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Biomedical subjects

J Bourhis

Publications and source records attributed to J Bourhis.

At least 19 recordsLinked to original sources
PubMed2002

End points for new agents in induction chemotherapy for locally advanced head and neck cancers.

More than 60% of patients diagnosed with squamous cell carcinoma of the head and neck present at a locally advanced stage. Although multimodality therapy has improved locoregional control, the 5-year survival rate of this population rarely exceeds 30%. In this review, we analyzed the impact of chemotherapy in the management of locally advanced head and neck cancer and we underline the potential benefit of induction chemotherapy. The Meta-Analysis of Chemotherapy in Head and Neck Cancer collaborative group has suggested a survival advantage of 5% at 5 years for platin-5-fluorouracil induction chemotherapy. We have analyzed cofactors that may affect the survival of head and neck patients and propose new end points for assessment of the efficacy of induction chemotherapy. The detrimental effect of second primary tumors on long-term results is stressed and we have suggested the use of overall 2-year survival as a surrogate end point for induction chemotherapy efficacy. Finally, we have examined the impact of new cytotoxic agents and present the promising results of new taxane-based combinations.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Tyrphostin AG 1024 modulates radiosensitivity in human breast cancer cells.

Insulin-like growth factor-1 (IGF-1) plays an important growth-promoting effect by activating the PI3K/Akt signalling pathway, inhibiting apoptotic pathways and mediating mitogenic actions. Tyrphostin AG 1024, one selective inhibitor of IGF-1R, was used to evaluate effects on proliferation, radiosensitivity, and radiation-induced cell apoptosis in a human breast cancer cell line MCF-7. Exposure to Tyrphostin AG 1024 inhibited proliferation and induced apoptosis in a time-dependent manner, and the degree of growth inhibition for IC20 plus irradiation (4 Gy) was up to 50% compared to the control. Examination of Tyrphostin AG 1024 effects on radiation response demonstrated a marked enhancement in radiosensitivity and amplification of radiation-induced apoptosis. Western blot analysis indicated that Tyrphostin AG 1024-induced apoptosis was associated with a downregulation of expression of phospho-Akt1, increased expression of Bax, p53 and p21, and a decreased expression of bcl-2 expression, especially when combined with irradiation. To our knowledge, this is the first report showing that an IGF-1 inhibitor was able to markedly increase the response of tumour cells to ionizing radiation. These results suggest that Tyrphostin AG 1024 could be used as a potential therapeutic agent in combination with irradiation.

Adenocarcinoma↗
PubMed2001

Full dose reirradiation combined with chemotherapy after salvage surgery in head and neck carcinoma.

BACKGROUND: The purpose of this study was to analyze the tolerance and efficacy of full dose reirradiation combined with chemotherapy in patients with head and neck carcinoma (HNC) with a high risk of recurrence after salvage surgery. METHODS: Between 1991 and 1996, 25 patients having a recurrence or a second primary tumor in a previously irradiated area (> 45 grays [Gy]) were entered in this prospective study. All of them received salvage surgery and had a positive surgical margin and/or lymph node involvement with capsular rupture (N+R+). Adjuvant radiochemotherapy was given, delivering 60 Gy per 30 fractions with concomitant hydroxyurea and 5-fluorouracil. The median total cumulative dose of the 2 irradiations was 118 Gy. The median follow-up after the second irradiation was 66 months. RESULTS: During the reirradiation course, Grade 3 and 4 mucositis were observed in 40% and 12%, respectively. Analysis of late effects (> 6 months after reirradiation) showed that 16% of the patients had osteoradionecrosis and 40% had Grade 2-3 cervical fibrosis (Radiation Therapy Oncology Group scoring system). The patterns of failure were as follows: local only (n = 9), lymph node only (n = 2), local and lymph node only (n = 1), and metastatic (n = 4). The 4-year survival rate after reirradiation was 43% (95% confidence interval, 25-62). CONCLUSIONS: Full dose reirradiation combined with chemotherapy after salvage surgery in high risk patients with HNC was feasible with an "acceptable" toxicity and led to a relatively good 5-year survival rate. These results prompted the authors to initiate a multicentric randomized trial that is ongoing (GETTEC-GORTEC 99-01) to evaluate the benefit of adjuvant radiochemotherapy in these types of patients.

