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F Lerebours

Publications and source records attributed to F Lerebours.

18 recordsLinked to original sources
PubMed2002

Effect of mutated TP53 on response of advanced breast cancers to high-dose chemotherapy.

TP53 activation by genotoxic drugs can induce apoptosis or cell-cycle arrest. Thus, whether the gene is mutated or wild type could affect the response of a tumour to chemotherapy. Clinical data are unclear, possibly as a result of heterogeneity of tumours, drugs, methods of assessing response, or TP53 status. We studied 50 non-inflammatory, locally advanced breast cancers that had been treated with high doses of a combination of epirubicin and cyclophosphamide. We noted eight complete responses, which all occurred in the 14 patients with tumours containing mutated TP53 (p<0.0001). In high-grade, advanced breast cancers, inactivation of the TP53 pathway could greatly improve the response to this chemotherapy regimen.

Adult↗
PubMed2002

Real-time reverse transcription PCR assay of CYP19 expression: application to a well-defined series of post-menopausal breast carcinomas.

Aromatase, the product of the CYP19 gene, plays a key role in androgenic steroids transformation into estrogens from various hormonal sensitive tissues. Thus, in situ expression of CYP19 has been suggested to be involved in breast tumor growth especially in post-menopausal patients.We developed a real-time quantitative RT-PCR assay based on fluorescent TaqMan methodology to quantify total CYP19 gene expression at the mRNA level in breast tumors. This method, based on nucleic acid quantification in homogeneous solutions, has the potential to become a standard in terms of its sensitivity, wide dynamic range and high-throughput capacity. In a well-defined series of 107 post-menopausal breast tumor samples, relative CYP19 mRNA levels ranged from 1 to 131. Among the four major CYP19 exon I-spliced transcripts, designated I.a, I.b, I.c and I.d, mRNA levels of the latter three correlated positively with total CYP19 mRNA levels. In ER alpha-positive breast tumors, CYP19 and ER alpha mRNA levels correlated negatively with each other (P=0.0078, r=-0.266), while CYP19 and ER beta mRNA levels correlated positively (P=0.00012, r=+0.388). Patients with high CYP19 mRNA levels did not relapse more frequently or have shorter relapse-free survival than other patients. Finally, mRNA levels of IL6, a major CYP19 regulatory factor, were significantly higher in tumors strongly expressing CYP19 than in tumors weakly expressing CYP19 (P=0.018). In conclusion, CYP19 expression did not influence the outcome of post-menopausal patients with breast cancer.

Aged↗
PubMed2002

Molecular alterations in sporadic breast cancer.

Breast cancer is a genetic disease. Like other human cancers, it is thought to occur as the result of progressive accumulation of genetic aberrations. These aberrations result in a deviation of the gene expression profiles from that of the normal progenitor cell. In up to 99% of cases, breast cancer is due to solely somatic genetic aberrations without germ-line ones. Considerable progress have already been made in understanding the genetic mechanisms underlying the development and progression of breast cancer. Several extensively studied genes are now well known to be involved. Unfortunately, our ability to make clinically useful interventions on the basis of these data is limited. Because of the involvement of multiple genes and complex pathways in a single cancer cell, the molecular dysfunctioning underlying breast cancer remains to be completely clarified. In a next future, studying the global gene expression of different types of tumors will allow the development of expression profiles unique for a breast cancer, its stage and prognostic category, leading to diagnostic assays and the identification of new therapeutic targets.

Breast Neoplasms↗
PubMed2001

ERBB2 status and benefit from adjuvant tamoxifen in ERalpha-positive postmenopausal breast carcinoma.

We examined the relation between ERBB2 gene expression (as determined by a real-time quantitative RT-PCR assay) and the response to adjuvant tamoxifen therapy in a well-defined cohort of 125 ERalpha-positive postmenopausal patients with breast cancer. Although ERBB2 overexpression was associated with shorter relapse-free survival in univariate analysis (P=0.00029), ERBB2 did not persist as an independent prognostic factor in multivariate analysis. Nevertheless, when we analyzed the ERBB2 mRNA level as a continuous variable, the higher the ERBB2RNA level, the poorer the outcome (P=0.00036). The results point to the need for a quantitative ERBB2 expression assay for use in future studies of ERBB2-based clinical management of breast cancer.

Aged↗
PubMed2001

High-dose sequential epirubicin and cyclophosphamide with peripheral blood stem cell support for advanced breast cancer: results of a phase II study.

