L'effet antitumoral des molécules dites « bioréduitesne se produit que si ces molécules sont réduites en condition d'hypoxie, entraînant la production de métabolites cytotoxiques. Des données récentes ont démontré que cette cytotoxicité pouvait être augmentée par une association aux radiations ionisantes ou à des molécules de chimiothérapie (cisplatine). Des paramètres comme la pression partielle en oxygène et la chronologie d'administration jouent un rôle important dans l'efficacité biologique de telles associations. L'objectif de ce travail était de définir la dépendance, vis-àvis de la pression partielle en oxygène, de la cytotoxicité observée après association tirapazamine, cisplatine et radiations ionisantes. L'étude a porté sur deux lignées tumorales humaines : l'une sensible à la tirapazamine, Na11+, un mélanome pigmenté avec un fort contingent de cellules hypoxiques, l'autre (HRT18) un adénocarcinome colique moins sensible à la tirapazamine. Des échanges gazeux (precise gas exchanges) ont permis d'obtenir quatre PO2 différentes : air (20,9 % d'O2), 10, 2 et 0,2 % d'O2. Les cellules étaient incubées avec la tirapazamine et/ou le cisplatine pendant une heure à 37 °C, puis irradiées et mises en culture (méthode des colonies). Pour la lignée Na11+, la survie cellulaire après irradiation était comparable dans l'air et à 10 % d'oxygène avec les deux molécules données individuellement ou associées. À 2 et à 0,2 % d'oxygène, la mortalité cellulaire était largement augmentée par la tirapazamine mais n'était pas modifiée par l'addition de cisplatine. Pour HRT18, la survie cellulaire n'était pas modifiée avec l'association cisplatine-irradiation par rapport à l'irradiation seule, quelle que soit la PO2. Pour des faibles PO2 (2 et 0,2 %), la cytotoxicité observée avec la tirapazamine était diminuée de façon non significative en cas d'association au cisplatine. En conclusion, l'association du cisplatine à la tirapazamine ne modifie pas la cytotoxicité observée avec la tirapazamine seule. Ceci démontre qu'en cas d'association radiations ionisantes-tirapazamine, l'importance de l'effet biologique observé est dépendante de la PO2 et de la sensibilité de la lignée cellulaire aux molécules utilisées. Cette constatation a d'importantes implications potentielles vis-à-vis des stratégies thérapeutiques fondées sur des chimioradiothérapies.

Recent data have shown that the in vitro and in vivo cytotoxicity of bioreductive drugs could be significantly increased by combination with ionising radiation or chemotherapy. Various parameters such as oxygen tension and timing of administration of the drugs could play a crucial role in the efficacy of combined treatment modalities. The aim of this study was to define the oxygen dependency of cell survival after in vitro irradiation and incubation with tirapazamine, a bioreductive drug, and cisplatin given alone or simultaneously. Two human cell lines were studied: one cell line sensitive to tirapazamine, Na11+, a pigmented melanoma with a high percentage of hypoxic cells, and a less sensitive cell line to tirapazamine, HRT18, a rectal adenocarcinoma. Gas changes were made to study cell survival at four different oxygen concentrations (pO2): air (20.9% O2), 10.2 and 0.2% O2. Cells were incubated with tirapazamine and cisplatin alone or combined for one hour at 37 degrees C, then irradiated and cultured. For Na11+, cell survival after irradiation was comparable in air and at 10% oxygen with the two drugs given alone or combined. At 2 and 0.2% oxygen, cell killing was largely increased by tirapazamine and was not modified by the addition of cisplatin. For HRT18, cell survival was not modified when cisplatin was added to radiation, whatever the oxygen partial pressure. At low pO2 (2 and 0.2%) the cytotoxic effect of tirapazamine was not significantly decreased by the addition of cisplatin. When cytotoxic and bioreductive drugs are combined to radiation, the magnitude of the observed effect is highly dependent on the partial oxygen pressure and on the sensitivity of the cell line to the individual drugs. This has very important implications for clinical strategies based on combined chemo-radiotherapy.

