RÉSUMÉ
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. Worldwide progressive population aging demands consensus development for decision making when treating elderly patients. Age itself might not be a critical determinant for the selection of a therapeutic option. In the past few years, the mechanisms of hepato-carcinogenesis have been elucidated, and the involvement of a number of pathways, including angiogenesis, aberrant signal transduction, and dysregulated cell cycle control, have been demonstrated, leading to evaluation of the activity and toxicity of some of the new molecularly targeted agents. Sorafenib was demonstrated to significantly increase the survival of patients with advanced HCC in two prospective, randomized, placebo-controlled trials. Subsequently, a number of retrospective or prospective studies have indicated that the effectiveness of sorafenib therapy in the treatment of HCC is similar in elderly and non-elderly patients. The aim of this review is to describe the impact of age on the effects of sorafenib-targeted therapy in patients with HCC, and the next treatment options with new targeted agents (everolimus, tivantinib, linifanib, etc.).
Sujet(s)
Antinéoplasiques/usage thérapeutique , Carcinome hépatocellulaire/traitement médicamenteux , Tumeurs du foie/traitement médicamenteux , Thérapie moléculaire ciblée/méthodes , Nicotinamide/analogues et dérivés , Phénylurées/usage thérapeutique , Sujet âgé , Carcinome hépatocellulaire/anatomopathologie , Essais cliniques de phase III comme sujet , Humains , Tumeurs du foie/anatomopathologie , Nicotinamide/usage thérapeutique , SorafénibRÉSUMÉ
The management of hepatocellular carcinoma (HCC) has substantially changed in the past few decades, the introduction of novel therapies (such as sorafenib) have improved patient survival. Nevertheless, HCC remains the third most common cause of cancer-related deaths worldwide. Decision-making largely relies on evidence-based criteria, as showed in the US and European clinical practice guidelines, which endorse five therapeutic recommendations: resection; transplantation; radiofrequency ablation; chemoembolization; and sorafenib. However, areas still exist in which uncertainty precludes a strong recommendation, such as the role of adjuvant therapies after resection, radioembolization with yttrium-90 or second-line therapies for advanced HCC. Many clinical trials that are currently ongoing aim to answer these questions. The first reported studies, however, failed to identify novel therapeutic alternatives (that is, sunitinib, erlotinib or brivanib). Efforts that focus on the implementation of personalized medicine approaches in HCC will probably dominate research in the next decade.
Sujet(s)
Antinéoplasiques/usage thérapeutique , Carcinome hépatocellulaire/traitement médicamenteux , Tumeurs du foie/traitement médicamenteux , Inhibiteurs de l'angiogenèse/usage thérapeutique , Antinéoplasiques hormonaux/usage thérapeutique , Doxorubicine/usage thérapeutique , Humains , Thérapie moléculaire ciblée/méthodes , Essais contrôlés randomisés comme sujetRÉSUMÉ
The epidermal growth factor receptor (EGFR) inhibitor erlotinib was found to significantly improve overall survival, time to progression, and cancer-related symptoms in locally advanced or metastatic non small cell lung carcinoma (NSCLC). Unfortunately, cutaneous side effects are not rare, the most common one being a follicular acneiform eruption. As it has been observed a positive correlation between rash severity and objective tumor response, it is critical for dermatologists early distinguish it from rashes carrying a different prognosis and needing a different management.
Sujet(s)
Éruptions acnéiformes/induit chimiquement , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Tumeurs du poumon/traitement médicamenteux , Inhibiteurs de protéines kinases/effets indésirables , Quinazolines/effets indésirables , Éruptions acnéiformes/traitement médicamenteux , Administration par voie cutanée , Antibactériens/usage thérapeutique , Carcinome pulmonaire non à petites cellules/anatomopathologie , Chlorhydrate d'erlotinib , Érythromycine/usage thérapeutique , Gels , Humains , Tumeurs du poumon/anatomopathologie , Mâle , Adulte d'âge moyen , Inhibiteurs de protéines kinases/administration et posologie , Quinazolines/administration et posologie , Résultat thérapeutiqueRÉSUMÉ
BACKGROUND: Erythema multiforme (EM) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are caused by a dysregulation of cellular immunity. OBJECTIVES: To evaluate further the potential role of certain cytokines and chemokine receptors in cutaneous lesions of patients affected by EM and SJS/TEN and to establish whether such diseases are polarized preferentially towards a T-helper (Th) 1 or Th2 pattern. METHODS: Biopsy specimens from eight patients with EM, six with SJS/TEN and three healthy controls were stained for immunohistochemical examination using the alkaline phosphatase-antialkaline phosphatase method. The monoclonal antibodies used included those to tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-2, IL-5, IL-13, receptor 3 for C-C chemokines (CCR3), receptor 3 for C-x-C chemokines (CXCR3) and CXCR4. RESULTS: The SJS/TEN specimens showed significantly higher expression of all the cytokines and chemokine receptors (except CXCR3) tested than the EM specimens. Both lesional series showed significantly higher expression of all the receptors tested than the healthy control specimens, with the sole exception of a lower expression of CCR3 in EM specimens. Comparison between molecules associated with a Th1 or Th2 response revealed a predominance of Th1 response in EM and no significant imbalance between Th1 and Th2 in SJS/TEN. CONCLUSIONS: We have provided further evidence that TNF-alpha is strongly expressed in SJS/TEN lesions and therefore it may be involved in the epidermal necrosis featured in such diseases. IFN-gamma may play an important role both in EM and SJS/TEN. IL-2, IL-5 and IL-13 may contribute to the cutaneous immunoinflammation in these diseases. Chemokine receptors may be involved strongly in the recruitment of inflammatory cells in lesional skin. In our cases we found a sharp polarization towards a Th1 pattern in EM, while the SJS/TEN lesions showed a mixed Th1/Th2 pattern.
