5-fluorouracil radiosensitization

An ideal radiosensitizer would be the one that can maximize radiation therapy benefit, can be easily administered, can be optimally sequenced with radiation therapy for best effects, and have no overlapping toxicities with radiation. Although falling short in certain of these characteristics, 5-fluorouracil (5-FU) has become the most promising clinical radiosensitizer in combined chemoradiotherapy regimens. 

The mechanisms of interaction between fluorouracil and radiation are not clearly understood. Different hypotheses have been postulated to explain the synergistic or potentiated effect of 5-FU with radiation including redistribution of cells to a more radiosensitive cell cycle phase, deranged pyrimidine pools with reduced capacity for repair of DNA damage, and activation of apoptosis. The effect of 5-FU on radiation damage also appears to vary in different cell lines, thus complicating the extrapolation of laboratory results into clinical practice. 

Smalley SR, Kinder BF, Evans RG. 5-fluorouracil modulation of radiosensitivity in cultured human carcinoma cells. Int J Radial Oncol Biol Phys 1991 20 207-211. 

Byfield JE. Theoretical basis and clinical applications of 5-fluorouracil used as a radiosensitizer. In Rosenthal CJ, Rothman M (eds) Clinical Applications of Continuous Infusion Chemotherapy and Concomitant Radiation Therapy, Plenum Publishing Corp. New York, 1986, pp. 113-125. 

Byfield JE. The clinical use of 5-fluorouracil and other halopyrimidines as radiosensitizers in man. In Lokich J (ed) Cancer Chemotherapy by Infusion. Precept Press, Chicago, 1987, pp. 479-501. 

Lawrence TS, Davis MA, Maybaum J. Dependence of 5-fluorouracil-mediated radiosensitization on DNA- directed effects. Int J Radiat Oncol Biol Phys 1994 29 519-523. 

Anne P, Mitchell EP, Ahmad N, et al. Radiosensitization in locally advanced adenocarcinoma of the rectum using combined modality therapy (CMT) with CPT-11, 5-fluorouracil concomitant irradiation [Abstract]. ProcAm Soc Clin Assoc 2000 19 250a. 

Menei P, Venier MC, Gamelin E, Saint-Andre JP, Hayek G, Jadaud E, Fournier D, Mercier P, Guy G, Benoit JP. Local and sustained delivery of 5-fluorouracil from biodegradable microspheres for the radiosensitization of ghoblastoma a pilot study. Cancer 1999 86 325-330. 

In contrast to ILK, overexpression of the prosurvival integrin signaling mediator FAK protects leukemia cells from radiation- and chemo-induced apoptosis (Kasa-HARA et al. 2002). Silencing of FAK protein expression with siRNA mediated knockdown increases the radiosensitivity of different tumor cell lines originating from pancreatic cancer (Cordes et al. 2007), breast cancer, and colorectal cancer (McLean etaL 2005). Others have shown that human melanoma cells become more sensitive to the chemotherapeutic agent 5-fluorouracil when FAK expression is downregulated (Smith etal. 2005). 

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