Module 17- Cancer Chemotherapy

Question 1

Characteristics of Cancer Cells

Answer 1

1) Persistent uncontrollable cell proliferation
2) Invasive – cancer cells invade adjacent tissue, facilitating cancer growth in different areas of the body.
3) Metastatic – the ability of cancer cells to travel to different sites in the body and invade to form new tumours.
4) Immortal – Cancer cells do not die, they continually divide.
5) Angiogenesis – Cancer cells develop their own blood vessels to supply nutrients. This is a critical step to allow them to proliferate.

Question 2

Treatment Modalities for Cancer

Answer 2

1) Surgery – the tumour is removed.

2) Radiation – high energy radiation is used to shrink tumours and kill cancer cells. Radiation therapy damages DNA of both cancerous and non-cancerous cells.

3) Chemotherapy – Drugs are used to treat cancer. As cancerous cells are dividing rapidly, chemotherapeutic drugs target rapidly dividing cells.

Question 3

G0 - Cell Cycle

Answer 3

resting, no replication

Question 4

G1 - Cell cycle

Answer 4

the cell prepares to synthesize its DNA (duplicate)

Question 5

S- Cell cycle

Answer 5

cell synthesizes DNA

Question 6

G2 - cell cycle

Answer 6

cell preps for mitosis

Question 7

M - cell cycle

Answer 7

cell divides in mitosis

Question 8

Toxicity to Normal Cells

Answer 8

Neoplastic cells (i.e. cancer cells) are very similar to normal cells. Therefore it is difficult to specifically target only cancer cells during chemotherapy

The most cellular toxicity occurs to cells with a high growth fraction. The growth fraction is the ratio of proliferating cells to cells in the resting (G0) state. Examples of cells with a high growth fraction include: bone marrow, GI epithelium, hair follicles and the germinal epithelium of the testes, that gives rise to sperm.

Aside from killing cancer cells, chemotherapeutic drugs kill normal cells.

Question 9

Cure of Cancer Requires 100% Cell Kill

Answer 9

In order to cure cancer, we must kill virtually all cancerous cells in the body. This is difficult as there are not good tests to determine whether cancerous cells are present in the body in low numbers.

The kinetics of cell death with chemotherapy are first-order. This means that a constant percentage of cancerous cells are killed at a given dose of drug.

Question 10

Breast Cancer Detection

Answer 10

Clinical Breast Examination every 2-3 years for women over 50. High risk patients should be screened more often and screening may start earlier than age 50.

Question 11

Cervical Cancer detection

Answer 11

The most important risk factor for cervical cancer is Human Papillomavirus (HPV) infection. HPV is spread primarily by genital skin-to-skin contact and it is estimated that over 75% of women AND men will have at least one HPV infection in their lifetime. Sexually active women should have a Pap test every 1-3 years.

Question 12

Colorectal Cancer detection

Answer 12

Men and women over 50 who are not at high risk should have a fecal occult blood test every two years.

Colonoscopy may also be performed every 5 years in high risk patients.

Question 13

Prostate detection cancer

Answer 13

Men over 50 should have the Digital Rectal Exam and/or the Prostate Specific Antigen blood test.

Question 14

Prostate detection cancer

Answer 14

Men over 50 should have the Digital Rectal Exam and/or the Prostate Specific Antigen blood test.

Question 15

Skin cancer detection

Answer 15

Self-checks should be performed regularly. In particular, look for changes to birthmarks and/or moles, any new skin growths, and sores that don’t heal properly.

Question 16

Testicular Cancer detection

Answer 16

Males over the age of 15 should regularly perform the Testicular Self Examination.

Question 17

Solid Tumours Respond Poorly To Chemotherapy

Answer 17

Solid tumours have a large fraction of cells in the resting (G0) state. As most chemotherapeutic drugs target proliferating cells, solid tumours don’t respond as well.

