Module 17- Cancer Chemotherapy Flashcards

1
Q

Characteristics of Cancer Cells

A

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.

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2
Q

Treatment Modalities for Cancer

A

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.

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3
Q

G0 - Cell Cycle

A

resting, no replication

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4
Q

G1 - Cell cycle

A

the cell prepares to synthesize its DNA (duplicate)

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5
Q

S- Cell cycle

A

cell synthesizes DNA

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6
Q

G2 - cell cycle

A

cell preps for mitosis

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7
Q

M - cell cycle

A

cell divides in mitosis

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8
Q

Toxicity to Normal Cells

A

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.

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9
Q

Cure of Cancer Requires 100% Cell Kill

A

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.

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10
Q

Breast Cancer Detection

A

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.

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11
Q

Cervical Cancer detection

A

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.

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12
Q

Colorectal Cancer detection

A

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.

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13
Q

Prostate detection cancer

A

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

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14
Q

Prostate detection cancer

A

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

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15
Q

Skin cancer detection

A

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.

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16
Q

Testicular Cancer detection

A

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

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17
Q

Solid Tumours Respond Poorly To Chemotherapy

A

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.

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18
Q

Drug Resistance

A

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.

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19
Q

Intermittent Chemotherapy

A

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.

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20
Q

Combination Chemotherapy

A

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.

21
Q

Bone Marrow Suppression

A

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.

22
Q

Neutropenia

A

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

23
Q

Thrombocytopenia

A

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.

24
Q

Anemia

A

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

25
Q

Digestive Tract Injury

A

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.

26
Q

Nausea and Vomiting

A

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.

27
Q

2 classes of drugs to treat cancer

A
  1. Cytotoxic agents
  2. Hormonal and other agents
28
Q

Cytotoxic Agents

A

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

29
Q

Cell Cycle Phase Specificity

A

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.

30
Q

Alkylating Agents

A

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.

31
Q

Platinum Compounds

A

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).

32
Q

Antimetabolites

A

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

33
Q

Antimetabolites can be further classified into 3 subclasses

A

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.

34
Q

Antitumour Antibiotics

A

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.

35
Q

Anthracyclines

A

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).

36
Q

Mitotic Inhibitors

A

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

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

37
Q

Vinca Alkaloids

A

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.

38
Q

Taxanes

A

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

Taxanes stabilize microtubule bundles and therefore prevent cell division.

39
Q

Glucocorticoids

A

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.

40
Q

Drugs for Prostate Cancer

A

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.

41
Q

Androgen deprivation can be achieved by

A
  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.

  1. 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.
42
Q

Drugs for Breast Cancer

A

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.

43
Q

Anti-estrogens – block estrogen receptors

A

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.

44
Q

Aromatase Inhibitors

A

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.

45
Q

Trastuzumab

A

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

46
Q

HER2

A

is a transmembrane receptor that helps regulate cell growth.

47
Q

Mechanism of action of Trastuzumab (marketed as Herceptin)

A

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

48
Q

Tyrosine Kinase Inhibitors

A

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

49
Q

Imatinib

A
  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.