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IHO Block 3 > Antineoplastics I > Flashcards

Antineoplastics I Flashcards

1
Q

What is differential sensitivity?

A

We try to use this concept to eradicate the cancer cells without affecting normal tissues.

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2
Q

What do we aim for in reality with cancer drugs?

A

Favorable therapeutic index

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3
Q

What two main classes can cancer drugs be divided into?

A
  • Cell cycle specific drugs (ex: plant alkaloids & antimetabolites)
  • Cell cycle non-specific drugs (ex: alkylating agents and some natural products)
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4
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)

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5
Q

What is primary resistance?

A

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

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6
Q

What is acquired resistance?

A

-Occurs when cancer cells become resistant during treatment

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7
Q

What is multi drug resistance?

A
  • Very problematic
  • When tumor cells become cross-resistant to a wide range of chemically dissimilar agents after exposure to a SINGLE (typically natural product) drug.
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8
Q

What are the 8 major categories of antineoplastic drugs?

A
  1. Drugs that prevent DNA synthesis
  2. Drugs that disrupt DNA and/or RNA synthesis
  3. Antimitotics
  4. Immune system modifiers
  5. Drugs that interfere with protein function
  6. Angiogenesis inhibitors
  7. Differentiating agents
  8. Drugs the interfere with hormone function
    [Also supporting agents!]
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9
Q

What was the old definition of cancer ‘cure’ and what is the new definition?

A

Old - 5 year survival

New - “no evidence of disease”

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10
Q

What are cancer cells derived from?

A

Normal tissue

  • This is why the immune system doesn’t recognize them as foreign
  • They may express different proteins than normal cells => differential sensitivity – this helps us find a mechanism for drugs to treat the cancer cells
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11
Q

What causes cancer cells to divide rapidly and not die?

A
  • Increased oncogene expression

- Decreased tumor suppressor gene function

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12
Q

Why are alkylating agents so effective?

A

p53 (a tumor suppressor gene) is affected in 50% of cancers

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13
Q

What type of disease is cancer? Do we have a treatment for it?

A
  • It is a DNA disease (genetic & epigenetic changes)

- No treatment to reverse the underlying genetic cause (fundamental problem!)

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14
Q

What about cancer type in regards to survival rates?

A
  • Breast cancer survival went from 5% (1950s) to 85% (now)

- Lung cancer survival stayed about the same

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15
Q

What processes are targeted by antineoplastic drugs?

A
  1. Rapidly dividing cells (least specific)
  2. Angiogenesis (blood supply development)
  3. Lack of differentiation
  4. Lack of immune response
  5. Cell markers
  6. Identify gene products and target them (most specific)
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16
Q

What types of antineoplastic drugs cause the most side effects and which cause the least side effects?

A 
Least specific (rapidly dividing cells) --> most side effects
Most specific (targeting gene products) --> least side effects
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17
Q

What types of cells are affected by cytotoxic drugs?

A
  1. Cancer
  2. Bone marrow –> major dose-limiting complication for any of the cytotoxic drugs (SO this is why you give the drugs in cycles - so normal, healthy cells can recover)
  3. GI mucosa –> nausea & vomiting (can lead to electrolyte imbalances)
  4. Hair follicles
  5. Fetus
  6. Radiation Recall RXN
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18
Q

What is a radiation recall reaction?

A
  • Desquamation (loss of skin cells) at site of previous radiation
  • “RUBICINs” - used for breast cancer (standard of care for breast cancer)
19
Q

How much time do cells spend in S phase and M phase (cells spend different amounts of time in different phases)?

A

M - 2% of time (this is the percent chance of you catching the cell at the right stage when you give a drug)
S - 40% of time

20
Q

When are CCS drugs less effective?

A

Slow growing cancers

21
Q

What is recruitment of cancer cells?

A

You give a CCNS drug, the drug enters the cell cycle and then you kill the cell with a CCS drug.