Sujet(s)
Cytokines/métabolisme , Érythème polymorphe/immunologie , Récepteurs aux chimiokines/métabolisme , Syndrome de Stevens-Johnson/immunologie , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Femelle , Humains , Techniques immunoenzymatiques , Mâle , Adulte d'âge moyen , Récepteurs CCR3 , Récepteurs CXCR3 , Récepteurs CXCR4/métabolisme , Lymphocytes auxiliaires Th1/immunologie , Lymphocytes auxiliaires Th2/immunologieRÉSUMÉ
BACKGROUND: Erythema multiforme (EM) and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) are determined by a dysregulation of cellular immunity. OBJECTIVES: To evaluate the effector role of cellular immunity and the involvement of the CD40/CD40 ligand (CD40L) system in the pathogenesis of EM and SJS/TEN. METHODS: Biopsy specimens from eight patients with EM and six with SJS/TEN were stained for immunohistochemical examination using the alkaline phosphatase/antialkaline phosphatase method. The monoclonal antibodies used included those to CD1a, CD4, CD8, CD40, CD40L, CD68, Fas, Fas ligand (FasL) and myeloperoxidase. RESULTS: The cellular infiltrate in both EM and SJS/TEN lesions was composed mainly of T lymphocytes and CD68+ macrophages. We also detected large amounts of neutrophils. Fas and FasL were very highly expressed in SJS and TEN, but weakly in EM. CD40 staining was strong in all tissue sections; there were numerous CD40L+ cells in SJS/TEN but much fewer in EM. CONCLUSIONS: Activated T lymphocytes and macrophages, but also neutrophils, are presumably the main triggers of mucocutaneous damage in the SJS/TEN disease spectrum. The Fas/FasL system is significantly expressed in SJS/TEN lesions, but not in EM, where this apoptotic pathway presumably does not play a pivotal role in the epidermal damage. We suggest that the CD40/CD40L system may represent an important pathway of induction of SJS/TEN lesions, while in EM it would contribute to the immunoinflammation only as a second-line mechanism.
Sujet(s)
Antigènes CD40/métabolisme , Érythème polymorphe/immunologie , Peau/immunologie , Syndrome de Stevens-Johnson/immunologie , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Lymphocytes T CD4+/anatomopathologie , Ligand de CD40/métabolisme , Lymphocytes T CD8+/anatomopathologie , Femelle , Humains , Techniques immunoenzymatiques , Immunophénotypage , Activation des lymphocytes , Mâle , Adulte d'âge moyenRÉSUMÉ
This study was performed to determine the activity of adding continuous infusion (CI) of 5-fluorouracil (5-FU) to gemcitabine (GEM) vs GEM alone in advanced pancreatic cancer (APC). In all, 94 chemo-naïve patients with APC were randomised to receive GEM alone (arm A: 1000 mg m(-2) per week for 7 weeks followed by a 2 week rest period, then weekly for 3 consecutive weeks out of every 4 weeks) or in combination with CI 5-FU (arm B: CI 5-FU 200 mg m(-2) day(-1) for 6 weeks followed by a 2 week rest period, then for 3 weeks every 4 weeks). Overall response rate (RR) was the primary end point and criteria for decision were planned according to the Simon's optimal two-stage design. The overall RR was 8% (arm A) and 11% (arm B) (95% confidence interval: 0.5-16% and 2-22%), respectively, and stable disease was 29 and 28%. The median duration of RR was 34 weeks (range 25-101 weeks) for GEM and 26 weeks (range 16-46 weeks) for the combination. The median progression-free survival (PFS) was 14 weeks (range 2-65 weeks) and 18 weeks (range 4-51 weeks), respectively. The median overall survival (OS) was 31 weeks (range 1-101 weeks) and 30 weeks (1-101 weeks). Toxicity was mild in both arms. This study does not show promising activity in terms of RR, PFS and OS for the double combination arm in APC.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Désoxycytidine/analogues et dérivés , Tumeurs du pancréas/traitement médicamenteux , Adulte , Sujet âgé , Désoxycytidine/administration et posologie , Évolution de la maladie , Femelle , Fluorouracil/administration et posologie , Humains , Perfusions veineuses , Mâle , Adulte d'âge moyen , Tumeurs du pancréas/anatomopathologie , Analyse de survie ,RÉSUMÉ
