Spontaneous contractions were recorded from the circular muscle layer at three sites along the isolated mouse colon. The interval between contractions was approximately 4.5 min. The mean duration of the contractions ranged from 26 sec in the distal colon to 45 sec in the proximal colon. Contractions migrating more than half the length of the colon were termed colonic migrating motor complexes (CMMCs). Over 90% of tissues demonstrated migration predominantly in an aboral direction. Hyoscine (10(-6) M) decreased the amplitude of the CMMCs by at least 40% but had no significant effect on the interval or duration of the CMMCs. Nifedipine (10(-6) M) significantly decreased the amplitude of the CMMCs by 95% but did not alter the duration or the interval between the CMMCs. Hexamethonium (5 x 10(-4) M) and tetrodotoxin (TTX; 2 x 10(-6) M) abolished all CMMC activity. TTX increased the resting tone of the preparations. Nitro-L-arginine (10(-4) M) increased the resting tone of the preparations and significantly decreased the interval between the CMMCs by approximately 80% but had no significant effect on the duration of the CMMCs. The results suggest CMMCs migrate predominantly in an aboral direction and are neurogenic in origin. Nitric oxide may be involved in maintaining inhibition of the muscle between CMMCs.

This study has used mechanical, together with pressure/volume recordings or electrophysiological recordings, to investigate the spontaneous activity in isolated preparations of mouse colon. In the former preparations, when not distended with fluid, spontaneous colonic migrating motor complexes (CMMCs) were observed using isotonic transducers. When the colons were distended with fluid, CMMCs continued at an increased frequency and in addition were associated temporally, with rises in intraluminal pressure and pulses of distally ejected fluid. 5-Hydroxytryptamine (1 micro mol L-1) or NG-nitro-l-arginine (100 micro mol L-1) increased the frequency of propulsive activity and this activity was abolished by hexamethonium (500 micro mol L-1). In a second preparation, myoelectric complexes recorded from circular muscle cells in colons using intracellular microelectrodes, were found to correlate in frequency and phase with CMMCs. The experiments indicate that CMMCs are intimately related to pressure waves in the fluid-filled viscus and the muscle membrane potential changes that have been recorded during myoelectric complexes are likely to be analogous to those occurring during fluid-filled propulsive activity.

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CYT997 is a wholly synthetic compound that possesses highly potent cytotoxic activity in vitro through inhibition of microtubule polymerization. CYT997 blocks the cell cycle at the G 2 -M boundary, and Western blot analysis indicates an increase in phosphorylated Bcl-2, along with increased expression of cyclin B1. Caspase-3 activation is also observed in cells treated with CYT997 along with the generation of poly(ADP-ribose) polymerase. The compound possesses favorable pharmacokinetic properties, is orally bioavailable, and is efficacious per os in a range of in vivo cancer models, including some refractory to paclitaxel treatment. CYT997 exhibits vascular disrupting activity as measured in vitro by effects on the permeability of human umbilical vein endothelial cell monolayers, and in vivo by effects on tumor blood flow. CYT997 possesses a useful combination of pharmacologic and pharmacokinetic properties and has considerable potential as a novel anticancer agent. [Mol Cancer Ther 2009;8 (11):3036-45]