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 M at 24, 48, and 72 h of treatment, with MTT assay. A concentration-dependent cell survival inhibition was observed, with an IC50 at 80 M. 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 M, and apoptosis at the higher concentration (160 M). 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 M) and gemcitabine (0.01 M) at 48 and 72 h of treatment. The same result was obtained with docetaxel (0.001 M) 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.
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Document Type: Research Article
Oncologia Medica A,
Pfizer Italia, Rome, Italy
Farmacologia e Neuroscienze, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
Azienda Ospedaliera Universitaria, Parma, Italy,
Publication date: January 1, 2005
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Formerly: Oncology Research Incorporating Anti-Cancer Drug Design
Oncology Research Featuring Preclinical and Clincal Cancer Therapeutics publishes research of the highest quality that contributes to an understanding of cancer in areas of molecular biology, cell biology, biochemistry, biophysics, genetics, biology, endocrinology, and immunology, as well as studies on the mechanism of action of carcinogens and therapeutic agents, reports dealing with cancer prevention and epidemiology, and clinical trials delineating effective new therapeutic regimens.
From Volume 23, Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics is Open Access under the terms of the Creative Commons CC BY-NC-ND license.