Adenocarcinoma↗
PubMed2001

BCR-ABL down-regulates the DNA repair protein DNA-PKcs.

This study demonstrates in both stable and inducible BCR-ABL-expressing hematopoietic cells a down-regulation of the major mammalian DNA repair protein DNA-PKcs by BCR-ABL. Similar results were found in BCR-ABL CD34(+) cells from patients with chronic myelogenous leukemia (CML). DNA-PKcs down-regulation is a proteasome-dependent degradation that requires tyrosine kinase activity and is associated with a marked DNA repair deficiency along with increased sensitivity to ionizing radiation. The conjunction of a major DNA repair deficiency and a resistance to apoptosis, both induced by BCR-ABL, provides a new mechanism to explain how secondary genetic alterations can accumulate in CML, eventually leading to blast crisis. The down-regulation of DNA-PKcs was reversible in CD34(+) CML cells suggesting that this approach might offer a novel and powerful therapeutic strategy in this disease, especially to delay the blast crisis. (Blood. 2001;97:2084-2090)

Acetylcysteine↗
PubMed2001

Individual patient-versus literature-based meta-analysis of survival data: time to event and event rate at a particular time can make a difference, an example based on head and neck cancer.

The objective of this study is to compare the results of an individual patient-based and a literature-based meta-analysis in chemotherapy in head and neck cancer and to identify the sources of difference. For all head and neck cancer randomized controlled clinical trials comparing chemotherapy and loco-regional treatment with loco-regional treatment alone, both the literature data and the individual patient data are retrieved and meta-analyses performed and compared. Only survival data are used as outcome, although both time to death and mortality at specific time points are considered in different analyses. There are substantial differences between the individual patient-based and the literature-based meta-analyses. The most important reason for the differing results is that the individual patient-based meta-analysis is based on a time to event analysis, whereas the literature-based meta-analysis is based on mortality at a specific time point. Mortality can change substantially with follow-up time. The absolute survival differences in the case study, for instance, increase from 2.6% at 2 years to 5.6% at 5 years.

Antineoplastic Agents↗
PubMed2001

[Method of radiotherapy planning for head and neck tumors using simulated CT images and radiographic data, developed at the Gustave Roussy Institute].

The paper deals with the recent improvements introduced in the most usual method applied in the Institut Gustave Roussy radiotherapy department for obtaining the anatomical data of patients treated for head and neck tumors. For each of these patients, five to seven transverses slices and a lateral radiographic film are taken from a Mecaserto simulator-CT. The anatomical representation of the patient sagittal plane is carried out from the digitalisation of the radiographic film on a Vidar Vxr-12 Plus film scanner and integrated into the Dosigray dose calculation programme in order to be used as a support for the laying out of the dose distribution in reference to the treatment. The sagittal anatomical representation obtained from the radiographic film digitalisation is compared with the one resulting from the interpolation between a limited number of irregularly-spaced transverse slices taken on the simulator-CT. The method using the simulator-scanner transverse slices and the radiographic film digitalisation represents an interesting alternative for obtaining an anatomy simulation representative of the patient in hospitals where a scanner is not available full-time for the needs of the radiotherapy process.

Cancer Care Facilities↗
PubMed2001

Antiviral approaches for cancers related to Epstein-Barr virus and human papillomavirus.

Epstein-Barr virus and human papillomaviruses (HPV) are DNA viruses underlying the carcinogenesis of 15-20% of human cancers worldwide. Viral oncoproteins are involved in malignant transformation and maintenance of the malignant phenotype, mainly through interaction between oncoproteins and products of tumour-suppressor genes. The use of vaccines to prevent the occurrence of HPV-related cancers is being investigated. Several approaches have been used to inhibit expression of viral oncoproteins. The first strategy uses antisense oligodeoxynucleotides against viral oncoproteins; downregulation of the oncoproteins can influence tumour cell growth and restore sensitivity to cytotoxic agents. Another approach uses antiviral drugs such as acyclic nucleoside phosphonates; inhibition of virus replication can lead to downregulation of viral oncoproteinsand ultimately reactivate tumour-suppressor-gene pathways. In addition, the combination of acyclic nucleoside phosphonates with conventional cytotoxic agents is more effective than either agent alone. These data provide the basis for a novel anticancer strategy to improve the therapeutic ratio in virus-related cancers, which needs to be further investigated for clinical applications.

