PubMed Health⌕ Search

Biomedical subjects

Maura Loprevite

Publications and source records attributed to Maura Loprevite.

6 recordsLinked to original sources
PubMed2005

In vitro study of CI-994, a histone deacetylase inhibitor, in non-small cell lung cancer cell lines.

CI-994 (N-acetyldinaline) is a novel oral compound with a wide spectrum of antitumor activity in preclinical models, in vitro and in vivo. The mechanism of action may involve inhibition of histone deacetylation and cell cycle arrest. We studied the action of CI-994 on two non-small cell lung cancer (NSCLC) cell lines: A-549 (adenocarcinoma) and LX-1 (squamous cell carcinoma). Different drug concentrations were tested, ranging from 0.01 to 160 microM at 24, 48, and 72 h of treatment, with MTT assay. A concentration-dependent cell survival inhibition was observed, with an IC50 at 80 microM. The effect of CI-994, as demonstrated by recovery experiments, was cytostatic and seemed to be superimposable in both cell lines. Cytofluorimetric analysis to assess cell cycle perturbation and apoptosis was performed after 24 h of treatment, indicating a cell block with concomitant increase at G0/G1 phase, a reduction at S phase level at 20, 40, 80, and 160 microM, and apoptosis at the higher concentration (160 microM). When CI-994 was combined with antineoplastic agents commonly used in NSCLC management, a marked synergism of action (R = 1.8, R = 1.5) was observed between CI-994 (40 microM) and gemcitabine (0.01 microM) at 48 and 72 h of treatment. The same result was obtained with docetaxel (0.001 microM) combination (R = 1.4, R = 1.2), but no synergism of action was noted with paclitaxel. CI-994 showed no radiopotentiating effects, when combined with 100, 200, or 400 cGy irradiation. In conclusion, our experiments indicate that CI-994 is a promising novel cytostatic for the treatment of NSCLC. Its use in combination with standard anticancer agents, such as gemcitabine and docetaxel, is warranted.

Antineoplastic Agents, Phytogenic↗
PubMed2004

Farnesylated proteins as anticancer drug targets: from laboratory to the clinic.

The knowledge that Ras was readily prenylated by protein FTase and that the inhibition of this reaction has the ability to revert the transformed phenotype, provided the rationale for the development of FTIs as anticancer drugs. Studies have shown that farnesylation of Ras is the first, obligatory first step in a series of post-translational modifications leading to membrane association, which, in turn, determines the switch from an inactive to an active Ras-GTP bound form. Based on the theorical assumption that preventing Ras farnesylation might result in the inhibition of Ras functions, a range of FTIs have been synthesized. Their biology is fascinating since after substantial investigation and their use in several phase II studies and at least two phase III trials, the exact mechanism of action remains unclear. FTIs can block the farnesylation of several additional proteins, such as RhoB, prelamins A and B, centromere proteins (CENP-E, CENP-F), etc. While the FTIs clearly do not or only partly target Ras, these agents appear to have clinical activity in leukemia and in some solid tumors regardless of their Ras mutational status. Although inhibition of FTase by these compounds has been well documented also in normal tissues, their toxic effects seem to be manageable. However, preliminary results of early Phase II-III studies suggest that the activity of FTIs, as a single-agent, is modest and generally lower than that obtained by standard cytotoxic drugs. Ongoing clinical studies are assessing the role of FTIs for early stage disease or in combination with cytotoxic agents or with other molecular targeted therapies for advanced stage tumors. Further insights in the molecular mechanism of action of FTIs might help in better define their optimal use in combination with standard therapies in the treatment of cancer patients.

Alkyl and Aryl Transferases↗
PubMed2004

In vitro study of farnesyltransferase inhibitor SCH 66336, in combination with chemotherapy and radiation, in non-small cell lung cancer cell lines.

K-ras alterations have been reported in 20-30% of non-small cell lung cancer (NSCLC) and represent a suitable target for the development of novel anticancer agents, such as Farnesyl transferase inhibitors (FTi), a new class of agents inhibiting the post-translational modification of the K-ras proteins. The effectiveness of FTi SCH66336 in inhibiting cell proliferation and deranging cell cycle of NSCLC cell lines as well as its interaction with chemotherapy or radiation have been evaluated. The activity of FTi SCH66336, alone or in combination with paclitaxel, gemcitabine, and radiotherapy, was examined in 3 cell lines, A-549, LX-1 and CaLu-6, by colorimetric MTT assay. Cell cycle perturbation and apoptosis were also assessed by cytofluorimetric analysis. The activity of SCH 66336 was found to be concentration- and time-dependent. The effect of SCH 66336, as demonstrated by cell growth recovery experiments, resulted cytostatic and it was superimposable in both cell lines bearing 2 different K-ras mutations (A-549 and LX-1) and in K-ras wild-type Ca-Lu-6. In all cell lines the combination of SCH 66336 and paclitaxel resulted in a synergism of action when SCH 66336 followed paclitaxel treatment, whereas, antagonism was found when SCH 66336 preceded paclitaxel treatment. No significant synergism or addition with SCH 66336 followed by radiation treatment was noted. Different cell cycle phase blocks at various drug concentrations were observed. In conclusion, SCH 66336 displays concentration-dependent cytostatic antitumour activity and schedule-dependent synergy with 2 commonly used anticancer agents in NSCLC cell lines. Further clinical testing of these combinations is warranted.

Alkyl and Aryl Transferases↗
PubMed2003

Enhanced effectiveness of last generation antiblastic compounds vs. cisplatin on malignant pleural mesothelioma cell lines.

The purpose of this study was to examine the antiproliferative potentialities of a pool of new generation compounds (Paclitaxel, Docetaxel, Gemcitabine, Topotecan, SN-38) together with fenretinide, a synthetic derivative of retinoic acid, in comparison with the current first choice treatment cisplatin molecule, on a pool of human malignant pleural mesothelioma cell lines derived from either bioptic and pleural effusions samples. To evaluate the chemosensitivity features of malignant mesothelioma cells in vitro, we resorted to a rapid and reproducible colorimetric assay, a useful widely recognized tool for preclinical drug screening. In addition, by DNA content analysis and cellular morphologic assessment, we focused on the apoptosis as a potential mechanism of drug activity. The main results clearly indicate that, in all the models of malignant mesothelioma we handled in vitro, each tested antineoplastic agent is more powerful than cisplatin in inhibiting cell proliferation. Moreover, on experimental evidences basis, we can assume that the cytotoxic activity of tested compounds could be related, at least partially, to the drug-induced programmed cell death. This experimental study gives substance to the expected pharmacologic worth of the second generation antineoplastic drugs even if, in order to afford the most satisfactory biopharmacological approach, allowing to bypass the refractoriness to chemotherapy of this highly lethal tumour, further investigations at preclinical level are required.

Antineoplastic Agents↗