The aim of this study was to evaluate the feasibility of a high-dose intensity and high-dose density multicycle epirubicin and cyclophosphamide regimen with peripheral blood stem cells (PBSC) and haematopoietic growth factor (G-CSF) support in advanced breast cancer patients. From August 1994 to September 1999, 56 breast cancer patients (8 stage IIIB and 48 stage IV) received 205 courses of cyclophosphamide 3 g x m(-2) and epirubicin 100 mg x m(-2) every 14 days. G-CSF 5 microg x kg(-1) x day(-1) was administered from day 3 to neutrophil recovery. 4 courses were planned. PBSC were collected after course 1, and reinfused after courses 3 and 4, with > or = 2 x 10(6) CD34+ PBSC x kg(-1) required for each reinfusion. 48 patients (86%) received all 4 planned courses. Early withdrawal was consecutive to infectious complications (n = 4), severe asthenia (n = 3), haemorrhagic cystitis (n = 1). A median number of 10.8 x 10(6) CD34+ PBSC x kg(-1) (range, 3-80) was harvested with 1 or 2 apheresis in 48 patients (94%). Median relative dose intensity was 91.3% (range, 72-102%). Grade 4 neutrophil toxicity was observed in 100% of patients. Febrile neutropenia was observed in 40% of courses (median duration 2 days). Red blood cells and platelets had to be transfused in 54% and 27% of courses, respectively. There were no toxic deaths. Objective response rate was 69% in stage IV patients (31/45 evaluable pts), with a 16% complete response rate. Their median progression-free and overall survivals were 22.5 and 37 months, respectively. This epirubicine-containing high-dose regimen appeared feasible, albeit with high toxicity. Time-related progression parameters exceed commonly reported ones. Controlled studies of upfront sequential high-dose chemotherapy are still needed to evaluate its real benefit.

Adult↗
PubMed2001

Allelic loss detection in inflammatory breast cancer: improvement with laser microdissection.

Solid tumors are composed not only of tumor cells but also of stromal nonneoplastic cells. In whole tumor samples, stromal cells retaining their alleles may therefore obscure detection of loss of heterozygosity (LOH) in tumor cells. An increasing number of studies have used laser-assisted tissue microdissection to improve LOH detection, but the real gain in sensitivity has been poorly quantified. We studied a group of 16 inflammatory breast carcinomas that were submitted to both standard DNA extraction from frozen whole tumor samples and laser microdissection performed on paraffin-embedded tumor samples. Using PCR with fluorescence-labeled primers, we comparatively analyzed ten polymorphic markers with both sources of DNA. With the LOH detection threshold set at -25%, we showed that 25 LOHs could not be diagnosed with whole tumor samples out of 73 LOHs positively diagnosed in microdissected samples (34%). With the LOH detection threshold set at -50%, the respective figures were 39 LOHs not diagnosed out of 55 LOHs (71%). Measuring the intensity of the allelic decrease, we showed that the mean decrease of the lost allele is -34% with whole tumor samples and -67% with microdissected samples. The increase in sensitivity of LOH detection with microdissection is associated with the density of stromal cells. This strong improvement in LOH detection in this aggressive type of breast cancer indicates that many other molecular studies performed on heterogeneous solid tumors may benefit from a first step of laser microdissection.

Breast Neoplasms↗
PubMed1999

Fine deletion mapping of chromosome 8p in non-small-cell lung carcinoma.

Several somatic genetic alterations have been described in non-small-cell lung carcinomas (NSCLC). Recurrent chromosomal deletions have suggested the presence of tumor-suppressor genes specifically involved in lung carcinogenesis. For one of these, 2 non-overlapping regions have been proposed on the short arm of chromosome 8, encompassing the LPL and NEFL genes. The LPL region has been extensively studied in NSCLC and other cancer types. Two genes, N33 and PRLTS, have been identified, but the small number of mutations excludes their involvement in the vast majority of tumors. In order to delineate a reliable region of deletional overlap on chromosome 8p in NSCLC, a series of 77 NSCLC was studied for 34 microsatellite polymorphisms distributed on chromosome 8p, using multiplex-PCR amplification. After purification of tumor nuclei by flow cytometry based on either the abnormal DNA index or the presence of a high expression of cytokeratin, allelic losses on chromosome 8p were observed in 39% of cases. Measurement of DNA index showed that 62% of tumors were hyperploid; allelic losses were more frequent in hyperploid than in diploid tumors (54% vs. 14%; p < 10(-4)). Deletions of part of the short arm were observed in 7 instances. Our data allow definition of an interval of common deletion, flanked by the loci D8S511 and D8S1992, where the putative tumor-suppressor gene might be localized.

