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This review focuses on the radiosensitization strategies that use high-Z nanoparticles. It does not establish an exhaustive list of the works in this field but rather propose constructive criticisms pointing out critical factors that could improve the nano-radiation therapy. Whereas most reviews show the chemists and/or biologists points of view, the present analysis is also seen through the prism of the medical physicist. In particular, we described and evaluated the influence of X-rays energy spectra using a numerical analysis. We observed a lack of standardization in preclinical studies that could partially explain the low number of translation to clinical applications for this innovative therapeutic strategy. Pointing out the critical parameters of high-Z nanoparticles radiosensitization, this review is expected to contribute to a larger preclinical and clinical development.

A new efficient type of gadolinium-based theranostic agent (AGuIX®) has recently been developed for MRI-guided radiotherapy (RT). These new particles consist of a polysiloxane network surrounded by a number of gadolinium chelates, usually 10. Owing to their small size (<5 nm), AGuIX typically exhibit biodistributions that are almost ideal for diagnostic and therapeutic purposes. For example, although a significant proportion of these particles accumulate in tumours, the remainder is rapidly eliminated by the renal route. In addition, in the absence of irradiation, the nanoparticles are well tolerated even at very high dose (10 times more than the dose used for mouse treatment). AGuIX particles have been proven to act as efficient radiosensitizers in a large variety of experimental in vitro scenarios, including different radioresistant cell lines, irradiation energies and radiation sources (sensitizing enhancement ratio ranging from 1.1 to 2.5). Pre-clinical studies have also demonstrated the impact of these particles on different heterotopic and orthotopic tumours, with both intratumoural or intravenous injection routes. A significant therapeutical effect has been observed in all contexts. Furthermore, MRI monitoring was proven to efficiently aid in determining a RT protocol and assessing tumour evolution following treatment. The usual theoretical models, based on energy attenuation and macroscopic dose enhancement, cannot account for all the results that have been obtained. Only theoretical models, which take into account the Auger electron cascades that occur between the different atoms constituting the particle and the related high radical concentrations in the vicinity of the particle, provide an explanation for the complex cell damage and death observed.

More than 80% of an administered dose of fluorouracil (FU) is eliminated by catabolism through dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme of pyrimidines (Diasio and Harris, 1989). Tuchman and colleagues (1985) were the first to describe a patient with severe FU toxicity associated with a pyrimidine metabolism disorder. On the basis of another case report, Diasio et al (1988) conducted a familial study, the conclusions of which suggested an autosomal recessive pattern of inheritance for DPD deficiency. Since then, similar pharmacogenetic syndromes have been reported by the same group (Harris et al, 1991;Lu et al, 1993), others (Houyau et al, 1993) and ourselves (Fleming et al, 1993). We recently performed a review analysis on previously published cases of DPD deficiency associated with FU toxicity. It appeared that a complete absence of DPD activity is extremely rare and even partial enzyme activity might result in more or less severe FU toxicity . In addition, the fact that among 15 cumulated cases (most with digestive cancer) 13 (87%) were women was very striking and suggestive of a sex-linked deficiency in DPD activity. We report on the clinical and pharmacological results from 19 cancer patients with more or less intense FU-related toxicity, who were phenotyped in our centre as carrying a DPD deficiency diagnosed in peripheral blood mononuclear cells. Different features were analysed including sex ratio, the toxicity profile, and a possible link between the intensity of DPD deficiency and the severity of FU toxicity. MATERIAL AND METHODS PatientsThis study represents a 3-year collection of blood lymphocytes taken from 53 consecutive patients treated by FU-based chemotherapy in different French institutions (general hospitals, cancer centres, private hospitals). These patients had experienced unpredicted more or less severe FU-related toxicity. Blood lymphocytes were collected in the respective hospitals within a period of 1 month after the FU toxicity episode. All lymphocyte samples were shipped in dry-ice to our laboratory. Among this group of 53 patients (23 men, 30 women, mean age 58, range 36Ð73), 19 exhibited a moderate or marked DPD deficiency (less than 70% of the mean population value, i.e. less than 150 fmol min Ð1 mg Ð1 protein; Etienne et al, 1994). A complete description of these 19 case reports is given in Table 1. We defined a toxicity score which was the sum of the toxicity grades (WHO classification) for mucositis, neutropenia, thrombocytopenia and digestive toxicity. The presence of neurotoxicity was graded 4. The maximal toxicity score was 20. Determination of DPD activityLymphocyte preparation was carried out in the hospital where the patient received the FU-based treatment. Because of a known circadian pattern of DPD activity (Harris et al, 1990), blood samples were drawn between 8 a.m. and 10 a.m. to minimize the influence of circadian variability. When patients developed severe haematological toxicity, a normalization of blood cell count (white blood cells) was awai...

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