Apoptosis is a form of cell death that is claimed to be involved in a number of chronic inflammatory and malignant skin diseases. The aim of this study was to investigate whether apoptosis may contribute to the pathogenesis of epidermal changes in dermatitis herpetiformis (DH) and, in particular, whether certain apoptosis-related markers such as Bax, Bcl-2, Fas and Fas ligand (FasL) take part in this process. For the detection of apoptotic nuclei, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling technique (TUNEL) was employed on cryostat sections. Skin lesions from six and perilesional skin from four DH patients were stained with monoclonal antibodies to Bax, Bcl-2, Fas and FasL. The same evaluation was also performed on three patients affected by bullous pemphigoid (BP) and in two healthy donors. Using TUNEL technique, a remarkable increase in the apoptotic rate within the epidermal compartment was observed in DH and BP patients in comparison with normal controls. In our immunohistochemical analysis, Bax/Bcl-2 ratio was almost the same in the epidermis of perilesional/lesional DH, BP and healthy skin specimens. In DH and BP specimens both Bax and Bcl-2 proteins were increased in the dermal perivascular compartment. Fas showed a prevalently epidermal staining, both in DH and BP lesions, while FasL was distributed in perivascular and subjunctional dermis; some FasL+ cells infiltrated the DEJ and the basal layer of epidermis. This study allowed us to highlight conspicuous apoptotic phenomena in basal and suprabasal keratinocytes within lesional and perilesional skin of DH. We conclude that in DH, as well as in BP, apoptosis plays a role in the pathogenesis of cutaneous lesions in concert with other pathogenetic mechanisms.
Sujet(s)
Apoptose/physiologie , Dermatite herpétiforme/anatomopathologie , Adolescent , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Apoptose/génétique , Enfant , Ligand de Fas , Femelle , Expression des gènes/physiologie , Gènes bcl-1/génétique , Gènes bcl-1/physiologie , Humains , Immunohistochimie , Méthode TUNEL , Kératinocytes/anatomopathologie , Mâle , Glycoprotéines membranaires/biosynthèse , Glycoprotéines membranaires/génétique , Adulte d'âge moyen , Pemphigoïde bulleuse/anatomopathologie , Peau/anatomopathologie , Facteurs de nécrose tumorale/biosynthèse , Facteurs de nécrose tumorale/génétique , Protéine Bax/biosynthèse , Protéine Bax/génétique , Antigènes CD95/biosynthèse , Antigènes CD95/génétiqueRÉSUMÉ
Docetaxel (75 mg m(-2) 3-weekly) is standard second-line treatment in advanced non-small-cell lung cancer (NSCLC) with significant toxicity. To verify whether a weekly schedule (33.3 mg m(-2) for 6 weeks) improved quality of life (QoL), a phase III study was performed with 220 advanced NSCLC patients, < or =75 years, ECOG PS < or =2. QoL was assessed by EORTC questionnaires and the Daily Diary Card (DDC). No difference was found in global QoL scores at 3 weeks. Pain, cough and hair loss significantly favoured the weekly schedule, while diarrhoea was worse. DDC analysis showed that loss of appetite and overall condition were significantly worse in the 3-week arm in the first week, while nausea and loss of appetite were more severe in the weekly arm in the third week. Response rate and survival were similar, hazard ratio of death in the weekly arm being 1.04 (95% CI 0.77-1.39). A 3-weekly docetaxel was more toxic for leukopenia, neutropenia, febrile neutropenia and hair loss; any grade 3-4 haematologic toxicity was significantly more frequent in the standard arm (25 vs 6%). The weekly schedule could be preferred for patients candidate to receive docetaxel as second-line treatment for advanced NSCLC, because of some QoL advantages, lower toxicity and no evidence of strikingly different effect on survival.