Carcinoma, Non-Small-Cell Lung↗
PubMed1999

Deletion mapping of the tumor suppressor locus involved in colorectal cancer on chromosome band 8p21.

Several somatic genetic alterations have been described in colorectal carcinoma (CRC). Recurrent chromosomal deletions have suggested the presence of tumor suppressor genes (TSG) specifically involved in colorectal carcinogenesis. For one of them, two non-overlapping regions have been proposed on the short arm of chromosome 8, encompassing the LPL and NEFL genes. The short arm of chromosome 8 has been extensively studied in colorectal cancer and in other cancer types. Both regions have been reported as candidate loci for a TSG. In order to delineate a reliable region of deletional overlap on chromosome arm 8p in CRC, a series of 365 CRC samples was selected for the absence of microsatellite instability (RER, replication error); tumor and normal matched DNAs were studied for 54 microsatellite polymorphisms distributed on 8p using multiplex-PCR amplification. After purification of tumor nuclei by flow cytometry based on either the abnormal DNA index or the presence of a high expression of cytokeratin, complete allelic losses on 8p were observed in 48% of cases. Measurement of the DNA index showed that 88% of RER tumors were hyperploid. Complete allelic losses of only part of the short arm were observed on 26 occasions. These data allowed us to define a 1 cM interval of common deletion, flanked by the loci D8S1771 and NEFL, where a putative TSG may be localized.

Animals↗
PubMed1999

Optimizing chemotherapy for patients with advanced breast cancer.

Chemotherapy is offered to almost all patients with metastatic breast cancer. Optimization of treatment has four major goals: (1) To improve access to chemotherapy. Orally active chemotherapy is an attractive option for those patients when access to hospital is limited by financial considerations, long journeys or patient reluctance. In the past, only alkylating agents (cyclophosphamide, chlorambucil, melphalan) could be administered orally. The activity (first- and second-line) of Xeloda (capecitabine) with limited side effects and the development of oral vinorelbine and anthracyclines should improve access to chemotherapy and also concentrate further interest on treatment with long-term administration of cytotoxic agents. (2) To improve response rates and duration in first-line treatment. Response rates have been increased by the use of combinations of taxoids and anthracyclines and/or alkylating agents and/or fluoropyrimidines (>60-70% with complete remission in 10-15% of patients). There is increasing interest in sequential use of active agents or combinations at their optimal doses. Nevertheless, such 'induction regimen' fail to prolong response duration (rarely longer than 9-12 months). The use of less-toxic maintenance chemotherapy regimens increases response duration and disease-free survival. Such maintenance regimens could be used on an outpatient basis and will be further simplified by the availability of active oral agents such as the novel fluoropyrimidine Xeloda. (3) To increase cure rates. This can only be considered with first-line treatment in selected patients (long disease-free interval, minimal number of visceral sites and ability to tolerate high-dose chemotherapy). The completed studies with high-dose chemotherapy and hematopoietic stem cell support have, in fact, shown only a minimal effect on cure rates. Incorporation of very active agents such as taxoids and use of multicycle high-dose therapy may improve these results. (4) To offer alternative active regimens in second and subsequent metastatic progression. Taxoids, vinorelbine and, more recently, Xeloda all achieve a 20-40% response rate in these situations. The reintroduction of agents previously used for adjuvant or first-line therapy can also be considered.

Administration, Oral↗
PubMed1998

[Clinical activity spectrum of irinotecan].

