RADIATION PROTECTORS AND RADIATION PROTECTORS AND SENSITIZERSSENSITIZERS

JING-MIN HWANG, MD, PHDJING-MIN HWANG, MD, PHD

Department of Radiation Oncology, Buddhist Tzu Chi General Hospital, Department of Radiation Oncology, Buddhist Tzu Chi General Hospital, Taipei Branch, and Tri-Service General Hospital; Division of Radiology, Taipei Branch, and Tri-Service General Hospital; Division of Radiology,

Tzu Chi University, National Defense Medical CenterTzu Chi University, National Defense Medical Center

Radiation absorptionRadiation absorption

Radiation absorptionRadiation absorptionIndirect action is dominant for sparsely Indirect action is dominant for sparsely

ionizing radiationionizing radiation

Radiation absorptionRadiation absorptionDirect action dominates for more densely ionizing Direct action dominates for more densely ionizing

radiations such as neutrons.radiations such as neutrons.

• About 2/3 of the biological damage by x-About 2/3 of the biological damage by x-rays is due to indirect action.rays is due to indirect action.

• Indirect action can be modified by Indirect action can be modified by chemical sensitizers or protectors.chemical sensitizers or protectors.

• High-LET radiations produce most High-LET radiations produce most biological damage by the direct action, biological damage by the direct action, which can’t be modified by chemical which can’t be modified by chemical sensitizers and protectors.sensitizers and protectors.

RadiobiologyRadiobiology

Survival curve for mammalian cells exposed Survival curve for mammalian cells exposed to radiationto radiation

RADIATION RADIATION PROTECTORSPROTECTORS

Radioprotectors containing SH group serve as free radRadioprotectors containing SH group serve as free radical scavengers and is most effective for low LET becaical scavengers and is most effective for low LET beca

use the dominant indirect DNA effectsuse the dominant indirect DNA effects

The discovery of radioprotectorsThe discovery of radioprotectors

• VasoconstrictionVasoconstriction• Upset metabolism to reduce the Upset metabolism to reduce the

oxygen concentration in critical oxygen concentration in critical organs: sodium cyanide, carbon organs: sodium cyanide, carbon monoxide, epinephrine, histamine, monoxide, epinephrine, histamine, serotonin. serotonin.

The discovery of radioprotectorsThe discovery of radioprotectors

• Dose reduction factor (DRF),Dose reduction factor (DRF),Cysteamine (150mg/kg in animal study, DRF = 1.8)Cysteamine (150mg/kg in animal study, DRF = 1.8)

DRF = Dose of radiation in the presence of drugs

Dose of radiation in the absence of drugs

(to produce a given level of lethality)

The mechanisms of SH-mediated cytoprThe mechanisms of SH-mediated cytoprotectionotection

• Free radical scavenging – protect against oxyFree radical scavenging – protect against oxygen-based free radical generation by ionizingen-based free radical generation by ionizing radiation or chemotherapy agents (e.g. alkg radiation or chemotherapy agents (e.g. alkylating agents).ylating agents).

• Hydrogen-atom donation to facilitate direct Hydrogen-atom donation to facilitate direct chemical repair at DNA damage sites.chemical repair at DNA damage sites.

The protective effect of sulfhydryl compoundsThe protective effect of sulfhydryl compounds

• Is parallel to the oxygen effectIs parallel to the oxygen effect• Being maximal for sparsely ionizing radiations (e.Being maximal for sparsely ionizing radiations (e.

g., x- or r-rays).g., x- or r-rays).• Being minimal for densely ionizing radiation (e.g.,Being minimal for densely ionizing radiation (e.g.,

low energy low energy αα -particle).-particle).• The largest DRF would equal to OER, with a value The largest DRF would equal to OER, with a value

of 2.5 ~ 3.of 2.5 ~ 3.

Development of more effective radioprotectorDevelopment of more effective radioprotectorss

Amifostine as a radioprotector in radiotherapyAmifostine as a radioprotector in radiotherapy

Amifostine dephosphorylation

Alkaline phosphatase(high conc. in normal cellsand capillary)

WR-1065 (active metabolitereadily enter normal cells and scavenges free radicals generate by irradiation or C/Tagents)

Mechanisms of amifostine as a radioprotectorMechanisms of amifostine as a radioprotector

• Protection of normal tissues versus tumor is Protection of normal tissues versus tumor is through a differential uptake and conversiothrough a differential uptake and conversion of amifostine to WR-1065 in tumors.n of amifostine to WR-1065 in tumors.

