carbocyanines and Endometrial-Neoplasms

Peritoneal carcinomatosis is an unmet medical need. Laparoscopy offers a unique opportunity to control and to steer the operating environment during surgery by loading carbon dioxide with a therapeutic substance and creating the so-called therapeutic capnoperitoneum. We have treated a human sample of peritoneal carcinomatosis from an endometrial adenocarcinoma ex vivo just after surgery.. A nontoxic therapeutic agent (Dbait) was aerosolized into a box containing diseased human peritoneum under a pressure of 12 mmHg CO(2). Dbait (noncoding DNA fragments) acts through jamming DNA damage sensing and signaling, ultimately inhibiting DNA repair system of cancer cells. Dbait were coupled to cholesterol molecules to facilitate intracellular uptake, and to Cyanine (Cy5) to allow detection by fluorescence. In a control experiment, the same solution was applied to the other half of the sample using conventional lavage.. Physical results revealed fluorescence within the tumor up to 1 mm depth in the therapeutic capnoperitoneum sample and no uptake in the lavage sample. Biological results showed intranuclear phosphorylation of H2AX in the nebulized sample and no activity in the lavage sample. Importantly, tumor nodules showed more activity than the neighbor, normal peritoneum. Detection of histone gamma-H2AX (phosphorylated H2AX) reveals activation of DNA-dependent protein kinase (DNA-PK) by Dbait, which has been shown to be the key step for sensitization to genotoxic therapy.. Dbait are taken up by cancer cells and have a biological activity up to 1 mm depth. Nebulization of the molecule is significantly more effective than conventional lavage. This proof of principle supports the need for clinical studies applying therapeutic capnoperitoneum together with Dbait for treating peritoneal carcinomatosis.

Topics: Adenocarcinoma; Adult; Aerosols; Antineoplastic Agents; Carbocyanines; Carbon Dioxide; Carcinoma; Combined Modality Therapy; Endometrial Neoplasms; Equipment Design; Female; Fluorescence; Fluorescent Dyes; Histones; Humans; Laparoscopy; Peritoneal Neoplasms; Pneumoperitoneum, Artificial; RNA, Small Interfering

Endometrial cancer remains a leading cause of death in women and therefore the development of new therapies is essential. The present study evaluated the effects of nimesulide alone, cisplatin alone, and combination of cisplatin and nimesulide on an Ishikawa cell line with respect to cytotoxicity and induction of apoptosis in vitro.. Ishikawa cells were treated with increasing doses of nimesulide alone, cisplatin alone, and a combination of cisplatin and nimesulide. Subsequently their effects on cytotoxicity were investigated by MTT assay, while apoptosis was investigated by DAPI and JC-1 staining and caspase-3 colorimetric assays.. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that nimesulide alone and combination of cisplatin and nimesulide have growth inhibitory effect on Ishikawa cells. Nimesulide alone and the combination of cisplatin and nimesulide induced apoptosis. Apoptosis induced by nimesulide might be related to caspase-3 activation.. These results suggest that nimesulide treatment is as effective as cisplatin treatment in Ishikawa cells. The combination of cisplatin and nimesulide treatment is more effective than cisplatin alone in Ishikawa cells.

Topics: Apoptosis; Benzimidazoles; Carbocyanines; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cisplatin; Cyclooxygenase 2 Inhibitors; Endometrial Neoplasms; Female; Humans; Sulfonamides