IN THE NAME OF GOD

CHEMICAL

RADIOSENSITIZATION

Elahe Ghasemloy

May-2014

The oxygen effect

•Oxygen fixation

• Tumor hypoxia reduces radio sensitivity in vitro and in vivo.

Well oxygenated cells (partial pressure of oxygen or Po, >10

mm Jig)are approximately 2.5 times more sensitive to a given

dose of ionizing radiation than their hypoxic counterparts.

• The correlation between pretreatment head and neck tumor

oxygenation and local-regional disease control after radiotherapy with

or without concurrent chemotherapy.Dashed line represents tumor

median partial pressure of oxygen PO2 >10 mm Hg,Solid line represents

tumor median PO2 <10 mm Hg,

III

increased delivery of oxygen to tumor

Augmentation of tumor oxygenation

preferential sensitization of hypoxic cells

with oxygen mimetic agents

preferential sensitization of hypoxic

cells with cytotoxic agents that

selectively target hypoxic tumor cells

I

II

Therapeutic attempts to overcome the

deleterious effect of tumor hypoxia have

followed three general lines of Investigation:

Hyperbaric oxygen(HBO)

Clinical trials of hyperbaric oxygen (HBO)

and RT were conducted from the 1950s

to the 1970s.

Lung, bladder and skin

carcinoma of the cervix and head and neck

show no benefit

show improvements

in locoregional

control and overall

survival.

• (95% oxygen / 5% carbon dioxide [C0 2])

• +nicotinamide

Carbogen

• 20% improvement in 2-year local control in the carbogen arm relative to the RT alone arm.

• 15% improvement in a -year cause-specific survival.

• hyperfractionated RT with or without

carbogen

• patients with T2 to T4 squamous cell

carcinoma of the oropharynx. larynx. and

hypopharynx

•TERIAL 1:University of Florida

• The use of accelerated RT with carbogen and nicotinamide

• In 215 head and neck cancer patients

Terial2:

cancer Five-year locoregional control

rate

hypopharynx primaries 48%

larynx 77%

oropharynx primaries 72%

Ways for correction or prevention of

anemia:

• blood transfusions

• erythropoiesis-stimulating agents

anemia

• in cervical cancer patients:

showing an improvement in pelvic control and cure

• In head and neck cancer patients:

negative effect on surviva1.

Blood transfusions

• Misonidazole:the prototype2-nitroimtdazole.

• Etanidazole (SR2508):an analog of

misonidazole

• Nimorazole: a 5-nitroimidazole of the same

structural class as metronidazole.

Sensitization of hypoxic cells

• 1.Mitomycin C (MMC)

• 2. Porfiromycin:a derivative of MMC

• 3. Tirapazamine

Pharmacologic targeting of

hypoxic cells

• Mitomycin C (MMC) is an alkylating agent metabolized in regions of low oxygen

concentration and preferentially cytotoxic to hypoxic cells. MMC plays an integral role inconjunction with RT and 5-FU (fluorouracil) in

the definitive non surgical management of squamous cell carcinomas of the anus.

1.Mitomycin C (MMC)

• Terial1:

• 195 head and neck cancer patients

• 68 Gy with or without MMC on days 1 and 43 of RT

•1.Mitomycin C (MMC)

RT+MMC RT

Local regional

recurrence-free

survival

76% 54%

Overall survival 48% 42%

• Terial2:

• conventionally fractionated (CF) RT (2 Gy daily to 70 Gy) against variation of continuous hyperfractionated accelerated RT with or without MMC

•1.Mitomycin C (MMC)

V-CHART+MMC V-CHART CF RT

Three-year actuarial

locoregioal control

48% 32% 31%

Surv ival including death

from all causes

41% 31% 24%

mucositis 90% 90% 33%

MMC+CF Porfiromycin+RT

5-year local

relapse-free survival

72.2% 91.6%

local-regional

relapse-free survival

65.3% 82%

disease-free survival 52.9% 72.8%

overall survival 49% 54%

distant metastasis-free 76% 80%

• Terial:

Porfiromycin

• is a bioreductive agent preferentially cytotoxic to

hypoxic cells in vitro

Terial:

Tirapazamine

cisplatin/tirapazamine+

RT

cisplatin/5-FU+RT

3 -year local regional

failure-free survival

84% 66%

local-regional failure(whit hypoxic tumor)

5% 62%

• epidermal growth factor rec eptor-1• (EGFR-1) Cetuximab (C225)

Biologic modifiers of radiation

response

• In patient with head and neck cancer(-oral cavity primary tumors)

• Terial:

RT Cituximab+RT

Two-year local

regional

48% 56%

S-year overall

survival

36.4% 45.6%

•Thank you