Purpose: Biological dosimetry based on scoring chromosomal aberrations in peripheral lymphocytes was compared to physical dosimetry done for total body irradiation (TBI) before bone marrow transplantation (BMT) in patients with hematologic malignancies.Patients and Methods: Fifteen patients undergoing TBI were included in the study, A total dose of 12 Gy in 2.5 days was fractionated into 2 or 3 daily doses of 1.8 Gy delivered by a 18 MV linear accelerator (dose rate: 15.8 cGy.min(-1)). Blood samples were obtained from patients before irradiation and after the first fraction of 1.8 Gy, A standard dose-effect curve was established by in vitro irradiation of healthy volunteer lymphocytes. Chromosomal aberrations were scored by the conventional cytogenetics (CCG) method for unstable anomalies and by fluorescent in situ hybridization (FISH) for stable anomalies.Results: Healthy donor lymphocytes before irradiation yielded 0.1% dicentrics and 0.3% translocations of chromosome 4 (Chr. 4), that is 2.5% for the whole genome. Patients before irradiation had 2% of dicentrics and 1.1% of chromosome 4 translocations. The biologically estimated dose of the 15 patients after exposure to 1.8 Gy was 1.93 Gy (95% CI: 1.85-2.05) according to CCG, and 2.06 Gy (95% CI: 1.75-2.15) by FISH.Conclusion: The dose estimated by biological dosimetry, in this case of homogeneously distributed radiation of TBI, agrees well with the absorbed radiation dose calculated by physical dosimetry, (C) 2000 Elsevier Science Inc.

The biological effectiveness of low energy transfer (LET) ionizing radiation is in part related to the amount of oxygen present at the time of the energy deposit. This dose modifying role of oxygen (oxygen enhancement ratio) is principally caused by the indirect effect ofradiation on DNA (1,2). Hypoxic cells are present in rodent and xenografted human tumors, and it has been known for a long time that the absence ofoxygen in tumors is a factor ofresistance against ionizing radiation (3–5). More recently, it has been shown that the decrease in tumor oxygen tension could also be a factor ofresistance for treatment with some cytotoxic drugs (6–8), not only directly through the low-oxygen partial pressures, but indirectly through modifications in some gene expression by O2 and other environmental factors (vascularization, pH, metabolism, angiogenic factors, and so on) (9,10). In patients, tumors are known to contain hypoxic areas (11–14), and the local control of human solid tumors could be improved if a clinically relevant test was able to identify tumors that would benefit from radiosensitization (5). Oxygen availability is dependent on oxygen supply, which depends on many parameters: microvasculature, blood flow, tissue temperature, and pH (15,16). Tissue oxygenation will result directly from 02 availability, and from the respiration rate ofthe cells. For normal tissues, changes in oxygenation reflect variations in blood flow, and partial oxygen pressure (pO2) distribution has been evaluated as a function of hemoglobin concentration, temperature, pH, and so on (15). In tumors, tissue vascularization is qualitatively poor with shunts, vessel collapses, and high interstitial pressure. All these parameters may represent a potential therapeutic target (16–18).

Between 1990 and 1998, oxygen tension was evaluated in more than 100 tumors in patients at the Institut Gustave Roussy. Variations between normal tissues and tumors have been described in head & neck and cervical carcinomas, and in metastatic melanomas. Procedures inducing changes in oxygen tensions such as carbogen breathing and accelerated radiotherapy are described.

