PURPOSE: The objective of this study was to evaluate the antitumor efficacy of trabectedin in clear cell carcinoma (CCC) of the ovary, which is regarded as an aggressive, chemoresistant, histologic subtype. EXPERIMENTAL DESIGN: Using 6 human ovarian cancer cell lines (3 CCC and 3 serous adenocarcinomas), the antitumor effects of trabectedin were examined in vitro, and we compared its activity according to histology. We next examined the antitumor activity of trabectedin in both cisplatin-resistant and paclitaxel-resistant CCC cells in vitro. Then, the in vivo effects of trabectedin were evaluated using mice inoculated with CCC cell lines. Using 2 pairs of trabectedin-sensitive parental and trabectedin-resistant CCC sublines, we investigated the role of mTOR in the mechanism of acquired resistance to trabectedin. Finally, we determined the effect of mTOR inhibition by everolimus on the antitumor efficacy of trabectedin in vitro and in vivo. RESULTS: Trabectedin showed significant antitumor activity toward chemosensitive and chemoresistant CCC cells in vitro. Mouse xenografts of CCC cells revealed that trabectedin significantly inhibits tumor growth. Greater activation of mTOR was observed in trabectedin-resistant CCC cells than in their respective parental cells. The continuous inhibition of mTOR significantly enhanced the therapeutic efficacy of trabectedin and prevented CCC cells from acquiring resistance to trabectedin. CONCLUSION: Trabectedin is a promising agent for CCC as a first-line chemotherapy and as a second-line treatment of recurrent CCC that had previously been treated with cisplatin or paclitaxel. Moreover, trabectedin combined with everolimus may be more efficacious for the management of CCC.
PURPOSE: The objective of this study was to evaluate the antitumor efficacy of trabectedin in clear cell carcinoma (CCC) of the ovary, which is regarded as an aggressive, chemoresistant, histologic subtype. EXPERIMENTAL DESIGN: Using 6 humanovarian cancer cell lines (3 CCC and 3 serous adenocarcinomas), the antitumor effects of trabectedin were examined in vitro, and we compared its activity according to histology. We next examined the antitumor activity of trabectedin in both cisplatin-resistant and paclitaxel-resistant CCC cells in vitro. Then, the in vivo effects of trabectedin were evaluated using mice inoculated with CCC cell lines. Using 2 pairs of trabectedin-sensitive parental and trabectedin-resistant CCC sublines, we investigated the role of mTOR in the mechanism of acquired resistance to trabectedin. Finally, we determined the effect of mTOR inhibition by everolimus on the antitumor efficacy of trabectedin in vitro and in vivo. RESULTS:Trabectedin showed significant antitumor activity toward chemosensitive and chemoresistant CCC cells in vitro. Mouse xenografts of CCC cells revealed that trabectedin significantly inhibits tumor growth. Greater activation of mTOR was observed in trabectedin-resistant CCC cells than in their respective parental cells. The continuous inhibition of mTOR significantly enhanced the therapeutic efficacy of trabectedin and prevented CCC cells from acquiring resistance to trabectedin. CONCLUSION:Trabectedin is a promising agent for CCC as a first-line chemotherapy and as a second-line treatment of recurrent CCC that had previously been treated with cisplatin or paclitaxel. Moreover, trabectedin combined with everolimus may be more efficacious for the management of CCC.
Authors: Ramesh Dasari; Andrzej Błauż; Derek C Medellin; Roaa M Kassim; Carlos Viera; Maximo Santarosa; Alet E van der Westhuyzen; Willem A L van Otterlo; Taryn Olivas; Tugba Yildiz; Tania Betancourt; Charles B Shuster; Snezna Rogelj; Błażej Rychlik; Todd Hudnall; Liliya V Frolova; Alexander Kornienko Journal: ChemMedChem Date: 2019-01-25 Impact factor: 3.466
Authors: Liliya V Frolova; Igor V Magedov; Anntherese E Romero; Menuka Karki; Isaiah Otero; Kathryn Hayden; Nikolai M Evdokimov; Laetitia Moreno Y Banuls; Shiva K Rastogi; W Ross Smith; Shi-Long Lu; Robert Kiss; Charles B Shuster; Ernest Hamel; Tania Betancourt; Snezna Rogelj; Alexander Kornienko Journal: J Med Chem Date: 2013-08-23 Impact factor: 7.446
Authors: Robert Scott; Menuka Karki; Mary R Reisenauer; Roberta Rodrigues; Ramesh Dasari; W Ross Smith; Stephen C Pelly; Willem A L van Otterlo; Charles B Shuster; Snezna Rogelj; Igor V Magedov; Liliya V Frolova; Alexander Kornienko Journal: ChemMedChem Date: 2014-03-18 Impact factor: 3.466
Authors: Erhong Meng; Aparna Mitra; Kaushlendra Tripathi; Michael A Finan; Jennifer Scalici; Steve McClellan; Luciana Madeira da Silva; Eddie Reed; Lalita A Shevde; Komaraiah Palle; Rodney P Rocconi Journal: PLoS One Date: 2014-09-12 Impact factor: 3.240