Sujet(s)
Antinéoplasiques d'origine végétale/administration et posologie , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Tumeurs du poumon/traitement médicamenteux , Taxoïdes/administration et posologie , Adulte , Sujet âgé , Antinéoplasiques d'origine végétale/effets indésirables , Carcinome pulmonaire non à petites cellules/mortalité , Docetaxel , Calendrier d'administration des médicaments , Femelle , Humains , Tumeurs du poumon/mortalité , Mâle , Adulte d'âge moyen , Qualité de vie , Taxoïdes/effets indésirables , Résultat thérapeutiqueRÉSUMÉ
BACKGROUND: Carboplatin is a milestone drug against ovarian carcinoma; it is used both in front-line and second-line chemotherapy. Hypersensitivity reactions to carboplatin may occur during the treatment as salvage therapy. The purpose of this study was to describe the feasibility of the replacing of carboplatin with cisplatin in patients presenting with severe hypersensitivity reactions to carboplatin. PATIENTS AND METHODS: Ten consecutive patients with platinum-sensitive, recurrent ovarian carcinoma, presenting with moderate/severe hypersensitivity reactions to carboplatin were treated with cisplatin 60 mg/m2 from January 2000 to December 2002. Hypersensitivity reactions consisted of respiratory distress (chest tightness, wheezing, dyspnea), urticaria/erythema with tachycardia, facial swelling and hypotension. RESULTS: The total number of cisplatin cycles given was 44 (range 2-5). The treatment with cisplatin was generally well tolerated. No serious allergic reactions occurred. A mild allergic reaction was recorded (urticaria) in only one case, after one cycle of cisplatin, and the patient was not rechallenged because of progressive disease. No reductions of chemotherapy doses were needed. CONCLUSION: To date, platinum-based regimens remain the most effective treatment in recurrent platinum-sensitive ovarian cancer with a high rate of objective responses. Although our experience is limited, we suggest that, under anesthesiologic surveillance and providing immunologic blockade, the replacement of carboplatin salvage therapy with cisplatin can be considered a safe therapeutic strategy in patients who cannot continue carboplatin due to allergic reactions.
Sujet(s)
Antinéoplasiques/effets indésirables , Antinéoplasiques/usage thérapeutique , Carboplatine/effets indésirables , Cisplatine/usage thérapeutique , Hypersensibilité médicamenteuse/étiologie , Récidive tumorale locale/traitement médicamenteux , Tumeurs de l'ovaire/traitement médicamenteux , Sujet âgé , Carboplatine/usage thérapeutique , Cisplatine/effets indésirables , Femelle , Humains , Adulte d'âge moyen , Récidive tumorale locale/immunologie , Tumeurs de l'ovaire/immunologie , Thérapie de rattrapageRÉSUMÉ
BACKGROUND: CD40, a member of the tumor necrosis factor receptor superfamily, is capable of mediating the induction of apoptosis in tumors including sarcomas. The expression of proapoptotic receptor contribute to the induction of apoptosis by chemotherapeutic drugs. The present study was undertaken to determine if there is a correlation between the expression of CD40 in spindle-cell sarcomas and the response to epirubicin and ifosfamide chemotherapy. PATIENTS AND METHODS: Immunohistochemical analysis of CD40 expression was performed on 59 paraffin-embedded archival tissues. Evaluation of objective tumor response was carried out according to the WHO criteria. Correlations with response to chemotherapy and baseline patients' characteristics were investigated using Chi-square tests. RESULTS: Positive CD40 staining was observed in 42 tumors; it was expressed in < 10% of cells in 14 (24%), in 10 to 50% in 16 (27%) and in more than 50% of cells in 12 (20%) tumors. No significant association was found between CD40 expression, response to chemotherapy and other clinical and pathological characteristics. CONCLUSION: CD40 expression in spindle-cell soft tissue sarcomas is not associated with response to ifosfamide plus epirubicin chemotherapy.
Sujet(s)
Antigènes néoplasiques/analyse , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Antigènes CD40/analyse , Résistance aux médicaments antinéoplasiques , Sarcomes/composition chimique , Tumeurs des tissus mous/composition chimique , Adulte , Sujet âgé , Épirubicine/administration et posologie , Épirubicine/pharmacologie , Femelle , Humains , Ifosfamide/administration et posologie , Ifosfamide/pharmacologie , Mâle , Mesna/administration et posologie , Adulte d'âge moyen , Valeur prédictive des tests , Résultat thérapeutiqueRÉSUMÉ
We used cultured cerebellar granule cells to examine whether native group-III metabotropic glutamate (mGlu) receptors are coupled to the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI-3-K) pathways. Cultured granule cells responded to the group-III mGlu receptor agonist, L-2-amino-4-phosphonobutanoate (l-AP4), with an increased phosphorylation and activity of MAPKs (ERK-1 and -2) and an increased phosphorylation of the PI-3-K target, protein kinase B (PKB/AKT). These effects were attenuated by the group-III antagonists, alpha-methyl-serine-O -phosphate (MSOP) and (R,S )-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG), or by pretreatment of the cultures with pertussis toxin. l-AP4 also induced the nuclear translocation of beta-catenin, a downstream effector of the PI-3-K pathway. To assess the functional relevance of these mechanisms we examined the ability of l-AP4 to protect granule cells against apoptosis by trophic deprivation, induced by lowering extracellular K(+) from 25 to 10 mm. Neuroprotection by l-AP4 was attenuated by MSOP and abrogated by the compounds PD98059 and UO126, which inhibit the MAPK pathway, or by the compound LY294002, which inhibits the PI-3-K pathway. Taken together, these results show for the first time that native group-III mGlu receptors are coupled to MAPK and PI-3-K, and that activation of both pathways is necessary for neuroprotection mediated by this particular class of receptors.
