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RadBio > Hyperthermia > Flashcards

Hyperthermia Flashcards

1
Q

How does hyperthermia differ from thermal ablation?

A

Thermal ablation uses VERY high temps (50C - 100C) to “cook” the tumor.

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2
Q

What’s hyperthermia?

A

Use of temps between 39C and 45C to kill tumor cells

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3
Q

Which phase of the cell cycle is most sensitive to hyperthermia?

A
  • S phase
  • Contrast with X Rays, which kill cells die when they attempt mitosis (mitotic catastrophe)
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4
Q

What is the transition temperature?

A
  • Temperature at which there is a drastic change in the effects of heat
    – 42.5C or b/w 42C - 43C
  • This corresponds to the break in the Arrhenius plot
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5
Q

What is the target for hyperthermia?

A

Protein

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6
Q

How does hyperthermia differently impact stem cells vs. differentiated cells?

A

It affects both cells equally.

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7
Q

Is there a delay in hyperthermia-induced cell damage?

A
  • No, heat damage is immediate
  • Unlike X Rays, which affect stem cells more than differentiated cells, so the radiation response Is delayed.
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8
Q

Can thermal tolerance be transmitted to daughter cells?

A

No, it is a temporary tolerance and not transmitted from parent to daughter cells.

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9
Q

What are some of the challenges of hyperthermia?

A
  • Difficulty producing uniform tumor heating
  • Difficulty accurately measuring temperature within the tumor
  • Thermotolerance after the first fx
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10
Q

What is the rationale behind limiting hyperthermia sessions to once or twice a week?

A

Thermotolerance

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11
Q

How does the tx temperature impact the development of thermal tolerance?

A
  • 39C - 42.5C → Tolerance may develop during prolonged heating, leading to a plateau in the survival curve.
  • 43C - 47C → Tolerance develops after brief heat exposure periods
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12
Q

What is induced thermal resistance?

A

It is transient resistance to hyperthermia

The slope of the survival curve can be altered 4-10 times.

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13
Q

What is the molecular mechanism for thermal tolerance and it’s reversal?

A

HSPs, after binding to damaged proteins and removing them, rebind to HSF1 and become inactive → tolerance restoration

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14
Q

How long does thermal resistance last?

A
  • Variable but can last up to 160 hours (6-7 days)
  • The greater the damage, the greater the time to reach thermal tolerance, and the slower the reversal
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15
Q

How does fractionation affect hyperthermia efficacy?

A

Fractionation allows for the development of thermal tolerance, therefore the slope of the survival curve decreases.

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16
Q

How is thermal tolerance brought about?

A

Through heat shock proteins (Hsp):

  • Hsp 70
  • Hsp 40
  • Hsp 28
  • Hsp 60
  • Hsp 90
  • Hsp 110

The numbers refer to their sizes in kilodaltons

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17
Q

What is the function of Hsps?

A

They are chaperone protiens that affect protein folding.

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18
Q

What does the level of thermal tolerance correlate with?

A

It correlates with the levels of Hsps

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19
Q

Do heat shock proteins play a role in DNA repair?

A

No! They are involved in protein repair.

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20
Q

What is the relationship of cell killing to temperature for hyperthermia treatment?

A

Heat kills cells exponentially more cells as a function of time above 42C (≥ 42.5C)

21
Q

How does the sensitivity of cells to hyperthermia vary with oxygenation?

A

It does not vary, and oxic cells are just as sensitive as hypoxic cells

22
Q

How does the hyperthermia response vary with pH/nutrient deficiency?

A

Cells with ↓ pH and nutrient deficiency are more sensitive to heat

23
Q

How does the hyperthermia response vary between normal tissues and tumors?

A

Tumors are more sensitive 2/2 sluggish blood flow.

24
Q

How does the concept of sublethal damage repair apply to hyperthermia?

A

It does NOT apply to hyperthermia.

25
Q

How does heat affect response to chemotherapy?

A

Heat may enhance the cytotoxic effects of chemotherapy.

26
Q

What are step up and step down procedures?

A

Step up: Second exposure temperature is higher than the first.

The converse for step down, which MAY inhibit thermal tolerance development.

27
Q

What is head dose?

A

Time in mins for which the tissue would have to be held at 43C to suffer the same biological damage as the actual temperature.

28
Q

What is T90?

A

Time for which 90% of intratumor temps exceeded some indicated temp.

Eg, T90 > 39.5C → 90% of the tumor achieved ≥ 39.5C

29
Q

What is T50?

A

Time for which 50% of intratumor temps exceeded some indicated temp.

