Sun, L-Q., Buchegger, F., Coucke, P. A. and Mirimanoff, R-O. Fractionated Irradiation Combined with Carbogen Breathing and Nicotinamide of Two Human Glioblastomas Grafted in Nude Mice.This study addressed the potential radiosensitizing effect of nicotinamide and/or carbogen on human glioblastoma xenografts in nude mice. U-87MG and LN-Z308 tumors were irradiated with either 20 fractions over 12 days or 5 fractions over 5 days in air-breathing mice, mice injected with nicotinamide, mice breathing carbogen, or mice receiving nicotinamide plus carbogen. The responses to treatment were assessed using local control and moist desquamation. In U-87MG tumors, the enhancement ratios (ERs) at the radiation dose required to produce local tumor control in 50% of the treated mice (TCD50) with nicotinamide and/or carbogen ranged from 1.13 to 1.24 for irradiation in 20 fractions over 12 days. In LN-Z308 tumors, the ERs at the TCD50 with nicotinamide and/or carbogen ranged from 1.22 to 1.40 for irradiation in 5 fractions over 5 days and from 1.11 to 1.30 in 20 fractions over 12 days, respectively. Skin injury was slightly enhanced, with ERs ranged from 1.06 to 1.15 when radiation was combined with carbogen and/or nicotinamide. Thus carbogen and nicotinamide can slightly improve the radiation response of human glioblastoma xenografts.
5-Iodo-2'-deoxyuridine (IdUrd) radiolabelled with the positron emitter I or with the gamma and Auger electron emitters I or I has been proposed for cancer diagnosis and therapy. We modified the synthesis to reliably obtain [I]IdUrd and [I]IdUrd by using an Iodogen supported destannylation reaction of 5-(tri-n-butylstannyl)-2'-deoxyuridine (Bu3SndUrd) which meets the requirements for good laboratory practice (GLP) and good clinical practice (GCP). A method of purification was developed to eliminate by-products as well as any unreacted starting material.[I]IdUrd, which originated from a trace of iodide in the Bu3SndUrd precursor, was identified as the unknown by-product reported for this method. This trace could be eliminated by modified purification of Bu3SndUrd. Stabilization of pH was essential for unequivocal identification of radiolabelled IdUrd and possible degradation products in the different systems tested for quality control. Biodistribution in tumour bearing nude mice was measured as early as 3 and 6 h after i.v. injection of [I]IdUrd. This compound showed high and specific activity uptake in tumour and dividing tissues when combined with 5-fluoro-2'-deoxyuridine pre-treatment. Uptake was specifically inhibited by injection of excess thymidine.
The aims of this study were to assess the intraindividual performance of F-fluorocholine (FCH) and C-acetate (ACE) PET studies for restaging of recurrent prostate cancer (PCa), to correlate PET findings with long-term clinical and imaging follow-up, and to evaluate the impact of PET results on patient management.Thirty-three PCa patients relapsing after radical prostatectomy (n = 10, prostate-specific antigen [PSA] ≤3 ng/mL), primary radiotherapy (n = 8, prostate-specific antigen ≤5 ng/mL), or radical prostatectomy + salvage radiotherapy (n = 15) underwent ACE and FCH PET-CT (n = 29) or PET-MRI (n = 4) studies in a randomized sequence 0 to 21 days apart.The detection rate for ACE was 66% and for FCH was 60%. Results were concordant in 79% of the cases (26/33) and discordant in 21% (retroperitoneal, n = 5; pararectal, n = 1; and external iliac nodes, n = 1). After a median FU of 41 months (n = 32, 1 patient lost to FU), the site of relapse was correctly identified by ACE and FCH in 53% (17/32) and 47% (15/32) of the patients, respectively (2 M1a patients ACE+/FCH-), whereas in 6 of 32 patients the relapse was not localized. Treatment approach was changed in 11 (34.4%) of 32 patients and 9 (28%) of 32 patients restaged with ACE and FCH PET, respectively.In early recurrent PCa, ACE and FCH showed minor discrepancies, limited to nodal staging and mainly in the retroperitoneal area, with true positivity of PET findings confirmed in half of the cases during FU. Treatment approach turned out to be influenced by ACE or FCH PET studies in one third of the patients.
The synthetic peptide TAT-RasGAP317–326 has been shown to potentiate the efficacy of anti-cancer drugs. In this study, we explored the action of TAT-RasGAP317–326 when combined with radiation by investigating its radiosensitizing activity in vitro and in vivo. To investigate the modulation of intrinsic radiosensitivity induced by TAT-RasGAP317–326, clonogenic assays were performed using four human cancer cell lines, HCT116 p53 / (ATCC: CCL-247), HCT116 p53–/–, PANC-1 (ATCC: CRL-1469) and HeLa (ATCC: CCL-2), as well as one nontumor cell line, HaCaT (CLS: 300493). Next, to investigate tumor growth delay after irradiation, HCT116 cell lines were selected and xenografted onto nude mice that were then treated with TAT-RasGAP317–326 alone or in combination with radiation or cisplatin. Afterwards, cell cycle and death modulation were investigated by quantification of micronuclei and apoptosis-related protein array. TAT-RasGAP317–326 radiosensitized all four human carcinoma cell lines tested but displayed no effect on normal cells. It also displayed no effect when administered as monotherapy. This radiosensitizing effect was confirmed in vivo in both p53-positive and p53-negative HCT116 xenografts. TAT-RasGAP317–326 combined with radiation enhanced the number of cells in S phase and subsequently delayed cell death, but had almost no effect on major apoptosis-related proteins. TAT-RasGAP317–326 is a radiosensitizing agent that acts on carcinoma cells and its radiosensitizing effect might be mediated, at least in part, by the enhancement of mitotic cell death.
