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IHO Week 3 - WLB > General Principles of Antineoplastics - Fitz > Flashcards

General Principles of Antineoplastics - Fitz Flashcards

1
Q

What is the goal of antineoplastic therapies?

A

Eradicate cancer cells without affecting normal tissues.

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2
Q

What is the reality of antineoplastic therapies (in relationship to the goal)?

A

All cytotoxic drugs affect normal tissues as well as malignancies → aim for a favourable therapeutic index.

(No treatment addresses the fundamental cause.)

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3
Q

What are five distinguishing features of cancer?

A
  • cancer alters DNA
  • rapidly dividing cells that don’t die
    • caused by upregulation of oncogenes or downregulation of tumour suppressor genes (p53 affected in 50% of cancers)
    • in solid tumours, angiogenesis is required to supply blood to the growing tissue
  • derived from normal tissue
    • cancer cells are not recognized by the immune system as foreign
    • may express different proteins (or different amounts of a protein) compared to normal cells
  • loss of differentiation (reverting to more developmental forms)
  • cancer stem cells (colony forming ability) → metastasis to other tissues
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4
Q

What is differential sensitivity?

A

Something that affects the cancer cell MORE than normal tissue.

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5
Q

What is meant by “cancer type” in non-evidence based medicine?

A
  • when determining chemotherapeutic treatment success, the generic term “cancer” is meaningless - certain cancers respond to certain drugs, and others do not
    • breast cancer survival in 1950’s 5-15%, now 85% survival rate
    • lung cancer survival rates 15%
  • New treatments make survival rate numbers irrelevant
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6
Q

What was the typical definition of a “cure”?

A

5 years of disease-free survival

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7
Q

What is the definition of “cure” in the cancer world?

A
  • Should not use the word “cure”, but, instead, refer to “no evidence of disease”.
  • Palliative goal for better/longer life
  • Control cancer OR convert into chronic disease (CML)
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8
Q

What is meant by “survival rate” in non-evidence based medicine?

A
  • Percent success is irrelevant to individual patients.
    • 95% alive in 5 years? → NO, alive/dead
    • all or nothing
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9
Q

Why is antineoplastic therapy “extremely conservative”?

A
  • for an individual patient, survival isn’t a percentage
  • there are no placebo groups - new therapies are tried in comparison to conventional approaches
  • new therapies are often first tried on patients where all else has failed
  • there may not be an opportunity to try something else
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10
Q

What are the six processes targeted by antineoplastic drugs?

A
  1. Rapid cell growth (cytotoxic drugs)
  2. Angiogenesis/metastasis
  3. Lack of differentiation
  4. Lack of immune response
  5. Cell surface markers
  6. Defective gene products

(from least specific → most specific)

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11
Q

What cells are affected by cytotoxic drugs?

A
  • Cancer Cells
  • Bone marrow
  • GI mucosa (nausea and vomiting)
  • Hair follicles (alopecia)
  • Taste buds (resulting in dysgeusia)
  • “Radiation recall reaction” - erythema and desquamation of the skin at sites of prior (or simultaneous) radiation therapy (RUBICINS)
  • Fetus (absolute contraindication in pregnancy)
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12
Q

What is the most common dose-limiting complication in administration of cytotoxic drugs?

A

Bone marrow suppression

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13
Q

What types of drugs are cell cycle specific (CCS)?

A
  • Plant alkaloids (G2/M phase)
  • DNA synthesis inhibitors/Antimetabolites (S phase)
    • only proliferating cells killed (high growth factor tumors preferentially eliminated)
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14
Q

What types of drugs are less effective in slow growing cancers?

A

Cell-cycle Specific Antineoplastics

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15
Q

Why is it is common to follow CCNS drug treatment with a CCS drug?

A

So that cancer cells are recruited into the cell cycle, where CCS drugs can be more effective.

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16
Q

What types of drugs are cell cycle non-specific?

A
  • Cross-linking/alkylating agents
    • kill cells in any phase, including G0, although final toxicity may be manifested during a specific phase
  • Anthracycline antibiotics
17
Q

What kind of cells do Cell Cycle Non-Specific antineoplastics kill?

A

both proliferating and non-proliferating cells killed (attack both high and low growth factor tumours)

18
Q

What type of drugs are schedule dependent?

A

Cell Cycle Specific

(duration and timing matter in addition to dose)

19
Q

What type of drugs are dose dependent?

A

Cell Cycle Non-Specific

(total dose matters more than schedule)

20
Q

What is the Cell Kill Hypothesis?

A

Proposes that actions of CCS drugs follow first order kinetics:

a given dose kills a constant PROPORTION of a tumor cell population (rather than a constant NUMBER of cells).