T50 ≥ 41.5C → Time for which 50% of the tumor achieved ≥ 41.5C

30
Q

How does the blood flow in tumor cells allow for more heat damage?

A

Tumors have poor blood flow and fragile neo-vasculature that’s relatively unresponsive to heat (ie does not dilate as well in response to increased temperature) → traps heat within the tumor.

Neo-vasculature is also more easily damaged by heart (fragile).

31
Q

How does hyperthermia cause radiosensitization?

A
  1. Increased blood flow → increased oxia and radiosensitivity
  2. If given right after radiation, it MAY inhibit sublethal damage repair → possibly 2/2 enzyme inhibition
32
Q

How do heat and radiation interact?

A

A combination of the following gives synergistic results:

  1. Independent but additive cytotoxic effects
  2. Heat sensitization of radiation cytotoxicity → inhibition of repair?
33
Q

What’s better, simultaneous of sequential heating?

A

Simultaneous, but it is not practical except perhaps in brachytherapy.

34
Q

What have clinical trials comparing RT with hyperthermia shown?

A

They have shown a consistent benefit to hyperthermia.

However, in reality, how successful hyperthermia is depends on the institution performing it (high volume centers are probably much more effective than low-volume centers).

35
Q

What are heat-sensitive (activated) liposomes?

A

Liposomes infused with chemotherapeutic drugs that can be burst open with heat inside tumor cells.

As an additional note, heat makes blood vessels leaky so more liposomes leach into the surrounding tissue anyway.

36
Q

What is the arrhenius plot?

A

It is the survival data of cell cultures exposed to increasing temperatures.

Y-axis = 1/Do
X-axis = 1/T

Do → temp required to reduce surviving fx to 37%

37
Q

How do HSPs respond to hyperthermia?

A
  1. HSPs are bound to heat shock factor 1 (HSF1) → inactive
  2. Heat causes HSF1 and HSPs to separate → activation
  3. HSPs stabilize misfolded or denatured proteins.
  4. HSF1 translocated to the nucleus and binds to the heat shock element (HSE)
  5. HSE is the promoter for HSPs → enhanced HSP gene transcription
38
Q

Why is hyperthermia non-uniform?

A

2/2 heat sink effect of blood vasculature, i.e. blood essentially carries away the heat.

39
Q

Does hyperthermia affect RT induced DNA damage repair?

A

Yes. If hyperthermia causes denaturation and aggregation of nuclear proteins, it can inhibit radiation-induced DNA-damage repair!

40
Q

What does the slope of the arrhenius plot show?

A

It shows the activation energy involved in cell killing. At 1/T corresponding to 43C, there is an abrupt DECREASE in the slope → more cell killing with temp

Activation energy before 43C = 365 kCal/mole
Activation energy after 43C = 148 kCal/mole

41
Q

How does the vasomotor fx of tumor capillaries compare to that of normal tissues?

A

In normal tissues, not all capillaries are utilized at all times. When there is increased demand or a need to dissipate heat, the vasomotor system increased blood flow and capillary utilization.

In tumors, the neo-vasculature is poorly equipped to match tumor oxygen demands. Therefore, all capillaries are open and used to capacity at all times.

42
Q

What is TER and what is the normal TER range?

A

Thermal enhancement ratio: a measure of the effectiveness of radiation with or without heat

TER Range: 1.5-4

43
Q

What’s the mode of cell death after heat?

A
  • Apoptosis
  • Happens immediately
44
Q

What is thermal dose equivalent and what are the formulas and rules for calculating it?

A
  • Thermal dose equivalent (TDE) is the time a tissue needs to be held at 43o to suffer the same damage as it does at another temperature.
  • At temps below < 43o, every 1C ↑ requires a ↓ in time by a factor of 4
    – TDE = 0.25(43-T2)
  • At temps above < 43o, every 1C ↑ requires an ↑ in time by a factor of 2
    – TDE = 2(T2-43)
45
Q

Why is only mild hyperthermia (41-42.5C) achievable in clinical settings?

A

It’s difficult to deliver and measure heat distribution

46
Q

What’s a promising way of non-invasive thermometry?

A

Magnetic Resonance Thermal Imaging (MRTI)

47
Q

What’s the advantage of mild vs. moderate hyperthermia?

A
  • Mild (40-41oC): ↑ oxygenation w/o vascular damage
  • Moderate (43.5oC): Initial ↑ oxygenation f/b vascular damage and resultant ↓ oxygenation.
48
Q

For temperatures above 43, does thermotolerance occur during heating?

A
  • No, it occurs after heating

RadBio (10 decks)

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