What are 3 serotonin antagonists given as anti-nausea agents in cancer pts?

Answer 6

1. Dolasetron
2. Granisetron
3. Ondansetron
   * these are the most effective drugs for the management of nausea and vomiting associated with radiotherapy or chemotherapy as well as many disease processes

Question 7

Describe the relationship between the CTZ and vomiting center and give 2 receptors in the vomiting center.

Answer 7

The chemoreceptor trigger zone (CTZ) sends signals to the vomiting center (VC) upon stimulation.
2 receptors in the VC are serotonin and dopamine receptor (in CTZ mostly, not VC)

Question 8

What are 3 antidopaminergics given as anti-nausea agents in cancer pts and how do they work?

Answer 8

1. Prochlorperazine
2. Fluphenazine
3. Chlorpromazine
   * they work by selectively depressing the CTZ and the vomiting center to a lesser extent
   * these are second line drugs useful in treating mild to moderate nausea and vomiting

Question 9

What is chemotherapeutic index (CTI) and how is toxicity measured?

Answer 9

CTI = toxicity to cancer cells (lethal dose)/toxicity to normal cells

*toxicity is measured by LD50 (lethal dose for 50% cell population)

Question 10

What normal cells are susceptible?

Answer 10

cells that divide quickly - GI cells, blood cells, platelets, sperm cells

Question 11

What defines the best chance for chemotherapy to have a cure?

Answer 11

administration of the drug that can acheive a fractional cell kill in a log fashion, i.e. 1-log kill is 90% of the cells, 2-log kill is 99% of cells)

Question 12

Describe the importance of rapid and frequent chemotherapy Tx in a fast-growing neoplasia.

Answer 12

If Tx is given rapidly and freqnetly, via combination Tx, tumor cell kill exceeds regrowth which can be a possible cure.
If Tx is given infrequently, there is prolongation of survival, but recurrence of Sx.

Surgery combined with combo therapy has rapid decline of cancer cells.

Question 13

A 40 yo man with no significant med Hx presents to physician with complaints of ab pain, N&V, and weight loss. Physical exam reveals only mild anemia (Hb 11gm/dL; hematocrit is 33%). A CT scan of the abdominal region revealed a mass present in the peri-pancreatci that is suggestive of malignancy. What should you not tell the man at this point. What Tx are available?

Answer 13

Should not tell him it is cancer if you are not certain, but don’t tell the pt to go home yet. Take a biopsy, pain management, surgery, cancer therapy as appropriate.

Question 14

What are 3 benefits of combination therapy?

Answer 14

1. maximum cell kill tolerated by host
2. broader range of coverage
3. prevents/slows development of new resistant lines

Question 15

What is the difference between primary and acquired resistance?

Answer 15

Cells ath don’t respond to the first type of Tx exhibit primary resistance. Acquired resistance develops in a number of drug-sensitive tumor types.

Question 16

Describe the relationship between efflux pumps and multidrug resistance,

Answer 16

P-glycoprotein (from MDR1 gene) is a cell surface drug efflux pump that can take out a number of anti-cancer and antibiotic drugs. It is present on many cancerous cells and allows the cell to be resistant to each specific drug. P glycoprpotein efflux pump pushes drug out which reduces effectiveness of drug.

Question 17

What are 3 Ca2+ channel blockers that can reverse multidrug resistance?

Answer 17

1. Verapamil
2. Quinidine
3. Cyclosporin

Question 18

A 23 yo man is Dx with Stage II favorable Hodgkin’s disease. He is begin on the ABVD Tx combo to be given in combo with irradiation. He is very reluctant because of his fear of side effects. He asks if he can receive 1 drug at a time rather than all 4 drugs at once. Is this a good idea?

Answer 18

No - it can lead to cancer cell resistance and cells would continue to grow if only 1 drug was given at a time. All 4 drugs must be taken at once.

Question 19

After Tx, Hodgkin’s pt undergoes assessment of cancer load of 2 cycles using PET-CT of mediastinum lymph nodes. It reveals a slight increase in neoplastic cell load. Why might this Tx be failing?

Answer 19

Perhaps the drug is not being given rapidly and frequently enough to kill enough tumor cells.

Question 20

Hodgkins pt is continued on ABVD with more frequent Txs. After 2 more cycles, there is a 20% reduction in lymph node size upon PET-CT, which is disappointing. Which agent may be failing and why?

Answer 20

Neoplasma has developed drug resistance to vinblastine via MDR-1 gene and P-glycoprotein efflux

Question 21

What are 3 goals of chemotherapy?