• The drug is active transport into normal tissThe drug is active transport into normal tissues and passive diffusion into tumors.ues and passive diffusion into tumors.

• Better vasculature in normal tissues.Better vasculature in normal tissues.• The differential sparing of normal tissue coThe differential sparing of normal tissue co

mpared with tumors achieved within minutempared with tumors achieved within minutes after the administration of the drugs.s after the administration of the drugs.

• Hydrophilic membrane structure of normal Hydrophilic membrane structure of normal cells.cells.

RADIATION RADIATION SENSITIZERSSENSITIZERS

The oxygen fixation hypothesisThe oxygen fixation hypothesis

Chemotherapeutic agents (cisplatinum and paChemotherapeutic agents (cisplatinum and paclitaxel) and radiobiologyclitaxel) and radiobiology

The basic strategy of hypoxic cells radiosensitiThe basic strategy of hypoxic cells radiosensitizerszers

Survival curves for BUdR and IUdR substituted Survival curves for BUdR and IUdR substituted cells exposed to x-rayscells exposed to x-rays

Properties of hypoxic cells radiosensitizersProperties of hypoxic cells radiosensitizers

• Selectively sensitize hypoxic cells Selectively sensitize hypoxic cells → acceptable toxi→ acceptable toxicitycity

• Chemically stable → metabolic breakdown↓.Chemically stable → metabolic breakdown↓.• High solubility in water and lipids and must be capaHigh solubility in water and lipids and must be capa

ble of diffusing a considerable distance (as far as 20ble of diffusing a considerable distance (as far as 200um from the nearest capillary) through a nonvascu0um from the nearest capillary) through a nonvascularized mass to reach the hypoxic cells.larized mass to reach the hypoxic cells.

• Be effective at the relatively low daily dose (a few GBe effective at the relatively low daily dose (a few Gy). y).

The basic ring structure of the nitroimidazolesThe basic ring structure of the nitroimidazoles

The basic ring structure of the nitroimidazolesThe basic ring structure of the nitroimidazoles

misonidazolemisonidazole

Randomized prospective controlled trials by the RTOG: no statistically significant advantage for misonidazole.The only promising trial: Denmark head-and-neck group.Limitation of misonidazole – dose-limiting toxicity (from peripheral neuropathy to CNS.

The development of misoniThe development of misonidazoledazole

• MetronidazoleMetronidazole

• ↓↓

• Misonidazole: more active and toxic; benefit in subgroups.Misonidazole: more active and toxic; benefit in subgroups.

• ↓↓

• Etanidazole: less toxic, no benefit.Etanidazole: less toxic, no benefit.

• ↓↓

• Nimorazole: less active, much less toxic; benefit in head-neck Nimorazole: less active, much less toxic; benefit in head-neck cancer. cancer.

Hypoxic cytotoxinsHypoxic cytotoxinsThree classes of agentsThree classes of agents• The quinone antibiotics (e.g. mitomycin-C, active agaThe quinone antibiotics (e.g. mitomycin-C, active aga

inst hypoxic cells).inst hypoxic cells).• Nitroaromatic compoundsNitroaromatic compounds• The benzotriazine di-N-oxideThe benzotriazine di-N-oxide

Tirapazamine (SR 4233, TPZ)

Response of mouse carcinoma to TPZ, RT, Response of mouse carcinoma to TPZ, RT, or bothor both

Clnical trial with Tirapazamine Clnical trial with Tirapazamine (TPZ)(TPZ)

• Little clinical trials with TPZ (activated by the enzymLittle clinical trials with TPZ (activated by the enzyme cytochrome p450): vomiting and muscle cramping.e cytochrome p450): vomiting and muscle cramping.

• A phase III study of cisplatin vs. cisplatin + TPZ for nA phase III study of cisplatin vs. cisplatin + TPZ for non-small cell lung cancer (stage IIB and IV): doublinon-small cell lung cancer (stage IIB and IV): doubling of response rate and increased survival rate.g of response rate and increased survival rate.

Markers of hypoxic cells: tritiated thymidine (by autoradiograMarkers of hypoxic cells: tritiated thymidine (by autoradiography), or positron-emitting radionuclide (iodine-123) using a sphy), or positron-emitting radionuclide (iodine-123) using a s

ugar molecule (by PET) labeled nitroimidazole; ugar molecule (by PET) labeled nitroimidazole;

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