Tumor radiosensitivity

Hirst, D.G., Wood, P.J., Schwartz, H.C. The modification of hemoglobin affinity for oxygen and tumor radiosensitivity by antilipidemic dmgs. Radiat. Res. 1987, 112, 164-172. 

Hirst, D.G. Wood, P.J. Chlorophenoxy acetic acid derivatives as hemoglobin modifiers and tumor radiosensitizers. 

S. J. Li, G.Y. Jin, J.E. Moulder, Prediction of tumor radiosensitivity by hexafluoromi-sonidazole retention monitored by [FI-1]/[F-19] magnetic-resonance spectroscopy. Cancer Commun. 3 (1991) 133-139. 

The above discussion has focused on a comparison of Y and l because these are the most frequently utilized radionuclides in endoradiotherapy however, the effect of particle range on therapeutic utility has been evaluated theoretically for other radionuclides as well. For a comprehensive discussion of the relationship between tumor size and therapeutic effectiveness for 22 uniformly distributed P emitters, the reader is referred to a paper by O Donoghue et al. (1995). In this study, a model was developed that took into account both tumor radiosensitivity and proliferation and yielded the diameter of tumor that could be optimally treated by each radionuclide. These ranged from 0.6 mm for to 3.4 cm for Y. A tumor control probability model has also been utilized to compare the potential therapeutic efficacy of six P emitters (Nahum 1996). 

Nicotinamide and benzamide are inhibitors of the chromatin bound enzyme poly(ADP-ribose) polymerase, which is involved in the mechanism of DNA repair after high doses of ionizing radiation. There have been reports that both benzamide and nicotinamide radiosensitize animal tumor models at doses of 200 mg/kg or higher (2,4,5). In order to evaluate if any differences in tumor radiosensitization between nicotinamide and benzamide are apparent at low doses, animals with transplanted adenocarcinomas were given these dmgs orally at a dose of 10 mg/kg five times a week from the day of transplantation rmtil irradiation (in total, 50-80 mg/kg). 

Kasten-Pisula U, Menegakis A, Brammer I et al (2008) The extreme radiosensitivity of the squamous cell carcinoma SKX is due to a defect in double-strand break repair. Radiother Oncol DOI 10.1016/j.radonc.2008.10.019 Kinner A, Wu W, Staudt C et al (2008) Gamma-H2AX in recognition andsignaling of DNA double-strand breaks in the context of chromatin. Nucleic Acids Res 36 5678-5694 Komuro Y, Watanabe T, Hosoi Y et al (2002) The expression pattern of Ku correlates with tumor radiosensitivity and disease-free survival in patients with rectal carcinoma. Cancer 95 1199-1205... 

Sonveaux, R, Dessy, C., Brouet, A., Jordan, B.F., Gregoire, V., Gallez, B., Balligand, J.L., and Feron, O. (2002). Modulation of the tumca vasculature functionality by ionizing radiation accounts for tumor radiosensitization and promotes gene delivery. FASEB J. 16, 1979-1981. 

Whereas epidermal growth factor (EGF) enhances the radiosensitivity of human squamous ceU carcinoma cells in vitro (197), addition of EGF to hormone-deprived MCE-7 breast cancer cells prior to irradiation results ia iacreased radioresistance (198). An anti-EGE-receptor monoclonal antibody blocks the abiUty of EGE to enhance growth and radioresistance. Tumor cells, the growth of which is stimulated by EGE, appear to be protected those where growth is iohibited are sensitized (198). 

Lloyd RD, Taylor GN, Jee WSS, et al. 1999. Relative radiosensitivity of bone tumor induction among beagles as a function of age at injection of 239Pu or 226RA. Health Phys 76(l) 75-81. 

SCLC is very radiosensitive. Radiotherapy has been combined with chemotherapy to treat limited disease SCLC. This combined-modality therapy prevents local tumor recurrences but only modestly improves survival over chemotherapy alone. 

The oral platinum compound 11 is capable of radiosensitizing a platinum-sensitive tumor line, as is cisplatin 1 (241). 

Misonidazole [27 l-methoxy-3-(2-nitroimidazol-l-yl)-2-propanol] and the model compound l-methyl-2-nitroimidazole have been used as radiosensitizers in the treatment of certain types of human tumors. One important property of these compounds is that they are more toxic to hypoxic cells than to aerobic cells, indicating that reductive metabolism of the drug is involved in the toxicity. Results of a number of studies suggest that intracellular thiols play a significant role in the hypoxic cell toxicity, and it was found that reduction products formed stable thio ethers with GSH (for literature see References 181-183). The reaction mechanism of thio ether formation has not been fully established. It has been suggested that the 4-electron reduction product was involved in thio ether formation181,184,185, and that the hydroxylamine rather than the nitroso derivative was the reactant. On the other hand, an intermediate nitroso derivative is expected to give a sulfenamide cation (see Scheme 1) which easily allows thio ether formation. 

Several genetic alterations can influence radiosensitivity of cancer cells and radioresponsive tumors are known to allow more easily radiation-induced apoptosis. Therefore, the proper functioning of the apoptotic machinery regulates radiosensitivity. As described above, a cracial role is played by p53, and its downstream genes p21 and bax, in activating the apoptotic process. Those cancers with mutations at these levels are expected to be radioresistant. 

Petersen C, Petersen S, Milas L, et al. Enhancement of intrinsic tumor cell radiosensitivity induced by a selective cyclooxygenase-2 inhibitor. Clin Cancer Res 2000 6(6) 2513-2520. 

Fig. 7. A schematic representation of treatment of 5-FU and external irradiation. The stippled rectangles represent weekly irradiation (9 Gy total/wk, given in five doses of 1.8 Gy). Concurrent 5-FU is represented by the solid bars beneath the irradiation, and the height of the bars represents the peak level of radiosensitizing chemotherapy. By using protracted infusional schedules of 5-FU, radiosensitizing chemotherapy can be given with each daily dose of irradiation (from 5 to 3 5 d). Newer schedules using continuous intermittent and circadian schedules have achieved high tumor activity with acceptable toxicity in recent trials.

Cyclicity of administration is vital in the use of 5-FU as a radiosensitizer. The concept of cyclical treatment has been well established in cancer chemotherapy and alien to classical radiation therapy (where it is termed split-course therapy). 5-FU radio-sensitizes tumor tissue as well as normal cells. However, this normal tissue radio-sensitizationis limited to the irradiated field. Suitable fractionation (i.e., cyclical therapy) can permit rapid normal tissue recovery (23). The results of infused 5-FU and radiation in head and neck cancer supports the principle that cyclical treatment with 5-FU does not suffer from the limitations apparent in split-course radiation treatments. 

FU. Tumors insensitive to 5-FU cannot be radiosensitized using this approach (42). 

Practically speaking, 5-FU infused at 25-30 mg/kg/d continuously for 5 d will radiosensitize virtually all 5-FU-sensitive tumors listed in Table 1. Although the optimal regimen has yet to be established, the 5-d schedule of 5-FU currently appears close to an ideal regimen. 

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