vinflunine and Adenocarcinoma

Vinflunine is a new Vinca alkaloid uniquely fluorinated, by the use of superacid chemistry, in a little exploited region of the catharanthine moiety. In vitro investigations have confirmed the mitotic-arresting and tubulin-interacting properties of vinflunine shared by other Vinca alkaloids. However, differences in terms of the inhibitory effects of vinflunine on microtubules dynamics and its tubulin binding affinities have been identified which appear to distinguish it from the other Vinca alkaloids. Vinflunine induced smaller spirals with a shorter relaxation time, effects, which might be associated with reduced neurotoxicity. Studies investigating the in vitro cytotoxicity of vinflunine in combination therapy have revealed a high level of synergy when vinflunine was combined with either cisplatin, mitomycin C, doxorubicin or 5-fluorouracil. Furthermore, although vinflunine appears to participate in P-glycoprotein-mediated drug resistance mechanisms, it has proved only a weak substrate for this protein and a far less potent inducer of resistance than vinorelbine. Vinflunine was identified in preclinical studies as having marked antitumour activity in vivo against a large panel of experimental tumour models, with tumour regressions being recorded in human renal and small cell lung cancer tumour xenografts. Overall its level of activity was superior to that of vinorelbine in many of the experimental models used. Interestingly, an in vivo study using a well vascularised adenocarcinoma of the colon has suggested that vinflunine mediates its antitumour activity at least in part via an antivascular mechanism, even at sub-cytotoxic doses. Therefore, these data provide a favourable preclinical profile for vinflunine, supporting its promising candidacy for clinical development. Phase I evaluations of vinflunine have been completed in Europe and phase II clinical trials are now ongoing.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line; Colonic Neoplasms; DNA Damage; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Forecasting; Humans; Leukemia P388; Lung Neoplasms; Melanoma, Experimental; Mice; Microtubules; Molecular Structure; Neoplasms, Experimental; Nervous System Diseases; Tubulin Modulators; Tumor Cells, Cultured; Vinblastine; Vinca Alkaloids; Xenograft Model Antitumor Assays

Vinflunine (VFL) (Javlor(®)), a novel fluorinated semisynthetic vinca alkaloid has shown significant antitumor activity in advanced non-small cell lung cancer (NSCLC). We propose to define the recommended dose (RD) of VFL in combination with carboplatin in advanced NSCLC patients.. This phase I and pharmacokinetic study was designed to determine the maximum tolerated dose and to establish the RD of VFL in combination with carboplatin. Twenty-one chemonaive patients with advanced NSCLC were treated with a first-line chemotherapy of VFL and carboplatin both given on day 1 every 3 weeks with 3 dose levels.. Five patients experienced a dose limiting toxicity consisting of constipation in 2 patients and febrile neutropenia in 2 patients. One patient experienced grade 3 abdominal pain concurrent with grade 4 neutropenia. The combination of VFL (320 mg/m(2)) and carboplatin AUC6 was defined as the maximum tolerated dose. The RD was established at the dose of VFL (320 mg/m(2)) combined with carboplatin AUC5. At the RD, 12 patients received a median number of 3 cycles of the combination. Neither VFL nor carboplatin seemed to be influencing the pharmacokinetics of the other. Among 19 patients evaluable for tumor response, 7 had a partial response and 7 experienced stable disease.. The combination of VFL (320 mg/m(2)) and carboplatin AUC 5 given once every 3 weeks is established as the RD of the combination, which was shown to be active in these chemonaive NSCLC patients.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Prognosis; Survival Rate; Tissue Distribution; Vinblastine

Vinflunine (Javlor) has shown significant antitumour activity in advanced non-small cell lung cancer (NSCLC). We propose to define the recommended dose of vinflunine in combination with gemcitabine for treatment of advanced NSCLC in chemonaive patients.. A phase I and pharmacokinetic study was conducted to determine the maximum tolerated dose and to establish the recommended dose of vinflunine (VFL) administered on day 1 every 21 days combined with gemcitabine given on days 1 and 8 every 3 weeks.. Nineteen patients were included in this study. Three patients experienced a dose limiting toxicity, with constipation in one patient, hypertension in one patient, and constipation and febrile neutropenia in one patient. The combination of VFL 320 mg/m² and gemcitabine 1250 mg/m² was defined as the maximum tolerated dose. The recommended dose was established at the dose of VFL 320 mg/m² combined with gemcitabine 1000 mg/m². Neither VFL nor gemcitabine seemed to be influencing the pharmacokinetics of each other. All patients were evaluable for tumor response. Seven presented a partial response and eight experienced a stable disease.. The combination of VFL 320 mg/m² administered on day 1 combined with gemcitabine 1000 mg/m² given on days 1 and 8 every 3 weeks is established as the RD and was shown to be active in these chemonaive NSCLC patients.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Deoxycytidine; Female; Follow-Up Studies; Gemcitabine; Humans; Lung Neoplasms; Lymphatic Metastasis; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Survival Rate; Tissue Distribution; Treatment Outcome; Vinblastine