Antineoplastic Agents↗
PubMed2001

The olivacine S16020 enhances the antitumor effect of ionizing radiation without increasing radio-induced mucositis.

The combination of a novel topoisomerase II inhibitor, S16020, and ionizing radiation (IR) was investigated with the aim of assessing normal tissue tolerance using a mouse mucosal lip model and antitumor activity in a human carcinoma (HEP2) cell line. No increase of acute mucosal reactions was seen when combining S16020 with IR as compared with IR alone. Using clonogenic cell survival assay, a marked enhancement of HEP2 cell killing was found when S16020 was combined with irradiation. Additional in vivo combination of S16020-IR was able to increase markedly the antitumor efficacy as compared with S16020 or irradiation alone. Interestingly, the radiosensitization effect in vivo was observed at relatively low and nontoxic concentrations of S16020, and no dose-effect relationship was found beyond 30 mg/kg. In conclusion, the combination of IR and S16020 seems promising to enhance antitumor activity without increasing deleterious effect in normal tissues and to provide the basis for a new radio-chemotherapy combination.

Animals↗
PubMed2000

A Ku80 fragment with dominant negative activity imparts a radiosensitive phenotype to CHO-K1 cells.

DNA non-homologous end joining, the major mechanism for the repair of DNA double-strands breaks (DSB) in mammalian cells requires the DNA-dependent protein kinase (DNA-PK), a complex composed of a large catalytic subunit of 460 kDa (DNA-PKcs) and the heterodimer Ku70-Ku80 that binds to double-stranded DNA ends. Mutations in any of the three subunits of DNA-PK lead to extreme radiosensitivity and DSB repair deficiency. Here we show that the 283 C-terminal amino acids of Ku80 introduced into the Chinese hamster ovary cell line CHO-K1 have a dominant negative effect. Expression of Ku(449-732) in CHO cells was verified by northern blot analysis and resulted in decreased Ku-dependent DNA end-binding activity, a diminished capacity to repair DSBs as determined by pulsed field gel electrophoresis and decreased radioresistance determined by clonogenic survival. The stable modifications observed at the molecular and cellular level suggest that this fragment of Ku80 confers a dominant negative effect providing an important mechanism to sensitise radioresistant cells.

Animals↗
PubMed2000

Radiation-induced expression of functional Fas ligand in EBV-positive human nasopharyngeal carcinoma cells.

Ionizing radiation remains a major therapeutic tool against human cancers, especially epithelial tumors, which account for the majority of human malignancies. Although Fas and Fas-L are essential determinants of apoptosis, few data support their role in the cytotoxic effect of ionizing radiation. Epstein-Barr-virus (EBV)-positive nasopharyngeal carcinoma (NPC) were chosen to address this question owing to their known sensitivity to ionizing radiation and their constitutive expression of the Fas-receptor. We here report that, in xenografted NPC cells, Fas-L expression, which was very low in basal conditions, was dramatically increased by tumor irradiation. Both the Fas receptor and the Fas ligand were found to be functional in this model, and a high proportion of irradiated NPC cells underwent apoptosis following tumor irradiation. Induction of Fas-L expression and apoptosis were observed for doses as low as 2 Gy. These data show an increase in Fas-L expression upon irradiation exposure, and strongly suggest that, in some epithelial malignancies, Fas-mediated apoptosis can play a major role in the anti-tumor effect of ionizing radiation, in the range of doses used for therapeutic applications.

Animals↗
PubMed2000

Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer.