Question 18

Drug Resistance

Answer 18

Mechanisms of resistance can include:

1. decreased drug uptake,
2. increased drug efflux,
3. decreased drug activation (in the case of prodrugs),
4. reduced target sensitivity, increased cellular (primarily DNA) repair.
5. Decreased apoptosis (programmed cell death).

P-glycoprotein is an efflux drug pump that pumps drugs out of cells (remember Module 2?). By not allowing cellular accumulation of chemotherapeutic drugs, P-glycoprotein can cause multiple drug resistance.

Resistant cells are not killed by chemotherapeutic agents and therefore this phenomenon can cause therapeutic failure.

Question 19

Intermittent Chemotherapy

Answer 19

The intent of this strategy is to kill cancer cells by administering chemotherapeutic drugs intermittently. This allows time for normal cells to recover.

For this approach to be successful, normal cells must grow back faster than cancerous cells as in the example on the right.

Question 20

Combination Chemotherapy

Answer 20

1) Decreased Resistance - Resistance may be acquired due to random mutations in cancer cells. It is unlikely that cancer cells will undergo multiple different mutations. Therefore using multiple drugs with different mechanisms of action makes therapy less likely to be affected by resistance.

2) Increased Cancer Cell Kill – Drugs with different mechanisms of action will kill more cancer cells than a single agent. Drugs with different mechanisms of action attack cancer cells in different ways resulting in greater cell kill.

3) Decreased Injury to Normal Cells – Using drugs that do not have overlapping toxicities allows us to achieve greater anti-cancer effects safely than we could with one drug alone.

Question 21

Bone Marrow Suppression

Answer 21

Bone marrow has a very high growth fraction and is therefore very susceptible to chemotherapy associated toxicity.

1) Neutropenia – decreased neutrophils in the blood. Neutrophils are a type of white blood cell that help the body fight infections.

2) Thrombocytopenia – decreased platelets in the blood. Platelets are involved in the coagulation (or blood clotting) process. Decreased circulating platelets increases the risk of serious bleeding events.

3) Anemia – decreased number of erythrocytes (red blood cells) in the blood. Although an important toxicity, anemia is less of a concern than neutropenia and thrombocytopenia.

Question 22

Neutropenia

Answer 22

decreased neutrophils in the blood. Neutrophils are a type of white blood cell that help the body fight infections.

Question 23

Thrombocytopenia

Answer 23

decreased platelets in the blood. Platelets are involved in the coagulation (or blood clotting) process. Decreased circulating platelets increases the risk of serious bleeding events.

Question 24

Anemia

Answer 24

decreased number of erythrocytes (red blood cells) in the blood. Although an important toxicity, anemia is less of a concern than neutropenia and thrombocytopenia.

Question 25

Digestive Tract Injury

Answer 25

Stomatitis (inflammation of the oral mucosa) may develop to some chemotherapeutic agents. If severe enough this may progress to ulceration.

Diarrhea may occur secondary to the damage the chemotherapeutic drugs cause to the epithelial lining of the intestine.

Question 26

Nausea and Vomiting

Answer 26

A serious and common adverse effect associated with chemotherapy. Sometimes these effects are treatment limiting, and patients will refuse further treatment because of chemotherapeutic drugs’ frequency and unpleasant emetic effects.

Anti-emetic drugs, prevention of dehydration, and prevention of malnutrition may be important adjuncts to chemotherapy.

Question 27

2 classes of drugs to treat cancer

Answer 27

1. Cytotoxic agents
2. Hormonal and other agents

Question 28

Cytotoxic Agents

Answer 28

1) Alkylating agents
2) Platinum compounds
3) Antimetabolites
4) Antitumour antibiotics
5) Mitotic inhibitors

Question 29

Cell Cycle Phase Specificity

Answer 29

Cytotoxic drugs can be separated into either cell cycle phase specific or cell cycle phase non-specific drugs.

Cell cycle phase-specific drugs are only effective if the cancer cell is in a specific cell cycle phase. For example, mitotic inhibitors are only effective when cancer cells are undergoing mitosis. Phase-specific drugs are only effective in cells that are actively part of the cell cycle and are ineffective for cells that are in Go.