Answer 21

1. control the spread of tumor cells (maybe shrink it before surgery)
2. possibly cure the disease
3. palliative care

Question 22

Where are the 2 locations where antiemetic drugs act?

Answer 22

both locations are in the vomiting center of the medulla:

1. chemoreceptor trigger zone (CTZ)
2. vestibular apparatus (VA)
   * drug therapy is more successful for prophylaxis than for Tx for nausea and vomiting

Question 23

What are 3 serotonin-receptor antagonists and what is special about them?

Answer 23

1. Dolasetron (ANZEMET)
2. Granisetron (KYTRIL)
3. Ondasetron (ZOFRAN)
   * these are 1st line antiemetic therapy - most effective drugs for the managemetn of N&V associated with radiotherapy or chemotherapy

Question 24

How many DA and 5HT receptors each are in the vomiting center?

Answer 24

2 DA receptors and 3 serotonin receptors

Question 25

what is located at the bottom of the 4th ventricle?

Answer 25

area postrema

Question 26

What is a special characteristic of the CTZ?

Answer 26

It is a zone that is leaky to blood so that if toxic materials are in blood and come into contact with CTZ, it will trigger a vomiting response

Question 27

What are 3 antidopaminergic drugs and how do they function?

Answer 27

1. Prochlorperazine (COMPAZINE)
2. Fluphenazine (PERMITIL, PROLIXIN)
3. Chlorpromazine (Thorazine)

• act by selectively depressing CTZ and VC to a lesser extent
• second-line drug for mild to moderate nausea and vomiting

Question 28

50yo pt treated for HD is using the MOPP region. Following 30 days of Tx, the pt develops severe N/V. What you prescribe?

Answer 28

prescribe first line serotonin receptor antagonists - dolasetron, granisetron, or ondasetron

Question 29

After 3 days of receiving first line antiemetic, N/V decreased but he developed drug-related dermatitis. What should you presecribe?

Answer 29

Prescribe antidopaminergic: prochlorperazine, fluphenazine, or chlorpromazine

Question 30

What is MOPP?

Answer 30

multidrug combo therapy

Question 31

What is metastasis?

Answer 31

Metastasis is the spread of cancerous cells to secondary sites through the body. Ther is a shift in the control mechanisms that moderate cell proliferation and differentiation. Proliferation of cells is in a of cells is in a dys-regulated manner and there is an invasion of surrounding tissues through secretion of proteolytic enzymes. Tumor cells can undergo repeated cycles of proliferation.

Question 32

What is 1 advantage of cell-surface antigens on some cancer cells?

Answer 32

Cancer cells show an alteration of cell-surface antigens. However, this can be advantageous as some of these alterations may be shed into the blood and are detectable by immunologic techniques as tumor markers.

Question 33

What are 3 types of daughter cells formed as a result of mitosis?

Answer 33

1. cells at are non-dividing and terminally differentiated (no genomic DNA replication)
2. Cells that are continually proliferating
3. Cells that are resting but may be recruited into the cell cycle such as stem cells

*all 3 may exist simultaneously in tumors

Question 34

What is the advantage of giving combinations of anti-cancer drugs in order to completely kill neoplasias?

Answer 34

combinations of anti-cancer drugs with differing toxicities and mechanisms of action are often employed in order to overcome the limited log kill of individual anti-cancer drugs

Question 35

What are 4 things to consider when choosing chemotherapy combinations?

Answer 35

1. may be synergistic
2. more effective if they do not share common mechanism of resistance
3. more beneficial if they do not overlap in major toxicities
4. drugs should be administered as frequently as possible in order to maximize does intensity, limiting tumor re-growth
   * in sum: maximum cell kill with each Tx cycle by using the highest dose possible and repeating doses as frequently as tolerable

Question 36

. What are 6 anticancer agents that are affected by MDR-1 mediated resistance?

Answer 36

1. Anthracyclines
2. Vinca alkaloids
3. Palcitaxel (Taxol)
4. Etoposide
5. Mitomycin (mUtamycin)
6. Plicamycin (Mithramycin)

*once a tumor has developed resistance to a single MDR-1 agent, it is unlikely that the addition of another MDR-1 agent will add significant clinical beneift

Question 37

What are 3 types of cells that are possibly reduced during myelosuppression?

Answer 37

1. RBCs
2. WBCs
3. Platelets

Question 38

What is a drig given to increase RBC counts in anemic cancer pts?

Answer 38

Recombinant erythropoietin is sued to increase RBC counts in anemic cancer pts.