Gerard Milano

..Reliable predictive tools are needed to apply these treatments for potentially sensitive tumors only. This review underlines the lack of clinically-validated tools so as to provide a firm answer to this crucial question...

..The lack of knowledge on resistance mechanisms to EGFR targeting is also a difficulty for an optimal development of EGFR targeting in the clinics...

..The new possibilities are to achieve pharmacomodulation of oral fluoropyrimidines, notably for UFT and capecitabine, that open up the prospect of establishing significant novel treatment protocols based on drug combinations...

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..Clinical trials are in progress so as to validate the clinical usefulness of these germinal genetic analyses so as to select treatments/doses adapted to individual profiles...

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..These experimental data were recently confirmed at the clinical level in locally advanced head and neck cancer...

..Several mechanisms have been discussed (alteration od DNA damage repair, facilitation of apoptosis, inhibition of tumour repopulation) and justify the current clinical trials combining these drugs and radiotherapy...

..Relationships between K-Ras mutations and EGFR status have not been examined so far. We analyzed relationships between K-Ras mutations and EGFR tumoral status based on EGFR germinal polymorphisms, gene copy number and expression...

..Because combinations of anti-EGFR with 5-fluorouracil (5-FU)-based chemotherapy are promising treatments, we analyzed the effect of K-Ras mutations in patients having received exclusive 5-FU therapy...

..The present data indicate that there is no redundancy in targeting the same angiogenic pathway with the presently tested clinically applicable drugs. The study provides a strong rationale for future clinical trials...

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..The aim of the study was to evaluate the anti-tumor activity of the association of Cet with TPF. In addition, the potential benefit from adding bevacizumab (Bev), an anti-VEGF monoclonal antibody, was examined...

..WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Numerous clinical studies, including a few prospective ones, have reported conflicting results on the impact of gene polymorphisms related to fluorouracil (FU) and oxaliplatin pharmacodynamics...

..These results suggest that temsirolimus exhibits synergistic antiproliferative effects when administered in combination with irradiation, anti-EGFR and anti-angiogenic therapies in head and neck cancer patients...

..Genes for which polymorphisms may potentially influence pharmacodynamics of fluoropyrimidines, including capecitabine, are thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), and dihydropyrimidine dehydrogenase (DPD)...

..These discrepancies may result from the interpatient variability arising from the individual folate status, as well as from the limited role of fluoropyrimidines in the current chemotherapy regimen administered in colorectal cancer...

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..As these innovative molecules start to be used in clinical practice, the identification of predictive markers for efficacy and toxicity becomes a crucial issue...

..The aim of the present study was to analyze the influence of VEGF-A gene polymorphisms on tumoral VEGF-A expression and to test their prognostic value in head and neck cancer patients...

..Whatever the drug, TS decreased tumor re-growth more efficiently than CS. This new drug schedule could be of interest in the management of anti-EGFR based therapies in H&N cancer...

..The results suggest that MTHFR genotypes are relevant and independent factors of patient outcome in 5FU-based treatment of advanced colorectal cancer...

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..The aim of this review article is to compare at both experimental and clinical levels the key points which govern the activity of these two types of targeting agents...

..To our knowledge, the only study reporting on the time dependency of UFT pharmacokinetics is a phase I study by Muggia et al...

..These preliminary findings strongly suggest that these observations could be new mechanisms in the development of acquired drug resistance in pancreatic cancer cells...

..So far there are no relationships between intracellular levels of F-ara-CTP and response to treatment...

..Here we tried to decipher the molecular mechanisms implicated in Sp3 accumulation observed in aggressive tumours...

..We therefore prospectively tested the impact of these five gene polymorphisms (blood DNA) on the pharmacodynamics of bevacizumab-based treatment administered in metastatic breast cancer patients...

..This assay was selective and sensitive enough (limit of detection approximately 1 ng/ml) to quantify minimal concentrations at steady state (Css min) of sunitinib and SU12662 in treated patients...

..The efficacy of the combination of bevacizumab+erlotinib and RT may be of clinical importance in the management of head and neck cancer patients...

..Real time RT-PCR and immunohistochemical analyses will be performed on selected genes. Finally, biological mechanisms will be investigated to look for new therapeutic targets...

..Active and efficient clinical research is currently ongoing to determine the place of molecular targeted therapies in the treatment of head and neck cancer, particularly in association with radiotherapy...

..Three days after tumor cell injection, sunitinib (20 mg/kg, p.o.), cetuximab (1 mg/kg, i.p.), both 5 days/week seven doses, and RT (6 Gy, 3 days/week, four doses) were administered alone and in combination during 9 days...

..To examine the impact of a frequent her2 gene polymorphism (Ile655Val) on tumor growth and on the pharmacodynamics of treatment by trastuzumab...

..As rectal cancer is presenting many different clinical situations, an individualised treatment appears justified...

..It also supports the notion of antitumour supra-additivity when combining gefitinib and ZD6126, and identifies neoangiogenesis as the main determinant of this synergistic combination...

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..68 for T staging and 2.65 for EGFR. Overall, EGFR remained an independent prognostic factor when response to treatment and T staging were considered in the multivariate analysis...

..The ELISA developed in the present study is thus an interesting alternative to other analytical methods used to measure HIF-1alpha protein levels and should be useful in preclinical pharmacological studies targeting HIF-1alpha...