22
Q

When do CCNS drugs work?

A
  • Primary action anytime but cells might die during specific phase
  • -alkylating agents
  • -anthro-cycline antibiotics
23
Q

When do CCS drugs work?

A

ONLY IN SPECIFIC PHASE

  • G2/M: plant alkaloids
  • S: antimetabolites
24
Q

What types of cells do CCS drugs target?

A

-Proliferating cells killed preferentially (high growth fraction)

25
Q

What types of cells do CCNS drugs target?

A

-Both rapidly & slowly dividing cells

26
Q

How does dose and schedule work with CCS drugs?

A

-They are SCHEDULE dependent
(duration & timing are more important than dose!)
-Dose

27
Q

How does dose and schedule work with CCNS drugs?

A

-Dose>Schedule

28
Q

What does the cell kill hypothesis tell us? What does it apply to?

A
  • Mostly applicable to acute leukemias
  • Tumor burden & kinetics of division determine the dosing frequency
  • Magnitude of kill is logarithmic (ex: 3 log kill = 10^12 –> 10^9)
29
Q

What happens with infrequent drug use?

A

Low kill for cancer cells

30
Q

What happens when you increase the dosing frequency with cancer drugs?

A
  • Successful “cure”, high kill for cancer cells

- You always need to treat past the time where cancer is detected!

31
Q

How does the cancer cell population grow over time?

A

Exponentially

32
Q

What are 3 critical points about cancer treatments?

A
  1. Earlier is better (lower burden of tumor cells)
  2. More frequent, higher dose is better
  3. Continue treatment past detection point
33
Q

What factors/traits of the cancer contribute to outcome?

A
  • Growth fraction rate
  • Doubling time (growth rate)
  • Cancer type
  • Cancer stage
  • Resistance
34
Q

What factors/traits of the patient contribute to outcome?

A
  • Performance status
  • Bone marrow capacity
  • Liver function (affect elimination)
  • Kidney function (affect elimination)
  • Age
  • Compliance
35
Q

What are contributing causes to drug resistance?

A
  1. Poor distribution = Dec. concentration at site of action!
  2. Sanctuary sites (esp. CNS-brain) –> places drugs can’t enter!
  3. CCS –> cells are not in cycle
  4. Cancers are heterogenous (what works on one population of cells might not work on others!!)
36
Q

What are mechanisms of drug resistance (for cancer)?

A
  1. Change the mechanism of action of a drug

2. Affect [ ] in cancer cell

37
Q

How can a cancer change the mechanism of action of a drug?

A
  1. Inc. DNA repair
  2. Form trapping agents (keep drug from working where you intend!)
  3. Change target protein
38
Q

How can a cancer change the concentration [ ] of drug in it?

A
  1. Decrease accumulation by:
    - -Dec. transport in
    - -Inc. export out (key to multi drug resistance = P-glycoprotein)
  2. Inc. inactivation of drug
  3. Dec. activation of drug
39
Q

What is a major cause of multi drug resistance?

A
  • MDR 1-9 genes

- P-glycoprotein = ADP dependent protein –> pumps drug out of the cell!

40
Q

What are the three mechanisms of action for cytotoxic drugs?

A
  1. Prevent DNA synthesis
  2. Disrupt DNA and/or prevent RNA synthesis
  3. Interrupt mitosis
    These are historically and practically the most critical drugs –> they kill rapidly dividing cells!
41
Q

What types of mechanisms prevent DNA synthesis?

A
  • Prevent nucleotide synthesis (antimetabolites)

- Inhibit DNA synthesizing enzymes

42
Q

What types of mechanisms disrupt DNA and/or prevent RNA synthesis?

A
  • Cross-linking agents
  • Intercalating agents
  • Drugs that cause DNA strand breaks
43
Q

What types of mechanisms interrupt mitosis?

A
  • Inhibit spindle formation

- Enhance spindle formation

IHO Block 3 (13 decks)

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