The study was performed to assess the effect of accelerated radiotherapy on oxygenation of primary tumours and metastatic nodes in patients with advanced head and neck tumours. In 14 patients with head and neck tumour, oxygen tension (pO2) was evaluated in normal tissues and tumours (primary tumour or metastatic neck node) before (0 Gy) and after 2 weeks (32 Gy) of accelerated radiotherapy (70 Gy in 3.5 weeks, with three daily fractions). Radiotherapy was combined with carbogen breathing in 5 patients. pO2 was measured using a polarographic technique. For pooled normal tissues, median pO2 was 38 mmHg before treatment and 46 mmHg after 2 weeks. For tumours, very low values (< 2 mmHg) represented 20% of the recorded values before treatment and 10% after 2 weeks. The relative increase in tumour oxygenation was more pronounced for primary tumours (median pO2 12 mmHg before treatment versus 26 mmHg after 2 weeks, P < 0.05) than for metastatic nodes (respectively, 20 and 27 mmHg P = 0.1). For the 5 patients who breathed carbogen during accelerated radiotherapy, the median pO2 was 44 mmHg at 2 weeks, compared with 13.5 mmHg before treatment (P = 0.05). Very low pO2 values, corresponding to tumour hypoxia, were found in the tumours (primary and metastatic neck nodes) prior to accelerated treatment. During the first 2 weeks of accelerated treatment, an increase in median pO2 was found in nine of the 14 tumours, together with a decrease in the frequency of very low values.

La plupart des tumeurs expérimentales renferment des cellules hypoxiques clonogènes situées soit à une certaine distance des vaisseaux soit au contact de vaisseaux collabés. La radiorésistance de ces cellules peut être réduite par différents procédés ; le meilleur traitement dépend de la proportion de celles dans les deux catégories d'hypoxie. Chez l'homme, des zones hypoxiques ont été mises en évidence dans la plupart des tumeurs solides. Le devenir de l'hypoxie au cours d'une radiothérapie accélérée ainsi que l'efficacité du carbogène (95 % O2- 5 % CO2) pour améliorer la radiothérapie sont en cours d'étude. Nous participons également au développement de teste prédicitifs de la réponse tumorale à une irradiation.

Tumour hypoxia can lead to a decrease in the biological effectiveness of radiation and alkylating agents. Few data are available on oxygen tension (PO2) in melanoma. In 20 patients with past history of melanoma, PO2 was evaluated in normal tissues and suspected metastatic lesions (nodes and skin metastases). Oxygen tension was measured using a needle probe technique (KIMOC-6650 histograph, Eppendorf, Germany), the day before the surgical removal of the suspected metastatic lesion. Histological confirmation of the malignant origin of the removed lesion was obtained in 18 cases. In two cases invasion by the known melanoma was not seen histologically. The median PO2 for normal tissues was 40.5 mmHg. For tumours, the median PO2 was 11.6 mmHg, and it was 17.1 mmHg in nodes and 6.7 mmHg in skin metastases. Very low values (< 2 mmHg) accounted for 20% of the recorded values in nodes and 15% in skin metastases. When analysed according to the node size (< or > or = 3 cm in diameter), the median PO2 was 10.4 mmHg in large nodes (six patients) and 53.3 mmHg in small nodes (six patients). For the two non-tumoral lesions, the median PO2 values were 20.9 and 25.1 mmHg, with no values below 10 mmHg. Thus a decrease in PO2 values, probably corresponding to tumour hypoxia, was found in most of the metastatic tumours when compared with normal tissues. The prognostic value of these PO2 measurements in melanoma remains to be demonstrated in the tumour response to radiotherapy or alkylating agents. However, tumour hypoxia can already be investigated as a target for new treatment modalities in metastatic melanoma.

Purpose: The aim of the study was to present the updated Institut Gustave Roussy experience of the predictive value of three biological parameters in patients with squamous cell carcinoma of the Head and Neck (HNSCC) treated with radiation therapy.Methods and Materials: Three parameters have been investigated independently: tumor cell kinetics (TS, T-pot and LI), oxygen tension measurements (PO2) and intrinsic radiosensitivity (SF(2)Gy).Results: No relationship has been found between local-regional control and T-pot or LI in a series of 74 patients, Our data also support that the surviving fraction at 2 Gy, (SF2) was unlikely to predict the clinical outcome in a series of 92 patients. Differences in PO2 measurements have been observed between tumors, and tumor oxygenation was lower than that of normal tissue for the majority of patient, However PO2 measurements did not predict clinical outcome, but further investigations are needed to draw definitive conclusions, given the limited number of patients entered in our study (35 patients), In addition, we were able to measure the three parameters in 10 patients showing no correlation between PO2, SF2 and T-pot.Conclusions: The method used to evaluate T-pot and SF2 did not provide clinically relevant predictive parameters for this type of cancer, Further investigations are needed to assess the predictive value of PO2 measurements and of new biological parameters in a multiparametric approach, taking into account other possible clinical and biological confounding factors. (C) 1997 Elsevier Science Inc.