A multicenter phase I/II trial of vinflunine administered in combination with cisplatin at 80 mg/m(2) was conducted in order to determine the dose-limiting toxicities, the maximum tolerated dose, and the recommended dose of the combination. An eventual mutual pharmacokinetic drug-drug interaction when vinflunine and cisplatin were coadministered was also evaluated. The study was also intended to define the response rate of vinflunine in combination with cisplatin as first-line chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) at the recommended dose.. Patients were required to have a histologically confirmed diagnosis of NSCLC not amenable to curable treatment or stage IV disease. Patients may have had previous surgery for NSCLC but were to be chemonaive and have at least 1 bidimensional measurable lesion outside an irradiated area.. The recommended dose was established at cisplatin 80 mg/m2 combined with vinflunine 320 mg/m(2). No unexpected adverse events were seen. Pharmacokinetic analysis supported the absence of mutual pharmacokinetic interaction when vinflunine and cisplatin are given in combination. Treatment of 53 patients at this recommended dose demonstrated a tumor response rate of 32.1% in the intent-to-treat population; disease control was achieved in 79.2% of the patients. The median progression-free survival and overall survival were estimated at 5 months and 10.4 months, respectively, and the 1-year survival rate was 43.4%.. These results place the vinflunine/cisplatin combination among the most active doublets in this treatment setting and warrant further development in phase III trials of first-line treatment of patients with advanced metastatic NSCLC.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cisplatin; Female; Humans; Injections, Intravenous; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Survival Rate; Tissue Distribution; Treatment Outcome; Vinblastine

According to the actual treatment strategies of lung cancer, the current therapeutic regimen is an individualized, multidisciplinary concept. The development of chemoresistance in the last decade represents the most important obstacle to an effective treatment. In our study, we examined a new therapeutic alternative in the treatment of multiresistant lung adenocarcinoma via siRNA-specific transfection of six crucial molecules involved in lung carcinogenesis [serum response factor(SFR), E2F1, Survivin, hypoxia inducible factor1 (HIF1), HIF2 and signal transducer and activator of transcription (STAT3)].. Three chemoresistant A549 adenocarcinoma cells were cultured under standard conditions at 37°C and 5% CO2. The chemoresistance against Vinflunine, Vinorelbine and Methotrexate was induced artificially. The A549 cells were transfected for 2 h at 37°C with specific siRNA targeting SRF, E2F1, Survivin, HIF1, HIF2 and STAT3 in a non-viral manner. The efficiency of siRNA silencing was evaluated via quantitative real-time polymerase chain reaction, whereas the surviving cells after siRNA transfection as predictor factor for tumoural growth were analysed with a CASY cell counter 3 days after transfection.. The response of the chemotherapeutic resistant adenocarcinoma cells after siRNA transfection was concentration-dependent at both 25 and 100 nM. The CASY analysis showed a very effective suppression of adenocarcinoma cells in Vinorelbine, Vinflunine and Methotrexate groups, with significantly better results in comparison with the control group.. In our study, we emphasized that siRNA interference might represent a productive platform for further research in order to investigate whether a new regimen in the treatment of multiresistant non-small-cell lung cancer could be established in vivo in the context of a multimodal cancer therapy.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents; Basic Helix-Loop-Helix Transcription Factors; Cell Line, Tumor; Drug Resistance, Neoplasm; E2F1 Transcription Factor; Genetic Therapy; Humans; Hypoxia-Inducible Factor 1; Inhibitor of Apoptosis Proteins; Lung Neoplasms; Methotrexate; RNA Interference; RNA, Small Interfering; Serum Response Factor; STAT3 Transcription Factor; Survivin; Transfection; Vinblastine; Vinorelbine

Anti-vascular effects of the novel Vinca alkaloid, vinflunine have been investigated in the MAC 15A transplantable murine colon adenocarcinoma model and compared with those induced by the most recently identified clinically useful third generation Vinca. Administration of the maximum tolerated dose of either vinflunine (50 mg kg(-1)) or vinorelbine (8 mg kg(-1)) resulted in significant tumour growth delay with subsequent histological analysis revealing substantial haemorrhagic necrosis. This suggested possible anti-vascular effects and these were confirmed by Hoechst 33342 perfusion studies. Vinflunine, currently undergoing Phase I trials in Europe, was found to be at least as effective as the clinically active vincristine and vinorelbine in this model and, remarkably, produced anti-vascular effects at doses much lower than the maximum tolerated dose. Although vinflunine caused apoptosis in HUVEC monolayer cultures this event did not occur within the first 8 hours of exposure whereas vascular shutdown in vivo was observed within the first 4 hours.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Humans; Male; Mice; Mice, Inbred Strains; Neoplasm Transplantation; Neoplasms, Experimental; Neovascularization, Pathologic; Time Factors; Tumor Cells, Cultured; Umbilical Veins; Vinblastine; Vincristine; Vinorelbine