ART-RIM, 25-Jan-09 1

Mitigation of Chronic Radiation Injuries by ACE Inhibitors and AII Blockers

John Moulder, Ph.D.Center for Medical Countermeasures Against Radiological Terrorism

Medical College of Wisconsin

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PRE RADIATION CLINICAL SYMPTOMS

PROPHYLAXIS/PROTECTION

MITIGATION TREATMENT

Why Mitigation Rather than Treatment?

• Practical: Rather than get the injuries treated, most cancer survivors

would prefer not to have the injuries in the first place.

• Medical: Known interventions work best if they are started before

the injury is clinically evident.

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Can Late Effects Be Mitigated?

• Mitigation proven in at least two experimental systems:Kidney (ACE inhibitors, AII blockers)Lung (ACE inhibitors, AII blockers, SOD/catalase mimetics)CNS (ACE inhibitors)Skin (ACE inhibitors)

• Promising mitigation data in one experimental system:Kidney (SOD/catalase mimetics, selenium)Lung (statins, genistein, curcumin?)CNS (statins)Skin (SOD/catalase mimetics)Cardiac (AII blockers, curcumin)Combined injury (ACE inhibitors, SOD/catalase mimetics)

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Can Late Effects Be Mitigated?

• Mitigation proven in at least two experimental systems:Kidney (ACE inhibitors, AII blockers)Lung (ACE inhibitors, AII blockers, SOD/catalase mimetics)CNS (ACE inhibitors)Skin (ACE inhibitors)

• Promising mitigation data in one experimental system:Kidney (SOD/catalase mimetics, selenium)Lung (statins, genistein, curcumin?)CNS (statins)Skin (SOD/catalase mimetics)Cardiac (AII blockers, curcumin)Combined injury (ACE inhibitors, SOD/catalase mimetics)

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Mitigation of Radiation Nephropathy (Moulder, Fish, Cohen et al, MCW)

Mitigator: Captopril (an FDA-approved ACE inhibitor) started 10 days after TBI.

Azotemia(as BUN in mg/dl)

after 26 wks

TBI Dose (Gy)

8 10 12

TBI + Captopril

TBI Alone

20

40

100

200

60

Normal

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Mitigation of Pulmonary Vascular Injury (Ghosh et al, Int J Rad Oncol Biol Phys, ’08)

Planar angiograms 2 months after irradiation • Irradiation causes vascular drop-out in the lung within 2 months after irradiation. • Captopril can mitigate this effect.

Mitigator: Captopril (an FDA-approved ACE inhibitor) started after irradiation

Unirradiated 10 Gy whole-thorax10 Gy whole-thorax

+ captopril

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Mitigation of Pulmonary Fibrosis (Medhora et al, MCW)

Unirradiated 12 Gy whole-thorax 12 Gy + captopril

Masson’s trichrome stained un-inflated lung 8 months after irradiation

Mitigator: Captopril (an FDA-approved ACE inhibitor) started after irradiation

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Untreated control 30 Gy 30 Gy + Ramipril

Mitigation of Optic Neuropathy(Kim, Brown et al, Radiat. Res., ‘04)

Myelin staining (Luxol Fast Blue) of the optic nerves 6 months after irradiation. Luxol Blue staining is normal for a functioning neuron.

Mitigator: Ramipril (an FDA-approved ACE inhibitor) started 2 wks after irradiation

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Mitigation of Cardiac Injury(Baker et al, Int J Rad Biol, ‘09)

Cardiac injury 120 days after TBI

Mitigator: Cozaar® (losartan, an FDA-approved AII blocker) started 5 days after TBI.

%0%0

30%30%

60%60%

Global Radial Strain

ControlControl Control +Control +losartanlosartan

10 Gy10 Gy 10 Gy + losartan10 Gy + losartan

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Mitigation of a Combined Injury(Lazarova et al, MCW)

30 Gy + vehicle 30 Gy + captopril

1 month after irradiation + wounding

Combined injury: Skin irradiation (4 x 7.5 cm) plus wound (8 mm full-thickness punch biopsy)Mitigator: Captopril (an FDA-approved ACE inhibitor) started 2 days after irradiation

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Mitigation of Radiation Injuries in Humans

• Clinically, there are no proven mitigators of radiation injury: ACE inhibition is as close as we have come.

• Two clinical trials to date: A Phase II RTOG trial of captopril after lung irradiation.

Terminated because of poor accrual. A single-institution Phase III trial of captopril after TBI/BMT.

Cohen et al, Int J Rad Oncol Biol Phys, 2008

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ACE Inhibition after TBI/BMT(Cohen et al, 2008)

Adults and children receiving TBI as preparation for BMT. Captopril (ACE inhibitor) started at engraftment and continued for one year.

Not proof of mitigation of radiation injuries: Radiation is not the only cause of chronic renal failure in these patients.

Incidence of Bone Marrow Transplant

Nephropathy

Years after Irradiation

0%

20%

40%

Captopril

No Drug

P=0.07

862 4 100

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ACE Inhibition after TBI/BMT(Cohen, Irving et al, MCW)

Survival continues to diverge after the last incidence of BMT nephropathy.• Something in addition to radiation nephropathy is being mitigated.

100%

50%

75%

0%

Patient Survival

Captopril

No drugP=0.03

Years after Irradiation862 4 100

25%

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Mitigation via Suppression of the Renin-Angiotensin System

• ACE inhibitors and AII blockers have shown mitigation efficacy in a broad range of experimental models. An ACE inhibitor (captopril) has shown mitigation efficacy in humans.

• These are FDA-approved drugs being used at doses (on a g/m2/day basis) equivalent to current human use. The drugs have good safety profiles. The drugs are widely available and cheap.

• As mitigators, these drugs could be used “off-label”. This is legal under the “practice of medicine” rule as long as it is

done on an individual patient basis. But the “practice of medicine rule” does not allow a government

agency (or anyone else??) to advocate such “off-label” use.

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Barriers to Widespread Use as Mitigators

• They are not FDA-labeled for this indication. And there is no obvious route to getting them labeled as such.

• The drugs are off-patent and relatively cheap. No one has a financial motive to develop them for this indication.

• Their mechanism of action (as mitigators) is unclear. This is not necessarily a problem for use in radiation oncology. This is an issue for labeling via the FDA “animal efficacy rule.”

• There may be toxicity issues. They are teratogens. They may exacerbate radiation-induced GI injury if given

immediately after irradiation.

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Can they mitigate chronic radiation-induced injuries?Yes, in experimental models

Possibly, in humans

Can they mitigate at FDA-approved doses?Yes

Will they be FDA-labeled for this purpose?Unlikely under current rules and conditions

Will they be used in radiation oncology?They have already been used off-label

Bottom Line: ACE Inhibitors and AII Blockers as Mitigators