..The occurrence of cardiac toxicity was relatively rare (1 out of 19, 5%). These data suggest that women are particularly prone to DPD deficiency and allow a more precise definition of the DD toxicity profile...

..7% in the PK-arm. The present study is the first to demonstrate, in a randomized design, the clinical interest of an individual 5FU dose adaptation based on pharmacokinetic survey, in terms of therapeutic index improvement...

..2 and 42% and reduction of the CDDP concentration between 13.8 and 72.7%. These observations may be beneficial for the design of more rational therapeutic trials associating CDDP, 5-FU and FA...

..Optimal enzymatic conditions for DPD activity measurement were studied: incubation time, protein and 5FU concentrations. The assay was successfully cross-validated with the existing method using HPLC with radiochemical detection...

..Examples of concrete applications of this strategy will be detailled particularly for the MINDACT Trial in breast cancer and for the KRAS status in the setting of EGFR targeting therapies in advanced colorectal cancer...

..The pharmacokinetics of trabectedin has never been reported in patients with impaired renal function or in patients on hemodialysis...

..055 and 0.085 without and with FA supplementation, respectively). These results suggest for the first time a potential role of A1298C MTHFR polymorphism on fluoropyrimidine sensitivity...

..4%; 0.02 less than P less than 0.05). Pharmacokinetic follow-up of these patients has proved to be an objective means to improve therapeutic index significantly...

..This observation could help to explain the supra-additive antitumour effect produced by this combination and could provide a basis for future innovative clinical trials...

..i.d.) continuous nonaccelerated radiotherapy with concomitant cisplatin (CP)-5-fluorouracil (5-FU) chemotherapy, both given at full dose. Feasibility, efficacy, survival, and pharmacokinetic-pharmacodynamic relationships were analyzed...

..Future research must focus on easy-to-obtain markers of specific rhythms to individualize the chronomodulated FU delivery...

..In complement to the direct antitumor effects of radiation therapy and anti-EGFR drugs, a strong antiangiogenic effect may be obtained with therapeutic strategies combining radiation therapy with EGFR and VEGFR-2 targeting agents...

..2). Results were in agreement between the two explored cell lines. The present data should be taken into account when establishing the rationale of future trials combining CPT11, LOHP and FU-FA...

..Advances in the understanding of tumor biology have led to the development of targeted therapies allowing progress in colorectal cancer treatment. One of the most promising targets is the epidermal growth factor receptor (EGFR)...

..Finally, the 5-FU-folinic acid combination could characterise a third level of pharmacomodulation where cytotoxic activity is optimised at the site of interaction between activated drug (5FdUMP) and target (thymidilate synthase)...

..A tendency suggested that the greater the p53, the shorter the progression-free survival (P = 0.076 as continuous and 0.069 as dichotomous)...

..CONCLUSIONS: The Chatelut carboplatin clearance model established for conventional carboplatin dosages (>100 mg/m(2)) is not applicable for targeting low AUC (<1 mg x min/ml)...

..The aim of this study was to test a novel rational therapeutic approach by combining docetaxel with an EGFR-targeting agent (cetuximab) and with an anti-angiogenic agent (sunitinib, SUTENT)...

..The first intron of EGFR gene is polymorphic (9-23 CA repeats) and transcription declines when the number of repeats increases...

..This observation may serve as a preclinical rationale for a next step testing the Taxotere-capecitabine combination at the clinical level in prostate cancer patients...

..This observation may have important clinical consequences such as a possible local pharmacological inhibition of TP for controlling HFS...

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..However, their effectiveness in improving minor depressive disorders and cancer-related fatigue has not been proved yet...

..The fact that oxaliplatin may reduce 5-fluorouracil catabolism could be central in explaining the supra-additive interaction between these drugs...

..Maximal tolerated doses have been highed and anti-tumour activity also. But 30% patients have toxicities expressed by mucositis in oral mucosa...

..We investigated whether circulating tumor cells (CTCs) and circulating endothelial cells (CECs) predict clinical outcome of first-line chemotherapy combined with bevacizumab in metastatic breast cancer patients...

..We analyzed the efficacy of using cytosine deaminase-bearing cancer cells as an autologous tumor vaccine in a rat model that mimics liver metastasis from colon carcinoma...

..These results, revealing the existence of a circadian rhythm in DPD expression, should stimulate further studies to enhance our understanding of the molecular mechanisms involved in the circadian regulation of the DPD enzyme...

..Using multivariable analysis, only histological grade, tumor size and node status remained independent predictors of survival. CONCLUSION: EGFR determination is of limited value as a prognostic indicator in breast cancer...

..In postmenopausal EM patients, tamoxifen may be as efficient as AI. In post-menopausal PM patients, a switch strategy may be inferior to a 5-year IA strategy, which would therefore be the standard of care...

..28, p < 0.001). In addition, when tumors were stratified according to SPF quartile values, there were statistically different overall survival curves in patients with small tumors (< 2 cm) and in axillary node-negative patients...

..The clinic and symptoms of hand-foot syndrome as the biological interpretation, the symptomatic treatment and the impact on the specific treatment of sorafenib are developed...

..Presence of the d-form had no influence on the MTX rescue capacity of the I-form; this suggests that the presence of the d-FA is unlikely to have any significant clinical consequences...