BACKGROUND: Despite more than 70 randomised trials, the effect of chemotherapy on non-metastatic head and neck squamous-cell carcinoma remains uncertain. We did three meta-analyses of the impact of survival on chemotherapy added to locoregional treatment. METHODS: We updated data on all patients in randomised trials between 1965 and 1993. We included patients with carcinoma of the oropharynx, oral cavity, larynx, or hypopharynx. FINDINGS: The main meta-analysis of 63 trials (10,741 patients) of locoregional treatment with or without chemotherapy yielded a pooled hazard ratio of death of 0.90 (95% CI 0.85-0.94, p<0.0001), corresponding to an absolute survival benefit of 4% at 2 and 5 years in favour of chemotherapy. There was no significant benefit associated with adjuvant or neoadjuvant chemotherapy. Chemotherapy given concomitantly to radiotherapy gave significant benefits, but heterogeneity of the results prohibits firm conclusions. Meta-analysis of six trials (861 patients) comparing neoadjuvant chemotherapy plus radiotherapy with concomitant or alternating radiochemotherapy yielded a hazard ratio of 0.91 (0.79-1.06) in favour of concomitant or alternating radiochemotherapy. Three larynx-preservation trials (602 patients) compared radical surgery plus radiotherapy with neoadjuvant chemotherapy plus radiotherapy in responders or radical surgery and radiotherapy in non-responders. The hazard ratio of death in the chemotherapy arm as compared with the control arm was 1.19 (0.97-1.46). INTERPRETATION: Because the main meta-analysis showed only a small significant survival benefit in favour of chemotherapy, the routine use of chemotherapy is debatable. For larynx preservation, the non-significant negative effect of chemotherapy in the organ-preservation strategy indicates that this procedure must remain investigational.

Antineoplastic Agents↗
PubMed2000

A randomized study of very accelerated radiotherapy with and without amifostine in head and neck squamous cell carcinoma.

PURPOSE: The aim of this study was to assess whether amifostine could minimize acute mucositis induced by a very accelerated irradiation regimen in patients with advanced head and neck squamous cell carcinoma (HNSCC). METHODS AND MATERIALS: Between May 1996 and February 1998, 26 patients with an inoperable nonmetastatic Stage IV HNSCC were entered in this study. The treatment consisted of very accelerated radiotherapy given 64 Gy in 3.5 weeks. The patients were randomized to receive or not 150 mg/m(2), amifostine (Ethyol, U.S. Bioscience) 15-30 min prior to each radiation session. RESULTS: Of the 13 patients who received amifostine, definitive interruption of amifostine occurred in 5 cases (38%), due to tolerance problems (vomiting, liver enzyme elevation, generalized erythema). The distribution of Grade 4 mucositis (WHO) was 1 case versus 8 cases, with and without amifostine, respectively. The mean duration of "at least Grade 3" mucositis (WHO) was 25.1 days versus 49.2 days with and without amifostine (p = 0.03). In the amifostine group, 11/13 of the patients required a feeding tube (nasogastric tube or medical gastrostomy), because of acute mucositis, whereas in the control group a feeding tube was necessary in all cases. The mean duration of the use of this feeding tube was 1 month versus 2.5 months with and without amifostine respectively (p < 0.01). Local-regional control was not different between both arms with a median follow-up of 15 months. CONCLUSION: Despite the limited number of patients, this pilot randomized study suggests that amifostine was able to markedly reduce the severity and duration of mucositis induced by very accelerated radiotherapy. However, the tolerance of this twice daily amifostine schedule was relatively poor.

Adult↗
PubMed2000

Radiotherapy in head and neck cancer in the elderly: a challenge.

Elderly patients represent the most rapidly growing subgroup of the patient population in France and in the majority of industrialized countries. The effect of age in terms of the prognosis and response to treatment remains unclear. The management strategy (curative versus palliative) for head and neck cancer in the elderly has given vent to divergent opinions and controversies in several respects (the type and quality of treatment, quality of life and economic consequences). This review only focuses on the radiotherapy schedule and head and neck cancers. We compare aged patients with head and neck cancer to younger patients in terms of clinical features, tumor biology, type of treatment, side effects and response. We conclude that if the patient is in a good general condition following a complete evaluation of the cancer, physicians should propose curative treatment with radiotherapy because retrospective trials demonstrate that response in older patients when treated aggressively is comparable to that of younger patients. However, specific trials concerning aged patients with head and neck cancer, quality of life and radiotherapy are warranted.

Age Factors↗
PubMed2000

Transfer of Ku86 RNA antisense decreases the radioresistance of human fibroblasts.