Irinotecan (CPT11), a topoisomerase I inhibitor, is a new cytotoxic agent with a broad spectrum of clinical activity. Two main schedules have been studied and produce similar activity and side-effects: the "european" one--350 mg/m2 every 21 days-, and the "japanese-north american" one where CPT11 is given at a weekly dose of 100-120 mg/m2 for 4 consecutive weeks followed by a 2 week rest period. Activity was initially characterized in advanced colorectal cancers; response rates, disease free-survival and overall survival were 11%, 7-10 months and 8-11 months in patients failing fluoropyrimidine based chemotherapy--statistically improved as compared to best supportive care and infusional fluorouracil-, and 20-30% in patients not previously treated. An interesting activity with response rates of 20-22% (increased to 65% in combination with CDDP) has been shown in relapsed cervix carcinomas; in gastric carcinomas response rates of 20% have been shown, reaching 48% in combination with CDDP. Response rates of 20-22%, increased to 40-60% when irinotecan was associated to CDDP have been reported in non small cell lung cancer and esophagal carcinomas. Further studies are needed for other GI tract cancers, ovarian and head and neck carcinomas while minimal or no clinically meaningful activity has been reported in advanced breast cancer, and haematological malignancies. Irinotecan can be combined to fluoropyrimidines, raltitrexed, cisplatin, carboplatin and oxaliplatin, to gemcitabine, etoposide, vinorelbine and taxanes with flexible schedules (weekly, every 2 weeks, every 21 days. Most of these combinations have an additive or supra additive activity. Its mechanism of action, the spectrum of activity and the acceptable risk-benefit ratio point to irinorecan as a major advance in the field of cytotoxic anticancer therapy.

Adenocarcinoma↗
PubMed1997

[Localization of a tumor suppressor gene distal to D22S270 in colorectal cancers].

Recurrent allelic losses on chromosome 22q have been reported in colorectal cancer, distal to the NF2 gene, suggesting that another tumor suppressor gene might be involved. We report here the typing of 256 sporadic colorectal tumors and 18 colonic cancer cell lines using a set of chromosome 22 polymorphisms, ranging from 20 to 45. A panel of somatic cell hybrids, that allows to distinguish 11 bins in the 22q13 region, was used to localize 19 of the 45 selected markers and the putative tumor suppressor gene BZRP. Allelic-loss was observed in 43% of tumors. The minimal region of deletion that could be determined, telomeric to locus D22S270, refines significantly the position of the gene. The localization of the BZRP gene in this region led to a systematic screening for somatic point mutation. Direct sequencing of its coding sequence in 36 tumors hemizygous for chromosome 22 allowed the identification of three polymorphisms but failed to detect somatic mutation.

Adenocarcinoma↗
PubMed1995

Regulation of Ras-related RhoB protein expression during the cell cycle.

The immediate-early gene rhoB codes for a small GTP-binding protein highly homologous to the RhoA protein. While RhoA is known to regulate the assembly of focal adhesions and stress fibers in response to growth factors, the function of RhoB remains unknown. In a first attempt to elucidate its function, we examined the variation of the RhoB protein expression in response to induction of its mRNA. We report here that RhoB is an unstable protein rapidly and transiently induced by growth factors in PC12 and HeLa cells. Moreover, RhoB protein accumulation is periodic through the cell cycle. First detected at the G1/S phase transition, the level of the RhoB protein is maximal during the S phase and declines at the S/G2-M transition. This timing suggests that RhoB plays a role in the G1/S phase transition and/or in the S phase of the cell cycle. We also confirm here a vesicular and perinuclear localization of the endogenous RhoB protein induced by growth factors.

Cell Cycle↗
PubMed1995

[Towards an allotype of second generation colon cancer].

A subset of genetic alterations distinguishes two groups of colon cancers. In the first group instability of microsatellite loci due to a defective DNA mismatch repair system is observed. The second group is characterized by recurrent losses of chromosome regions, frequently associated with hyperploidization. We have developed a technique which enables a fine description of allelic losses in this second group of tumours. The typing of 278 loci in 47 hyperploid colon cancers has provided information for an average of 160 loci per tumour. The high frequency of allelic losses on chromosomes 17, 18 and 5 was confirmed thus validating our methodological approach. Several additional chromosome segments were observed lost in over 40% of the cases, suggesting that tumour suppressor genes may map within these regions. Further technical development should contribute to the identification of these genes.

Alleles↗
PubMed1987

Combined short- and long-term therapy for the treatment of cytomegalovirus retinitis using ganciclovir (BW B759U).

A total of 66 eyes in 41 patients were treated for cytomegalovirus (CMV) retinitis with a new acyclic nucleoside, ganciclovir (BW B759U). At the completion of the short-term therapy period of 21 days, 87.7% of eyes had stabilized or improved. Seventy-two percent of eyes stabilized or improved during long-term home maintenance therapy. Leukopenia and increased liver function abnormalities were the most common adverse drug reactions seen in this series. Ganciclovir dramatically improved the quality of life in these patients, but clinical evidence suggests that it is a virostatic medication requiring indefinite long-term maintenance therapy.

Acquired Immunodeficiency Syndrome↗