***Most applicable to leukemias.

21
Q

What two components determine the dosing frequency in terms of the Cell Kill Hypothesis?

A
  • Tumor burden
  • Kinetics of division
22
Q

What are the four curves on the Cell Kill Hypothesis Graph and what do they stand for?

A
  • Exponential growth of cancer cells without treatment
  • Low frequency treatment prolongs life (kill rate < growth rate)
  • High frequency treatment results in successful “cure” (kill rate > growth rate)
  • Decreased treatment time if surgery first, then high frequency treatment (decreased tumor burden)
  • Magnitude of the kill is LOGARITHMIC
    • e.g. 3log kill = 1012 → 109 or 109→ 106
23
Q

What are three critical points about treatment according to the Cell Kill Hypothesis?

A
  1. Early start to the treatment is (obviously!) helpful
  2. Treatment must continue past the time when cancer cells can be detected using conventional techniques
  3. Appropriate scheduling of treatment courses and care to ensure that a sufficient log-kill is obtained are also crucial factors that enable success
24
Q

What factors on the cancer side directly determine the effectiveness of antineoplastic therapy?

A
  • growth fraction determines efficacy of CCS drugs
  • doubling time affects course scheduling
  • type and stage can determine cure vs. palliation
  • resistance can limit treatment and/or force a switch in medication
25
Q

What factors on the patient side directly determine the effectiveness of antineoplastic therapy?

A
  • bone marrow suppression is the major dose-limiting toxicity for many drugs, so capacity will determine both dose and duration of treatment
  • many antineoplastic drugs are metabolized in the liver and/or eliminated in the urine, so liver and kidney function will determine drug selection and/or dosage
  • the side effects of many cancer drugs are so severe that patients will choose to stop treatment (for example, the nausea and vomiting associated with CISPLATIN and MECHLORETHAMINE are particularly disabling)
26
Q

What is primary/inherent resistance?

A

occurs when some inherent characteristic of the cancer cells prevents the drugs from working

27
Q

What is secondary/acquired resistance?

A
  • resistance develops after being exposed to treatment
  • resistance occurs during treatment
28
Q

What is Multi-Drug Resistance? When does it occur?

A

this occurs when tumour cells become cross-resistant to a wide range of chemically dissimilar agents after exposure to a SINGLE (typically natural product) drug

29
Q

What are four contributing causes of resistance to antineoplastic drugs?

A
  1. Poor drug distribution
  2. Sanctuary sites (esp. brain)
  3. Tumor cells not in cycle
  4. Heterogeneity of tumour cells leading to clonal selection
30
Q

What is the most problematic form of Multi-drug Resistance? How does it develop?

A
  • Natural Product MDR results from increased expression of:
    • MDR-1 gene → increased levels of P-glycoprotein
    • experimentally, calcium channel blockers (e.g. verapamil) can reverse this resistance
    • multidrug resistance proteins (MRP1-9)
    • lung resistance protein (LRP)
31
Q

What are the two categories of resistance mechanisms?

A
  1. Changes that affect the mechanism of action of a drug
    1. increase DNA repair
    2. form trapping agents
    3. change target protein
  2. Affect concentration in the cancer cell
    1. decrease accumulation (by decreasing transport or increasing export)
    2. increase inactivation
    3. decrease activation
32
Q

What are the seven categories of antineoplastic drugs that we need to know for IHO?

A
  1. Prevent DNA synthesis*
  2. Disrupt DNA and/or prevent RNA synthesis*
  3. Interrupt mitosis*
  4. Immune system modifiers
  5. Drugs that alter protein function
  6. Angiogenesis inhibitors
  7. Differentiating agents

(* = cytotoxic drugs)

33
Q

What three components can be targeted with antineoplastic drugs that prevent DNA synthesis?

A
  1. Purines/Pyrimidines
  2. Ribonucleotides
  3. Deoxyribonucleotides
34
Q

What two processes are disrupted by antineoplastic drugs that disrupt DNA and/or prevent RNA synthesis?

A
  • Transcription
  • DNA replication
35
Q

What is a reason to stop an antineoplastic drug? What is a reason to switch an antineoplastic drug?

A
  • Drug stop
    • bone marrow suppression
    • non-compliance due to severe side effects
  • Drug switch
    • resistance
    • develop severe disease (CHF with Doxorubicin)
36
Q

What is an example of a drug that some people have a primary resistance to?

A
  • Temozolamide
  • Methotrexate - decreased folate receptors
37
Q

What is an example of an antineoplastic drug that develops acquired resistance?

A
  • Multidrug resistance
    • give one drug → become resistant to many
    • e.g. Natural products resulting in increased P-glycoprotein
    • e.g. Alkylating agents resulting in increased glutathione

IHO Week 3 - WLB (10 decks)

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