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Purpose: This study sought to determine the maximum tolerated dose (MTD) of oral etoposide in combination with radiotherapy in head and neck squamous cell carcinoma (HNSCC)., Patients and Methods: Phase I, multicenter, open-labelled, non-comparative and dose escalating trial. Patients with locally advanced HNSCC were enrolled onto cohorts of escalating dose of etoposide. Oral etoposide was administered on five consecutive days every week for 7 weeks (7 treatment cycles) in combination with daily radiotherapy (70 Gy /35 fractions). Two dose levels (25 mg/day and 50 mg/day) of etoposide were planned and three to six patients were to be enrolled at each level according to the potential DLTs., Results: Fourteen patients were allocated to two dose levels: 25 mg/day (3) and 50 mg/day (11). Cisplatin was contra-indicated in all the patients included. Only one patient (50 mg/day) presents a grade 4 neutropenia (DLT), no other DLTs were observed. The most frequently adverse events (AEs) were radiomucositis. Two deaths before 3 months of end of treatment were not related to treatment. Seven patients were still alive with a median follow-up of 30 months (12-58 months). Nine patients had a complete response (CR) at 3 months after the radiotherapy; Among the 9 patients, 3 patients had a local relapse; one patient with local and distant relapse., Conclusion: Due to only one DLT experienced, it is possible to a dose of 50 mg/day for phase II studies, however this should be considered with caution.

In this paper, we describe the effect of the inhibitor of farnesyltransferase (FTI-277) on radioresistance induced by the 24-kDa isoform of FGF2 in human cells expressing wild-type RAS. Treatment with FTI-277 (20 microM) for 48 h prior to irradiation led to a significant decrease in survival of radioresistant cells expressing the 24-kDa isoform (HeLa 3A) but had no effect on the survival of control cells (HeLa PINA). The radiosensitizing effect of FTI-277 is accompanied by a stimulation of postmitotic cell death in HeLa 3A cells and by a reduction in G(2)/M-phase arrest in both cell types. These results clearly demonstrate that at least one farnesylated protein is involved in the regulation of the radioresistance induced by the 24-kDa isoform of FGF2. Furthermore, the radiation-induced G(2)/M-phase arrest is also under the control of farnesylated protein. This work also demonstrates that FTase inhibitors may be effective radiosensitizers of certain human tumors with wild-type RAS.

The variation in the risk of solid second malignant neoplasms (SMN) with time since first cancer during childhood has been previously reported. However, no study has been performed that controls for the distribution of radiation dose and the aggressiveness of past chemotherapy, which could be responsible for the observed temporal variation of the risk. The purpose of this study was to investigate the influence of the treatment on the long-term pattern of the incidence of solid SMN after a first cancer in childhood. We studied a cohort of 4400 patients from eight centres in France and the UK. Patients had to be alive 3 years or more after a first cancer treated before the age of 17 years and before the end of 1985. For each patient in the cohort, the complete clinical, chemotherapy and radiotherapy history was recorded. For each patient who had received external radiotherapy, the dose of radiation received by 151 sites of the body were estimated. After a mean follow-up of 15 years, 113 children developed a solid SMN, compared to 12.3 expected from general population rates. A similar distribution pattern was observed among the 1045 patients treated with radiotherapy alone and the 2064 patients treated with radiotherapy plus chemotherapy; the relative risk, but not the excess absolute risk, of solid SMN decreased with time after first treatment; the excess absolute risk increased during a period of at least 30 years after the first cancer. This pattern remained after controlling for chemotherapy and for the average dose of radiation to the major sites of SMN. It also remained when excluding patients with a first cancer type or an associated syndrome known to predispose to SMN. When compared with radiotherapy alone, the addition of chemotherapy increases the risk of solid SMN after a first cancer in childhood, but does not significantly modify the variation of this risk during the time after the first cancer.

The basic fibroblast growth factor-(bFGF) mediated signal transduction pathway has been implicated in cellular resistance to ionizing radiation. bFGF is synthesized from the same mRNA in four isoforms resulting from alternative initiations of translation at three CUG start codons (24, 21.5, and 21 kDa) and one AUG start codon (18 kDa). We analyzed the implication of high- and low-molecular forms of bFGF in radioresistance acquisition. For this, we transfected HeLa cells with retroviral vector containing either the CUG-initiated 24-kDa molecular form (HeLa 3A cells), the AUG-initiated 18-kDa molecular bFGF form (HeLa 5A cells), or the vector alone (HeLa PINA cells). A significantly increased radioresistance was obtained only in HeLa 3A cells (Dq = 810 +/- 24 cGy) compared with wild-type cells (Dq = 253 +/- 49 cGy) or HeLa PINA cells (Dq = 256 +/- 29 cGy; P < 0.001). This radioprotective effect was independent of an inhibition of radiation-induced apoptosis but related to an increased G2 duration after irradiation and to an hyperphosphorylation of p34cdc2 kinase. Knowledge of the high-molecular bFGF form-induced radioresistance pathway could offer novel targets for decreasing the radioresistance phenotype of tumors expressing high amounts of bFGF, such as glioblastoma.

Duration of the G2-phase delay and arrest after exposure to ionizing radiation is thought to influence radiosensitivity. The kinase activity of the p34cdc2-cyclin B complex and the p34cdc2-cyclin A complex is implicated in G2- to M-phase transition and in G2-phase arrest after exposure to ionizing radiation. We analyzed the expression level and the subcellular location of p34cdc2, cyclin A and cyclin B in head and neck squamous cell carcinoma (SCC) tumors; samples were obtained from patients with locally nonrecurrent and recurrent tumors that had been treated by surgery and radiotherapy. No significant difference was noticed in cyclin A, cyclin B and p34cdc2 expression. However, we noted a significant preferential cytoplasmic location of p34cdc2 in recurring tumors compared to the nonrecurring ones (P < 0.001). This abnormal location of p34cdc2 occurs even in primary tumors in patients with recurring tumors, suggesting that a default in the activation of p34cdc2 kinase could be implicated in clinical radioresistance.