Sensitizers, Radioprotectors, and Bioreductive DrugsAditya Juloori and Michael A. Weller

RADIATION SENSITIZERS, RADIOPROTECTORS, AND BIOREDUCTIVE DRUGS

ADITYA JULOORI AND MICHAEL A. WELLER

Question 1

What is the mechanism by which antiangiogenesis agents increase radiosensitivity?

Question 2

What is the only radioprotective drug approved by the Food and Drug Administration (FDA) and what is the mechanism of this drug?

Question 3

Gemcitabine is a chemotherapy drug that is a well-known radiosensitizer. What is the mechanism by which this occurs?

Question 4

What is nimorazole?

Question 1 What is the mechanism by which antiangiogenesis agents increase radiosensitivity?

Answer 1

Tumor angiogenesis is characterized by abnormal blood vessels—with irregular shape and high permeability—thus impairing the ability for oxygen to be delivered to the tumor. It is well understood that oxygen is a radiosensitizer. Thus, use of antiangiogenesis agents normalizes the vasculature of the tumor environment, increasing oxygen delivery to the tumor and thereby improving radiosensitivity.

Jain RK. Antiangiogenic therapy for cancer: current and emerging concepts. Oncology. 2005;19(4 suppl 3):7–16.

Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307:58–62.

Question 2 What is the only radioprotective drug approved by the Food and Drug Administration (FDA) and what is the mechanism of this drug?

Answer 2

Amifostine is approved by the FDA and has been shown to prevent the development of xerostomia in patients undergoing radiation therapy (RT) for head and neck cancer, as demonstrated by a Radiation Therapy Oncology Group (RTOG) trial. Amifostine is a prodrug and its active metabolite travels intracellularly and scavenges free radicals produced by ionizing radiation.

Anne PR, Machtay M, Rosenthal D, et al. A phase II trial of subcutaneous amifostine and radiation therapy in patients with head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2007;67:445–452.

Hall EJ, Giaccia AJ. Radiation carcinogenesis. In: Hall EJ, Giaccia AJ, eds. Radiobiology for the Radiologist. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:135–153.

Question 3 Gemcitabine is a chemotherapy drug that is a well-known radiosensitizer. What is the mechanism by which this occurs?

Answer 3

Gemcitabine is a nucleoside analog that interferes with DNA replication. Ribonucleotide reductase is an enzyme that plays an important role in DNA synthesis and serves to catalyze the production of deoxyribonucleotides from ribonucleotides. Gemcitabine is metabolized to 5′-diphosphate (dFdCDP), which interferes with the normal function of ribonucleotide reductase; by this process, it is believed gemcitabine acts as a radiosensitizer.

Pereira S, Fernandes PA, Ramos MJ. Mechanism for ribonucleotide reductase inactivation by the anticancer drug gemcitabine. J Comput Chem. 2004;25(10):1286–1294.

Shewach DS, Lawrence TS. Antimetabolite radiosensitizers. J Clin Oncol. 2007;25:4043–4050.

Question 4 What is nimorazole?

Answer 4

Nimorazole is a nitroimidazole compound, similar to misonidazole and etanidazole, which works as a radiosensitizer in hypoxic environments—mimicking the role oxygen plays in increasing radiosensitivity in regions that are not well vascularized.

Hall EJ, Giaccia AJ. Radiation carcinogenesis. In: Hall EJ, Giaccia AJ, eds. Radiobiology for the Radiologist. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:135–153.

Question 5

What are the common side effects of amifostine?

Question 6

How is amifostine administered and why is this important?

Question 7

What did the Danish Head and Neck Cancer Study (DAHANCA) trial of nimorazole demonstrate?

Question 8

How does the radiosensitization potential of nimorazole compare to that of misonidazole and etanidazole?

Question 5 What are the common side effects of amifostine?

Answer 5

Nausea, emesis, hypotension, and allergic reactions are the most common side effects.

Gu J, Zhu S, Li X, Wu H, Li Y, Hua F. Effect of amifostine in head and neck cancer patients treated with radiotherapy: a systematic review and meta-analysis based on randomized controlled trials. PLoS One. May 2014;9(5):e95968.

Question 6 How is amifostine administered and why is this important?

Answer 6

Amifostine is given 30 minutes prior to radiation, reflective of the fact that it penetrates tumor at a slower rate than it penetrates normal tissue. By administering the radiation soon after amifostine is given, you are taking advantage of this differential penetration so that tumor is more radiosensitive than normal tissue.

Hall EJ, Giaccia AJ. Radiation carcinogenesis. In: Hall EJ, Giaccia AJ, eds. Radiobiology for the Radiologist. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:135–153.

Only gold members can continue reading. Log In or Register to continue