Lecture 26 - Therapeutic Approaches to Tumor Hypoxia

ONCOL 335 - Radiobiology. University of Alberta

three reasons why hypoxia is a problem for radiation therapy

1. it leads to less indirect DNA damage

2. hypoxia induces HIF-1a, aids stem cell renewal

3. enhances plasticity of cancer cells to undergo EMT

are most measurs of tumor hypoxia direct or indirect

indirect

• We try to use uptake of compounds that prefer to get uptaken in hypoxic cells and then use PET imaging

what is the only direct way to measure tumor hypoxia

Only direct way is to stick probes into tumor and measure O2

• not possible for all tumors

what does this graph tell us?

the more hypoxic the tumor, the lower the patient survival after 3 years

• patient responds less to radiation

two ways to reduce tumor hypoxia

1. increase partial oxygen pressure in blood

2. target vasculature surrounding the tumor

two ways of increasing partial oxygen pressure in blood

1. HBO therapy

2. increase Hg levels

what is hyperbaric oxygen (HBO) therapy

put cancer patients into a hyperbaric chamber and increase the partial pressure of oxygen so lungs take up more oxygen

does HBO therapy work?

yes, there are clear improvements for patients who underwent HBO before radaition therapy

• with exception ot bladder cancer patients

although HBO therapy works, why is not commonly used

it is very uncomfortable and claustrophobic for patients

what is HBO therapy used commonly to rtreat

osteoradionecrosis

what is osteoradionecrosis

radiation damaging the blood vessels to bone, causing bone death

why are people told to get their teeth cleaned before radiotherapy

cleaner teeth decreases chance of osteoradionecrosis in H+N patients

theoretically, why would increasing EPO levels increase RT efficacy

there is a correlation between tumor control and the amount of RBCs carrying oxygen to tumor

why does smoking lead to decrease radiation efficacy

smoking decreases the ability of the lungs to transfer oxygen to red blood cells, thus their tumors may be more hypoxic

did giving EPO to radiation patients work?

EPO increased hemoglobin concentrations but had no effect or even worse effect for patients

what is ARCON

Accelerated Radiotherapy with Carbogen and Nicotinamide

what is carbogen

a mixture of oxygen and carbon dioxide

• helps regulate pH levels better than straight O2 for patients

What does nicotinamide do ?

enhances blood glow and inhibits PARP

how does ARCON affect radiotherapy tx time

it decreases radiotherapy time by delivering several fractions per fay

how do tumor blood vessels compare to regular blood vessels

very sporadic and chaotic

results in the ability to leak or collapse = hypoxia

what are two classes of drugs that were tested to target tumor vasculature

1. Angiogenesis Inhibiting Agents (AIAs)

2. Vascular Disrupting Agents (VDAs)

How do Angiogenesis inhibiting agents (AIAs) work?

inhibit VEGF, helping the tumor blood vessels become more regular and lead to more oxygen entering the tumor

how did tumors respond do radiation therapy after AIAs

there didn’t seem to be a benefit unfortunately

• but many questions still remain, like what would happen if it was used with SBRT

how do vascular disrupting agents (VDAs) work?

VDAs lead to the destruction of endothelial of cells, resulting in starving the tumors of more oxygen

- Work opposite to AIAs

how did VDAs work in animals

worked well animals, particulary if you gave it to them before treatment

how did VDAs work in humans

no success in human trials

what are hypoxic cell radiosensitizers

chemicals that can mimic oxygen that would travel to hypoxic sites and make them more radiosensitive

• would not affect well oxygenated normal healthy tissue

what kind of compounds are needed for hypoxic cell radiosensitizers

conpounds with high electron affinities to fix indirect damage in place to tumor cells

why can hypoxic cell radiosensitizers penetrate deeper into hypoxic tumors than oxygen can

drugs are not metabolized/used by the tumor cells!

what class of drugs have been studied as hypoxic cell radiosensitizers

nitromidazole

example of a nitromidazole hypoxic cell radiosensitizer

Misonidazole

what does this graph tell us about misonidazole

no effect on normal oxygen cells

strong effect on hypoxic tumor cells!

what does this graph tell us about misonidazole

giving the drug before radiation therapy works better than giving it after!

why is misonidazole not used in humans very often

because it is toxic to the CNS

what hypoxic cell radiosensitizer is used in head and neck cancers for patients

nimorazole

• control is better than placebo when given before treatment

does nimorazole work for all cancers

no, only head and neck cancers have seen benefit

what are bioreductive drugs

compounds that undergo reduction reactions to become activated in low oxygen tensions

• drugs will become activated in hypoxic regions

three groups of bioreductive drugs

1. quinones

2. nitroimidazole (derived from misonidazole)

3. N-oxides

did bioreductive drugs work in clinical trials

they had promising phase I trials but didnt work in later clinical trials

why did bioreductive drugs work better in mice than humans?

Drugs were getting broken down with the reductase enzymes in mice which worked well

• Humans have different levels of reducatase, lowering the efficacy

what is the major side effect of bioreductive drugs

can cause blindness since the retina of the eye is hypoxic

what is thermoradiotherapy

heating of tumors/patients above normal body temperatures causes enlarged blood vessels to increase oxygen

• combined with radiotherapy

essentially give the patient a fever before treatment