Before conclusions about their significance to atherosclerosis are established it will be necessary to investigate these same processes within the framework of the artery wall. Pre-clinical studies show effectiveness in various breast, cervix, colorectal, ovary, and pancreas neoplasms. That antitumor effect was enhanced by the addition of docetaxel in vitro and in vivo a murine model with acceptable toxicity, aside from treatment sequence. The HDACI, vorinostat and the combination of MK 5108, was investigated in multiple lymphoma cell lines. The inclusion of MK 5108 to reversible HDAC inhibitor vorinostat sensitized the cell lines to apoptosis, with inhibition of c Myc playing an important role. A phase 1 study in patients with advanced solid tumors investigated the toxicities of singleagent MK 5108 and MK 5108 in mixture with docetaxel 60mg/m2 IV every 21 days. Febrile neutropenia and myelotoxicity was identified because the dose limiting toxicity in combination individuals, but no DLT was identified in the arm. While partial reaction was seen in 2 of 17 patients in the combination arm and 0 of 17 within the arm, Illness stabilization was seen in 11 of 34 patients from both arms. MLN8054 potently stops aurora A kinase Lymph node by competitively blocking the ATP binding pocket. Notably, MLN8054 is functionally and structurally similar to benzodiazepines, leading to the DLT of somnolence at clinically relevant doses. Pre-clinical studies in a many cell culture and murine xenograft designs displayed strong anti-tumor activity as determined by direct growth description and surrogate markers, in line with aurora A kinase specific inhibition. Moreover, MLN8054 was able to induce senescence both in vivo and in vitro. This study was the first to ever link aurora A kinase inhibition and senescence, a result classically seen with antimitotic agents. In murine versions, dose related and reversible somnolence and neutropenia were the DLTs. A dose finding study of MLN8054 was performed in 63 patients with advanced level cancer using once-daily doses of 5 40mg/day as a single dose or 25 80mg/day conjugating enzyme in four divided doses. Amounts above 45mg/day were applied with methylphenidate to offset sedation. The maximum tolerated dose for once daily administration was 30mg/day, 45mg/day if divided into 4 daily doses and 60mg/day if divided into 4 daily doses and used concomitantly with methylphenidate for 7 21 consecutive days of the 35 day period. Somnolence was the only real DLT and no responses were seen with any dose level. A second dose finding study was performed in 43 patients with advanced cancers checking daily doses from 10mg to 80mg orally per day in divided doses. The DLTs revealed were grade 3 reversible somnolence and liver function test elevations. In relation to these results, MLN8054 development was abandoned in favor of MLN8237. MLN8237 shares structural homology to MLN8054, but has four fold higher inhibitory potency for aurora A kinase and decreased tendency to cause somnolence.