Cell cycle phase non-specific drugs can act during any stage of the cell cycle including Go. Although phase non-specific drugs are effective at any stage of the cell cycle, they are more toxic to cells that are proliferating than to cells in Go.

Question 30

Alkylating Agents

Answer 30

Are highly reactive chemicals that act by transferring an alkyl group to cell components (primarily DNA).

They act by forming cross-bridges between nitrogen atoms on guanine nucleotides that make up our DNA.

The result of treatment with alkylating agents is miscoding, breaking of DNA, and possibly inhibition of DNA replication.

Alkylating agents are cell-cycle phase non-specific, meaning they may be effective during any phase of the cell cycle.

Cyclophosphamide is the most widely used drug in this class. Cyclophosphamide is a prodrug and must be converted to its active form by the liver. For this reason its onset of effect is often delayed.

Common indications for cyclophosphamide include Hodgkins disease and solid tumours of the head, neck, ovary and breast.

Question 31

Platinum Compounds

Answer 31

Are drugs with platinum in their chemical structure.

Act by cross-linking DNA and therefore inhibiting DNA replication.

They cross-link DNA by binding to guanine nucleotides, similar to alkylating agents.

Are cell-cycle phase non-specific.

Cisplatin is the most widely used platinum compound, and is used in the treatment of metastatic ovarian and testicular cancers as well as advanced bladder cancer.

Cisplatin is extremely nephrotoxic, ototoxic (toxic to the ear and may cause deafness) and emetogenic (causes nausea and vomiting).

Question 32

Antimetabolites

Answer 32

Are structurally similar to natural compounds the body uses to:
a) synthesize cellular constituents or b) incorporate into DNA.

They act by inhibiting particular enzymes or by preventing DNA replication.

Antimetabolites are phase specific and most (although not all) act during S-phase

Question 33

Antimetabolites can be further classified into 3 subclasses

Answer 33

1) Folic acid Analogs – block the conversion of folate to its active form.

2) Purine Analogs – purines are used to make DNA and RNA. Purine analogs inhibit the synthesis of DNA and RNA.

3) Pyrimidine Analogs – pyrimidines are used to make DNA and RNA. Pyrimidine analogs inhibit the synthesis of DNA and RNA.

Question 34

Antitumour Antibiotics

Answer 34

Kill cancer cells by intercalating DNA. This means that they move between the bases of DNA and bind to DNA. This causes a change in the structure of DNA. The altered DNA structure is unable to be used as a template by DNA polymerase and therefore DNA synthesis is inhibited.

Antitumour antibiotics are very poorly absorbed and therefore are given intravenously.

Question 35

Anthracyclines

Answer 35

Are a type of antitumour antibiotic.

Although they are effective and widely used chemotherapeutic agents, anthracyclines can cause severe bone marrow suppression and are cardiotoxic (toxic to the heart).

Question 36

Mitotic Inhibitors

Answer 36

Act during the cell cycle to inhibit mitosis and therefore prevent cell division.

Are separated into 2 different subclasses: vinca alkaloids and taxanes.

Question 37

Vinca Alkaloids

Answer 37

are derived from the periwinkle plant.

Block the process of mitosis during metaphase.

They block metaphase by binding to the protein tubulin, a major component of the microtubule. This disrupts the organization of microtubules during cell division and leads to inappropriate distribution of chromosomes and eventually cell death.

Question 38

Taxanes

Answer 38

Act in the late G2 phase of the cell cycle, just prior to mitosis.

Taxanes stabilize microtubule bundles and therefore prevent cell division.

Question 39

Glucocorticoids

Answer 39

HORMONAL AGENTS
Are used as an adjunct to other chemotherapeutic agents in cancers that are derived from lymphoid tissue.

Are beneficial because they are directly toxic to lymphoid tissue.

Side effects from long term use include osteoporosis, adrenal insufficiency, susceptibility to infection, GI ulceration, electrolyte disturbance and growth retardation.