Hypoxia is a factor of radioresistance in the treatment of solid tumours. One way to radiosensitize these tumours is to use carbogen (95% O-2-5% CO2) and it is important to irradiate when the increase in oxygenation created by the inhalation is at the maximal level. The DADOT is a non-invasive item of equipment that allows one to evaluate the relative proportion of oxygenated and deoxygenated forms of haemoglobin in tissues. The principle used is to measure the evolution of the absorption of red or infrared light by haemoglobin. Two light-emitting diodes at respectively 0.66 and 0.94 mu m are coupled in two optical fibres the distal ends of which are applied on the tumour. These wavelengths are absorbed differently by the oxygenated and deoxygenated forms of haemoglobin. The light which is back-scattered towards the surface of the skin is detected by an amplified photodiode through a third fibre applied on the tumour. The modifications of tumour oxygenation during carbogen inhalation were followed for two tumour cell lines. They were also studied in a patient. These first results suggest that the DADOT is a reliable item of equipment that gives reproducible results and that could be used routinely to monitor changes in tumour oxygenation in patients.

Background and Objectives: The median of pO(2) values in tumor measured by Eppendorf ''Histograph'' with a needle-type electrode has been used as a prognostic indicator in cancer patients. However, it is not established that a pretreatment measured pO, value can be used as a universal predictor of local control probability, because the variation in pO(2) values, especially in hypoxic tissue, among institutes may not allow comparison of measured ''absolute pO(2) values.'' The purpose of this study was to examine the variation in oxygen tension measurement by Eppendorf ''Histograph'' among six laboratories using a single batch of mice and tumors and the same detailed protocol. These results were also compared to the immunohistochemical staining of 2-nitroimidazole adducts.Methods: C3H mice bearing FSaII murine fibrosarcoma subcutaneously were shipped to all laboratories, and the oxygen status in tumors and in normal subcutis was examined using Eppendorf ''Histograph'' and immunohistochemical hypoxic marker.Results: All laboratories showed that the FSalI turner was hypoxic with at least 77% of measured points under 10 mmHg in pO(2) and with a median pO(2) value less than that of normal subcutis. These results were further confirmed immunohistochemically. These findings are interpreted as evidence that the pO(2) values measured by Eppendorf ''Histograph'' can be useful. However, the median values of tumor pO(2) varied from 1.5 mmHg to 5.6 mmHg among the laboratories, and pO(2) of normal subcutis also varied from 28 mmHg to 38 mmHg. There were also significant differences in hypoxic fraction, defined as the fraction under a given oxygen partial pressure (i.e., under 2.5, 5, or 10 mmHg), among institutes.Conclusions: Caution needs to be exercised in using the absolute, median, or distribution of pO(2) values measured by the Eppendorf ''Histograph'' to compare the data between laboratories or to predict the radiation response in an individual subject. (C) 1997 Wiley-Liss, Inc.

This review is provided a detailed overview of the synthesis, properties and applications of nanoparticles (NPs) exist in different forms. NPs are tiny materials having size ranges from 1 to 100 nm. They can be classified into different classes based on their properties, shapes or sizes. The different groups include fullerenes, metal NPs, ceramic NPs, and polymeric NPs. NPs possess unique physical and chemical properties due to their high surface area and nanoscale size. Their optical properties are reported to be dependent on the size, which imparts different colors due to absorption in the visible region. Their reactivity, toughness and other properties are also dependent on their unique size, shape and structure. Due to these characteristics, they are suitable candidates for various commercial and domestic applications, which include catalysis, imaging, medical applications, energy-based research, and environmental applications. Heavy metal NPs of lead, mercury and tin are reported to be so rigid and stable that their degradation is not easily achievable, which can lead to many environmental toxicities.