Sujet(s)
Mitogen-Activated Protein Kinases/métabolisme , Phosphatidylinositol 3-kinases/métabolisme , Protein-Serine-Threonine Kinases , Récepteurs métabotropes au glutamate/métabolisme , Transduction du signal/physiologie , Transactivateurs , Transport nucléaire actif/effets des médicaments et des substances chimiques , Amino-butyrates/pharmacologie , Animaux , Apoptose/effets des médicaments et des substances chimiques , Division cellulaire/effets des médicaments et des substances chimiques , Division cellulaire/physiologie , Cellules cultivées , Protéines du cytosquelette/métabolisme , Activation enzymatique/effets des médicaments et des substances chimiques , Antienzymes/pharmacologie , Agonistes des acides aminés excitateurs/pharmacologie , Antagonistes des acides aminés excitateurs/pharmacologie , Système de signalisation des MAP kinases/physiologie , Mitogen-Activated Protein Kinases/antagonistes et inhibiteurs , Neurones/effets des médicaments et des substances chimiques , Neurones/enzymologie , Neuroprotecteurs/pharmacologie , Inhibiteurs des phosphoinositide-3 kinases , Phosphorylation/effets des médicaments et des substances chimiques , Potassium/métabolisme , Potassium/pharmacologie , Protéines proto-oncogènes/métabolisme , Protéines proto-oncogènes c-akt , Rats , Récepteurs métabotropes au glutamate/agonistes , Récepteurs métabotropes au glutamate/antagonistes et inhibiteurs , bêta-CaténineRÉSUMÉ
We induced apoptosis in primary cultures of cerebellar granule neurons by switching the growing medium into a medium containing lower concentrations of K(+) (5 or 10 mM instead of 25 mM) or, alternatively, by addition of staurosporine. The apoptotic phenotype was always preceded by an early increase in the intracellular levels of the disialoganglioside GD3, which peaked at 2-6 h and returned back to normal at 12 h. GD3 synthase, the enzyme that forms GD3 from the monosialoganglioside GM3, was also induced at early times after the induction of apoptosis in granule cells. Immunofluorescent staining showed that GD3 increased in neuronal cell bodies and neurites, but was never localized in cell nuclei. In cultures switched into a low K(+)-containing medium, exogenously applied GD3, but not the disialoganglioside GD1a, accelerated the development of neuronal apoptosis. In contrast, the antisense-induced knock-down of GD3 synthase was protective against granule cell death induced by lowering extracellular K(+) from 25 to 10 - but not 5 - mM. These results demonstrate that an early and transient increase in GD3 synthesis is one of the factors that contribute to the induction of neuronal apoptosis in culture.
Sujet(s)
Apoptose/physiologie , Gangliosides/physiologie , Neurones/physiologie , Animaux , Cellules cultivées , Technique d'immunofluorescence , Rats , Rat Sprague-DawleyRÉSUMÉ
L-Acetylcarnitine (LAC, 100 mg/kg, s.c.), a drug commonly used for the treatment of painful neuropathies, substantially reduced mechanical allodynia in rats subjected to monolateral chronic constriction injury (CCI) of the sciatic nerve and also attenuated acute thermal pain in intact rats. In both cases, induction of analgesia required repeated injections of LAC, suggesting that the drug induces plastic changes within the nociceptive pathway. In both CCI- and sham-operated rats, a 24-day treatment with LAC increased the expression of metabotropic glutamate (mGlu) receptors 2 and 3 in the lumbar segment of the spinal cord, without changing the expression of mGlu1a or -5 receptors. A similar up-regulation of mGlu2/3 receptors was detected in the dorsal horns and dorsal root ganglia of intact rats treated with LAC for 5-7 days, a time sufficient for the induction of thermal analgesia. Immunohistochemical analysis showed that LAC treatment enhanced mGlu2/3 immunoreactivity in the inner part of lamina II and in laminae III and IV of the spinal cord. An increased mGlu2/3 receptor expression was also observed in the cerebral cortex but not in the hippocampus or cerebellum of LAC-treated animals. Reverse transcription-polymerase chain reaction combined with Northern blot analysis showed that repeated LAC injections selectively induced mGlu2 mRNA in the dorsal horns and cerebral cortex (but not in the hippocampus). mGlu3 mRNA levels did not change in any brain region of LAC-treated animals. To examine whether the selective up-regulation of mGlu2 receptors had any role in LAC-induced analgesia, we have used the novel compound LY 341495, which is a potent and systemically active mGlu2/3 receptor antagonist. LAC-induced analgesia was largely reduced 45 to 75 min after a single injection of LY 341495 (1 mg/kg, i.p.) in both CCI rats tested for mechanical allodynia and intact rats tested for thermal pain. We conclude that LAC produces analgesia against chronic pain produced not only by peripheral nerve injury but also by acute pain in intact animals and that LAC-induced analgesia is associated with and causally related to a selective up-regulation of mGlu2 receptors. This offers the first example of a selective induction of mGlu2 receptors and discloses a novel mechanism for drug-induced analgesia.