Ku86 has been shown to be involved in DNA double-strand break (DSB) repair and radiosensitivity in rodents, but its role in human cells is still under investigation. The purpose of this study was to evaluate the radiosensitivity and DSB repair after transfection of a Ku86-antisense in a human fibroblast cell line. Simian virus 40-transformed MRC5V1 human fibroblasts were transfected with a vector (pcDNA3) containing a Ku86-antisense cDNA. The main endpoints were Ku86 protein level, Ku DNA end-binding and DNA protein kinase activity, clonogenic survival, and DSB repair kinetics. After transfection of the Ku86-antisense, decreased Ku86 protein expression, Ku DNA end-binding activity, and DNA protein kinase activity were observed in the uncloned cellular population. The fibroblasts transfected with the Ku86-antisense showed also a radiosensitive phenotype, with a surviving fraction at 2 Gy of 0.29 compared with 0.75 for the control and 20% of unrepaired DSB observed at 24 hours after irradiation compared with 0% for the control. Several clones were also isolated with a decreased level of Ku86 protein, a surviving fraction at 2 Gy between 0.05 and 0.40, and 10-20% of unrepaired DSB at 24 hours. This study is the first to show the implication of Ku86 in DSB repair and in the radiosensitivity of human cells. This investigation strongly suggests that Ku86 could constitute an appealing target for combining gene therapy and radiation therapy.

Amino Acid Sequence↗
PubMed2000

p53-dependent G2 arrest associated with a decrease in cyclins A2 and B1 levels in a human carcinoma cell line.

In vivo transfer of wild-type (wt) p53 gene via a recombinant adenovirus has been proposed to induce apoptosis and increase radiosensitivity in several human carcinoma models. In the context of combining p53 gene transfer and irradiation, we investigated the consequences of adenoviral-mediated wtp53 gene transfer on the cell cycle and radiosensitivity of a human head and neck squamous cell carcinoma line (SCC97) with a p53 mutated phenotype. We showed that ectopic expression of wtp53 in SCC97 cells resulted in a prolonged G1 arrest, associated with an increased expression of the cyclin-dependent kinase inhibitor WAF1/p21 target gene. A transient arrest in G2 but not in G1 was observed after irradiation. This G2 arrest was permanent when exponentially growing cells were transduced by Ad5CMV-p53 (RPR/INGN201) immediately after irradiation with 5 or 10 Gy. Moreover, levels of cyclins A2 and B1, which are known to regulate the G2/M transition, dramatically decreased as cells arrived in G2, whereas maximal levels of expression were observed in the absence of wtp53. In conclusion, adenoviral mediated transfer of wtp53 in irradiated SCC97 cells, which are mutated for p53, appeared to increase WAF1/p21 expression and decrease levels of the mitotic cyclins A2 and B1. These observations suggest that the G2 arrest resulted from a p53-dependent premature inactivation of the mitosis promoting factor.

Adenoviridae↗
PubMed2000

Decreased DNA-PK activity in human cancer cells exhibiting hypersensitivity to low-dose irradiation.

Low-dose hyper-radiosensitivity (HRS) (below 0.5 Gy) has been extensively documented in the past few years. The molecular basis of this phenomenon remains largely unknown and the purpose of this study was to investigate the possible implication of the DNA repair DNA-PK complex. The activity of the DNA-PK complex, i.e. Ku DNA-end binding activity and kinase activity of the whole complex, was studied in 10 human cancer cell lines, 2 h after 0.2, 0.5 and 1 Gy irradiation. After low-dose irradiation (0.2 Gy), a marked decrease in DNA-PK activity was found in all six cell lines exhibiting HRS, whereas the DNA-PK activity was increased in the four cell lines which did not exhibit HRS. This modulation of DNA-PK activity was a rapid phenomenon occurring within the 2 h following low-dose radiation exposure. These data strongly suggest the implication of the DNA-PK repair complex in the HRS phenomenon.

Amino Acid Sequence↗
PubMed2000

[Biomodulation and radiotherapy].

Recent improvement in the understanding of the mechanisms involved in the response to ionizing radiation have made it possible to identify new therapeutic targets to increase the anti-tumor efficacy or, alternatively, to decrease the effect on normal tissues. These approaches included targeting genes involved in the regulation of radio-induced DNA-repair and cell death as well as genes involved in the regulation of radio-induced apoptosis. Many other molecular targets have been recently identified to potentially interfere with the response to ionizing radiation, such as some cell membrane growth factor receptors (EGFr, TGFb) or molecules involved in intra-cellular signal transduction pathways, cell cycle regulation, etc. In addition, other promising ways to modulate radiation-induced response concern extracellular or tissue factors such as hypoxia and angiogenesis.

Antineoplastic Agents↗