Module 17: Chemotherapy Flashcards
Define cancer:
- Referred to as…
- Which means… (2)
The uncontrolled proliferation of cells
- Cancer cells are often referred to as neoplastic
- Meaning they have abnormal and uncontrollable cell growth.
What are the (5) characteristics of cancer cells?
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.
What are the treatments for cancer (3)?
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.
What are the (5) phases of the cell cycle?
G0 - Resting, cells do not replicate.
G1 - The cell prepares to synthesize (duplicate) its DNA
S - The cell synthesizes DNA
G2 - The cell prepares for mitosis
M - The cell divides in a process called mitosis
What are obstacles to successful chemotherapy?
1) Toxicity to normal cells
- Neoplastic cells are similar to normal cells so they are hard to target
- High growth fraction = most cellular toxicity (Ex. Bone marrow, Gi epithelium, hair follicles, germinal epithelium of testes)
2) Cure of cancer requires 100% cell kill
- Tests do not 100% determine if cells were kills
- First-order cell death = constant % of cancerous cells are killed at a given dose of a drug
3) Difficult early detection
- Detection at 10^9 tumour cells
- Breast cancer: Exam 2-3y over 50y; high risk screened more often before 50y.
- Cervical cancer: Sexually active PAP 1-3y.
- Colorectal cancer: Low risk every 2y 50y+; colonoscopy every 5y for high risk.
- Prostate cancer: Men over 50y need DRE and/or Prostate Specific Antigen blood test.
- Skin cancer: Self-checks regularly (birthmarks, moles growths, sores)
- Testicular cancer: Men 15y regular self-exams
4) Solid tumours
- Large fraction of cells resting in G0 state which chemo drugs do not target well
5) Drug resistance
- During chemo, cells develop resistance
Mechanisms:
- decreased drug uptake,
- increased drug efflux,
- decreased drug activation (in the case of prodrugs),
- reduced target sensitivity, increased cellular (primarily DNA) repair.
- 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.
What are (2) strategies to achieve maximum benefit from chemotherapy?
a) Intermittent Chemotherapy
- 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.
b) Combination Chemotherapy
- Using a number of chemotherapeutic agents is often more effective than administering a single drug.
The reasons for this include:
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.
What are (3) associated toxicities?
Remember toxicity typically occurs in cells with a high growth fraction
A) Bone Marrow Suppression:
- Bone marrow has a very high growth fraction and is therefore very susceptible to chemotherapy associated toxicity.
- Bone marrow suppression may result in:
i) Neutropenia – decreased neutrophils in the blood. Neutrophils are a type of white blood cell that help the body fight infections.
ii) 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.
iii) 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.
B) Digestive Tract Injury
- 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.
C) Nausea and Vomiting
- A serious and common adverse effect associated with chemotherapy. Sometimes these effects are treatment limiting and patients will refuse further treatment because of the frequency and unpleasant emetic effects of chemotherapeutic drugs.
- Anti-emetic drugs, prevention of dehydration, and prevention of malnutrition may be important adjuncts to chemotherapy.
What are the (2) classes of drugs that treat cancer?
- Cytotoxic agents
2. Hormonal and other agents
What are the (5) cytotoxic agents?
There are several different types of cytotoxic anti-cancer drugs as summarized below:
1) Alkylating agents
2) Platinum compounds
3) Antimetabolites
4) Antitumour antibiotics
5) Mitotic inhibitors
Cytotoxic agents:
- Specific vs. non-specific drugs
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 phase of the cell cycle.
- 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.
Cytotoxic agents:
- Alkylating Agents
- 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.
Figure: Mechanism of action of alkylating agents. Alkylating agents (pink molecules) bind to nitrogen residues of guanine nucleotides. This may result in cross-linking of DNA.
Cytotoxic agents:
- Platinum Compounds
- 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).
Cytotoxic agents:
- Anti-metabolites
- 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.
Antimetabolites can be further classified into 3 subclasses:
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.
Cytotoxic agents:
- Anti-tumour antibiotics
- 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.
Anthracyclines
- 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).
Cytotoxic agents:
- Mitotic Inhibitors
- Act during the cell cycle to inhibit mitosis and therefore prevent cell division.
Are separated into 2 different subclasses:
1) Vinca Alkaloids – 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.
2) Taxanes
- Act in the late G2 phase of the cell cycle, just prior to mitosis.
- Taxanes stabilize microtubule bundles and therefore prevent cell division.