Sujet(s)
Acétyl-carnitine/pharmacologie , Analgésie , Nootropiques/pharmacologie , Récepteurs métabotropes au glutamate/métabolisme , Nerf ischiatique/effets des médicaments et des substances chimiques , Animaux , Mâle , Rats , Rat Sprague-Dawley , Nerf ischiatique/métabolisme , Nerf ischiatique/anatomopathologie , Température , Régulation positiveRÉSUMÉ
5-Fluorouracil (5-FU), in association with leucovorin (LV), is the most used chemotherapy agent in the treatment of colorectal cancer. Response rate, as well as side-effect incidence, increases with the dose intensity of regimens that are used. The most common dose-limiting toxicity for 5-FU/LV modulation is diarrhea. To assess the modification of small intestinal function, we investigated the changes in intestinal permeability (IP) and intestinal absorption (IA) in 41 chemo-naive patients (21 men and 22 women; mean age, 61 +/- 9 years) with advanced colorectal cancer after treatment with the association of folinic acid and 5-FU. After chemotherapy administration, we found a marked increase in IP and a reduction in IA, measured as cellobiose-mannitol (CE-MA) ratio (p < 0.0001) and D-xylose absorption (p = 0.0001), respectively. Patients who experienced diarrhea have an increase in CE-MA ratio and a reduction in D-xylose absorption values, both statistically significant. Cellobiose-mannitol ratio and D-xylose absorption tests can be used for the assessment of toxic effect of 5-FU on mature intestinal epithelium and also for evaluating the role of cytoprotective agents.
Sujet(s)
Antimétabolites antinéoplasiques/pharmacologie , Tumeurs colorectales/traitement médicamenteux , Tumeurs colorectales/métabolisme , Fluorouracil/pharmacologie , Antimétabolites antinéoplasiques/usage thérapeutique , Tumeurs colorectales/anatomopathologie , Fluorouracil/usage thérapeutique , Humains , Absorption intestinale , Stadification tumorale , PerméabilitéRÉSUMÉ
The aim of this study was to evaluate the differential expression and the function in cell movement and proliferation of the urokinase plasminogen activator (u-PA) system in muscle satellite cells (MSC) of normal individuals and patients with Duchenne muscular dystrophy (DMD). By immunoenzymatic, zymographic, and radioligand binding methods and by quantitative polymerase chain reaction of the specific mRNA we have shown that both normal and DMD MSC produce u-PA and the plasminogen activator inhibitor-1 and express u-PA receptors (u-PAR). During the proliferation phase of their growth-differentiation program, MSC from DMD patients show more u-PAR than their normal counterpart, produce more plasminogen activator inhibitor-1, and release low amounts of u-PA into the culture medium. By Boyden chamber Matrigel invasion assays we have shown that normal MSC are more prone than DMD cells to spontaneous invasion but, when subjected to a chemotactic gradient of u-PA, DMD MSC sense the ligand much better and to a greater extent than normal MSC. u-PA also stimulates proliferation of MSC, but no difference is observable between normal and DMD patients. Antagonization of u-PA/u-PAR interaction with specific anti-u-PA and anti-u-PAR monoclonal antibodies and with antisense oligonucleotides inhibiting u-PAR expression indicates that u-PA/u-PAR interaction is required in spontaneous and u-PA-induced invasion, as well as in u-PA-induced proliferation.
