Drug radiotherapy combinations: Review of previous failures and reasons for future optimism

Synthesis and cytotoxic activity evaluation of some novel 1-(3-(aryl-4,5-dihydroisoxazol-5-yl)methyl)-4-trihalomethyl-1 H -pyrimidin-2-ones in human cancer cells

“…[2]. Worldwide, there were 14.1 million new cancer cases, 8.2 million cancer deaths, and 32.6 million people living with cancer (with 5 years or less of diagnosis) in 2012.…”

Communication: “Position” does matter: The photofragmentation of the nitroimidazole isomers

“…The understanding of these radiosensitising mechanisms is of fundamental importance in the design and characterisation of novel drugs, reducing the risk of negative trials. 11,12 2-and 5-nitroimidazole (C 3 H 3 N 3 O 2 , m = 113 amu) isomers, i.e., derivatives of imidazole containing one nitro group a) Authors to whom correspondence should be addressed. Electronic addresses: paola.bolognesi@cnr.it and annarita.casavola@cnr.it are, respectively, the building blocks of misonidazole and nimorazole radiosensitisers used in clinical trials as "oxygen mimetic" compounds.…”

“…2,12 The fundamental reasons for such different behaviour are not yet understood and even though these drugs have a certain level of toxicity, there are still ongoing clinical trials aiming to refine the use of nimorazole. 12 In this work we present a joint experimental and theoretical study of the radiation induced fragmentation of 4-, 5-, and 2-nitroimidazole isomers, providing clear evidence of their different fragmentation patterns. The results suggest that particular products of their decomposition may influence the effectiveness of the radiosensitising action of their derivatives.…”

“…These effects, in addition to the redox mechanism, may provide the explanation of the potential of all nitroimidazoles as radiosensitisers active on hypoxic tumours. 12 On the other hand, the release of carbon monoxide, CO, and hydrogen cyanide, HCN, more pronounced in 4(5)NI isomers, may induce an opposite effect by efficiently attaching to haemoglobin 30 and inhibiting the cytochrome c oxidase 31 in mitochondria, respectively, therefore effectively reducing the needed oxygenation and the overall radiosensitising effect. The importance of these processes when nitroimidazole derivate radiosensitizers operate in real biological media depends on how the bio-environment influences their energetics.…”

Radiotherapy in the Era of Precision Medicine

“…This precise treatment delivery is juxtaposed by the imprecision of combinatorial genotoxic therapies. Several trials have largely shown that the addition of targeted agents to radiation does not result in improved outcomes in unselected patient populations [ (10,11)]. Moreover, standard radiation doses and fractionation schemes delivered based on site of anatomic origin of disease do not take into account the genetic complexity that not only drives oncogenesis, but may also regulate therapeutic response.…”