Can also be helpful in management of complications of other chemotherapy drugs including reduction in nausea and vomiting, reduction of pain, and improved appetite.

Question 40

Drugs for Prostate Cancer

Answer 40

HORMONAL AGENT

Prostate tissue (normal and neoplastic) is androgen dependent and therefore the primary goal in the treatment of prostate cancer is androgen (i.e. testosterone) deprivation.

Question 41

Androgen deprivation can be achieved by

Answer 41

1. Gonadotropin Releasing Hormone (GnRH) agonist or surgically by castration.

GnRH agonists cause a transient increase in testosterone production in the testes, so cancer symptoms may increase at the start of therapy.

Over time, testosterone synthesis and release is decreased.

2. Androgen Receptor Antagonists

• Used in combination with a Gonadotropin Releasing Hormone agonist or castration.
• Act by blocking androgen receptors in tumour cells.
• GnRH (here shown as LHRH) causes release of testosterone from the testes.
• Testosterone “feeds” prostate cancer cells but also acts by negative feedback to inhibit further GnRH release.
• GnRH agonists cause a transient increase in testosterone but then cause decreased GnRH activity through desensitization and negative feedback.
• The net effect is decreased testosterone synthesis and release.

Question 42

Drugs for Breast Cancer

Answer 42

Breast cancer is the most common cancer affecting women.

Estrogen causes breast tumour cells to proliferate.

Depriving breast cancer cells of estrogen is the primary pharmacological treatment of breast cancer.

It should be noted the estrogen receptor antagonism is used as an adjunct to surgery and radiation therapy.

Pharmacological treatment of breast cancer can be divided into three major classes 1) The anti-estrogens, 2) aromatase inhibitors and 3) Trastuzumab.

Question 43

Anti-estrogens – block estrogen receptors

Answer 43

The most commonly prescribed drug for breast cancer is tamoxifen.

Tamoxifen is a partial estrogen receptor agonist meaning that it minimally activates the estrogen receptor but also blocks endogenous estrogen from binding to its receptor. The net effect of tamoxifen is blocking the binding of endogenous estrogen to the estrogen receptor.

Question 44

Aromatase Inhibitors

Answer 44

drug for breast cancer

Aromatization is the process of converting androgens into estrogen.

Aromatase inhibitors inhibit the conversion of androgens to estrogens, and therefore decrease the amount of estrogen available to breast cancer cells.

It is important to note that aromatase inhibitors do not block ovarian estrogen synthesis, and therefore aromatase inhibitors are only useful in postmenopausal women.

Question 45

Trastuzumab

Answer 45

drug for breast cancer

Some patients with breast cancer have an increased number of human epidermal growth factor receptor 2 (HER2).

HER2 is a transmembrane receptor that helps regulate cell growth.

Tumours with increased HER2 have especially aggressive tumour growth

Question 46

HER2

Answer 46

is a transmembrane receptor that helps regulate cell growth.

Question 47

Mechanism of action of Trastuzumab (marketed as Herceptin)

Answer 47

Trastuzumab is a monoclonal antibody that binds to HER2 and prevents cell proliferation.

As trastuzumab is an antibody, it must be administered intravenously (antibodies are degraded in the stomach and poorly absorbed).

The most prominent adverse event is cardiotoxicity

Question 48

Tyrosine Kinase Inhibitors

Answer 48

Protein kinases are enzymes that phosphorylate proteins on specific amino acid residues (i.e. tyrosine).

Activity of tyrosine kinases can activate gene transcription and/or DNA synthesis, therefore making them an attractive option for the treatment of cancer.

Increased activity of tyrosine kinases has been observed in many human cancers

Question 49

Imatinib

Answer 49

1. Is the prototype tyrosine kinase inhibitor.
2. Effective in the treatment of chronic myelogenous leukemia (CML) and gastrointestinal stromal tumours (GIST).
3. Causes complete inhibition of cellular proliferation and cell death via apoptosis (programmed cell death).
4. Primary toxicities include nausea, vomiting, edema, and muscle cramps.