Sujet(s)
Muscles squelettiques/cytologie , Muscles squelettiques/métabolisme , Myopathie de Duchenne/métabolisme , Myopathie de Duchenne/anatomopathologie , Récepteurs de surface cellulaire/métabolisme , Activateur du plasminogène de type urokinase/métabolisme , Séquence nucléotidique , Différenciation cellulaire/effets des médicaments et des substances chimiques , Division cellulaire/effets des médicaments et des substances chimiques , Mouvement cellulaire , Enfant , Enfant d'âge préscolaire , Amorces ADN/génétique , Expression des gènes , Humains , Techniques in vitro , Nourrisson , Mâle , Muscles squelettiques/effets des médicaments et des substances chimiques , Myopathie de Duchenne/génétique , Inhibiteur-1 d'activateur du plasminogène/génétique , Inhibiteur-1 d'activateur du plasminogène/métabolisme , ARN messager/génétique , ARN messager/métabolisme , Récepteurs de surface cellulaire/génétique , Récepteurs à l'activateur du plasminogène de type urokinase , RT-PCR , Activateur du plasminogène de type urokinase/génétique , Activateur du plasminogène de type urokinase/pharmacologieRÉSUMÉ
A multicentre phase 2 trial (single-stage design) was undertaken to test the efficacy and toxicity of carboplatin (AUC 6 according to Calvert) plus paclitaxel (175 mg/m(2)3-h infusion) every 4 weeks in the first line treatment of patients affected by extensive small cell lung cancer. The primary end-point of the trial was the objective response rate. 31 objective responses among 50 patients were considered necessary to proceed to a phase 3 trial. 48 patients were enrolled (median age 59 years). Treatment was very well tolerated. 3 patients (6.2%) had a complete response and 23 (47.9%) a partial response, for an overall response rate of 54.2% (95% CI: 39.2-68.6). Median time to progression was 5.7 months (95% CI: 5.2-6.2). Median survival was 9.6 months (95% CI: 7.2-14.6), with a median follow-up time of alive patients of 12 months. At 1 year, the probability of being progression-free or alive was 0.16 and 0.43, respectively. In conclusion, carboplatin plus paclitaxel as given in the present study is very well tolerated but not sufficiently active to warrant phase 3 comparison with standard chemotherapy regimens.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Carcinome à petites cellules/traitement médicamenteux , Tumeurs du poumon/traitement médicamenteux , Adulte , Sujet âgé , Carboplatine/administration et posologie , Carcinome à petites cellules/anatomopathologie , Survie sans rechute , Calendrier d'administration des médicaments , Femelle , Études de suivi , Humains , Tumeurs du poumon/anatomopathologie , Mâle , Adulte d'âge moyen , Paclitaxel/administration et posologieRÉSUMÉ
BACKGROUND: 5-Fluorouracil (FU) in association with folinic acid (FA) is the most frequently used chemotherapeutic agent in colorectal cancer but it often causes diarrhoea. Animal and human studies suggest that glutamine stimulates intestinal mucosal growth. AIM: To determine if oral glutamine prevents changes in intestinal absorption (IA) and permeability (IP) induced by FU/FA. METHODS: Seventy chemotherapy naive patients with colorectal cancer were randomly assigned to oral glutamine (18 g/day) or placebo before the first cycle of FU (450 mg/m(2)) and FA (100 mg/m(2)) administered intravenously for five days. Treatment was continued for 15 days, starting five days before the beginning of chemotherapy. IA (D-xylose urinary excretion) and IP (cellobiose-mannitol test) were assessed at baseline and four and five days after the end of the first cycle of chemotherapy, respectively. Patients kept a daily record of diarrhoea, scored using the classification system of the National Cancer Institute (Bethesda, Maryland, USA). Duration of diarrhoea was recorded and the area under the curve (AUC) was calculated for each patient. RESULTS: Baseline patient characteristics and basal values of IP and IA tests were similar in the two arms. After one cycle of chemotherapy, the reduction in IA (D-xylose absorption) was more marked in the placebo arm (7.1% v 3. 8%; p=0.02); reduction of IP to mannitol was higher in the placebo arm (9.2% v 4.5%; p=0.02); and urinary recovery of cellobiose was not different between the study arms (p=0.60). Accordingly, the cellobiose-mannitol ratio increased more in the placebo arm (0.037 v 0.012; p=0.04). Average AUC of diarrhoea (1.9 v 4.5; p=0.09) and average number of loperamide tablets taken (0.4 v 2.6; p=0.002) were reduced in the glutamine arm. CONCLUSIONS: Glutamine reduces changes in IA and IP induced by FU and may have a protective effect on FU induced diarrhoea.
Sujet(s)
Antimétabolites antinéoplasiques/effets indésirables , Diarrhée/prévention et contrôle , Fluorouracil/effets indésirables , Glutamine/administration et posologie , Administration par voie orale , Adulte , Sujet âgé , Tumeurs du côlon/complications , Tumeurs du côlon/traitement médicamenteux , Diarrhée/induit chimiquement , Méthode en double aveugle , Femelle , Humains , Absorption intestinale/effets des médicaments et des substances chimiques , Mâle , Adulte d'âge moyen , Statistique non paramétriqueRÉSUMÉ
Experimental studies have shown that vinorelbine is a powerful radiosensitizer in vitro. To date, no reports on clinical activity of the single agent vinorelbine as radiosensitizer have been published. The aim of the present phase I study was to determine the maximum tolerated dose (MTD) of vinorelbine administered daily concurrently with thoracic radiotherapy, with or without amifostine support, in the treatment of locally advanced non small cell lung cancer. In vitro studies have shown that vinorelbine can potentiate the antitumor effects of radiation therapy. Amifostine is a sulphydril compound that has shown to protect normal tissues from chemotherapy and radiotherapy-induced toxicities. Radiotherapy lasted 6 weeks and the total dose was 55 Gy. The daily fraction was 1.8 Gy, administered 5 days a week for 5 weeks and increased to 2.0 Gy during the sixth and last week. Concurrent vinorelbine was administered daily with a planned escalation of the dose from 4, to 5 and 6 mg/m(2). Fourteen patients were enrolled in the study. The first dose of vinorelbine was 4 mg/m(2) and it showed to be feasible without dose-limiting toxicity (DLT). Instead, the second dose level of 5 mg/m(2) was unfeasible because three out of six patients had DLT (grade 4 neutropenia, treatment interruption longer than 2 weeks for prolonged grade 2 neutropenia and treatment interruption longer than 2 weeks for prolonged grade 3 esophagitis together with grade 4 dyspnea). At that time, the study continued adding amifostine to vinorelbine in order to increase its MTD. Amifostine was administered by means of subcutaneous injection 15 min before each radiotherapy fraction at the fixed dose of 300 mg/m(2). However, 5 mg/m(2) of vinorelbine were considered unfeasible even with amifostine support because three out of five patients showed DLT (grade 4 neutropenia, febrile grade 4 neutropenia and grade 3 liver toxicity). Among 14 patients enrolled in the study, eight completed the planned treatment because six patients experienced DLT, which determined treatment interruption. Overall, four partial and two complete responses were observed. Two partial and one complete response were observed in those three patients who had been treated with the first dose of vinorelbine. In conclusion, our data show that the MTD of daily vinorelbine is 4 mg/m(2). Therefore, this is the recommended dose of daily vinorelbine to be administered with concurrent thoracic radiotherapy in a phase II trial. Finally, amifostine administered subcutaneously failed to increase the MTD of daily vinorelbine.
Sujet(s)
Antinéoplasiques d'origine végétale/administration et posologie , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Carcinome pulmonaire non à petites cellules/radiothérapie , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/radiothérapie , Radiosensibilisants/administration et posologie , Vinblastine/analogues et dérivés , Adénocarcinome/traitement médicamenteux , Adénocarcinome/radiothérapie , Sujet âgé , Amifostine/administration et posologie , Antinéoplasiques d'origine végétale/effets indésirables , Carcinome pulmonaire non à petites cellules/anatomopathologie , Carcinome épidermoïde/traitement médicamenteux , Carcinome épidermoïde/radiothérapie , Association thérapeutique , Calendrier d'administration des médicaments , Femelle , Humains , Perfusions veineuses , Injections sous-cutanées , Tumeurs du poumon/anatomopathologie , Mâle , Adulte d'âge moyen , Récidive tumorale locale , Radioprotecteurs/administration et posologie , Radiosensibilisants/effets indésirables , Résultat thérapeutique , Vinblastine/administration et posologie , Vinblastine/effets indésirables , VinorelbineRÉSUMÉ
PURPOSE: to evaluate the activity and toxicity of the combination cisplatin plus vinorelbine plus amifostine in advanced non small cell lung cancer (NSCLC). PATIENTS AND METHODS: a two-stage Simon design was applied. To proceed after the first stage, responses from seven of 19 patients were needed. Overall, 17 responses from 40 treated patients were required to comply with the design parameter. Inclusion criteria were cyto-histologically proven stage IIIB-IV NSCLC; age of 70 years or less; Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less; normal cardiac, hepatic, renal and bone marrow functions; and no previous chemotherapy. Patients were staged by physical examination, biochemistry, chest radiograph, brain, thoracic and abdominal computed tomographic (CT) scans, and bone scan. All patients received cisplatin 100 mg/m(2) intravenously (iv) day 1, vinorelbine 25 mg/m(2) iv days 1-8-15-22, amifostine 740 mg/m(2) iv day 1 every 4 weeks up to six cycles. Eleven of 40 enrolled patients were stage IIIB and 29 stage IV, with a median age of 57 years (range, 38-70 years). RESULTS: all patients were evaluable for response and toxicity (intention to treat analysis). We observed 20 (50%) objective responses, with four (10%) complete responses. Median time to progression was 20 weeks, and median survival was 45 weeks. The toxicity was manageable. The reported main toxicities were neutropenia grade 4 in 10% of patients, grade 1 and grade 3 nephrotoxicity both in 5% of patients and grade 1 amifostine-related hypotension in 15% of patients. CONCLUSION: these data show that cisplatin plus vinorelbine plus amifostine is an active and feaseable regimen in stage IIIB-IV NSCLC. A phase III trial comparing cisplatin plus vinorelbine versus cisplatin plus vinorelbine plus amifostine in advanced NSCLC is warranted.